Publications by authors named "Daniela Massi"

265 Publications

Editorial: Advancements in Molecular Diagnosis and Treatment of Melanoma.

Front Oncol 2021 9;11:728113. Epub 2021 Jul 9.

Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy.

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http://dx.doi.org/10.3389/fonc.2021.728113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299098PMC
July 2021

Overexpression of helper T cell type 2-related molecules in the skin of patients with eosinophilic dermatosis of hematologic malignancy.

J Am Acad Dermatol 2021 Jul 13. Epub 2021 Jul 13.

Department of Health Sciences, Section of Dermatology, University of Florence, Florence, Italy.

Background: Eosinophilic dermatosis of hematologic malignancy (EDHM) is a rare dermatosis associated with blood tumors.

Objective: To characterize the expression of T-cell and B-cell markers and pruritogenic mediators in EDHM skin.

Methods: Immunohistochemical and immunofluorescence analysis were performed in 12 skin samples of EDHM, 11 samples of bullous pemphigoid (BP), and 5 samples from healthy controls (HC). Serum levels of interleukin (IL) 4 were analyzed in 11 patients with EDHM, 11 BP patients, and 5 HC by enzyme-linked immunosorbent assay.

Results: T-cell markers, including clusters of differentiation (CD) 3, CD4, CD8, and CD5 were significantly overexpressed in EDHM and BP skin compared to HC. A predominance of CD4 over CD8 cells and GATA3 (helper T cell type 2 [Th2] marker) over T-bet (Th1 marker) cells were observed. FOXP3 expression was increased but the FOXP3/CD4 ratio was low. B-cell markers were under-represented, without significant differences between the 3 groups. IL-4 and IL-31 were significantly overexpressed in EDHM and BP compared to HC and colocalized with the Th2-associated marker GATA3. Eotaxin-1 was significantly overexpressed in EDHM compared to BP and HC. IL-4 serum concentration was significantly increased in EDHM and BP compared to HC.

Limitations: Small sample size; retrospective design.

Conclusions: Targeting Th2-related molecules, in particular IL-4, holds promise for EDHM management.
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http://dx.doi.org/10.1016/j.jaad.2021.07.007DOI Listing
July 2021

NGS-Based Analysis of Atypical Deep Penetrating Nevi.

Cancers (Basel) 2021 Jun 19;13(12). Epub 2021 Jun 19.

Section of Pathological Anatomy, Department of Health Sciences, University of Florence, 50121 Firenze, Italy.

Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that β-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the β-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series.
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http://dx.doi.org/10.3390/cancers13123066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234376PMC
June 2021

An Upgrade of Apparatus and Measurement Systems for Generation of Gaseous Formaldehyde: A Review.

Crit Rev Anal Chem 2021 Jun 7:1-15. Epub 2021 Jun 7.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Formaldehyde (FA) is ubiquitous in the atmospheric environment. It is generally the dominant atmospheric carbonyl compound. Due to its well-known carcinogenicity, FA is a compound that arises the attention in the scientific community. In studies concerning the toxicological effects of FA on humans, animals, and the environment, testing and calibration of air sampling systems and analytical instruments are pivotal. Therefore, the preparation of controllable standard gaseous atmospheres containing FA at levels known with precision and accuracy is essential. This review summarizes the procedures for generating the FA atmosphere, given that operative solutions have been evolving recently. Furthermore, an overview on the available system to collect and store gaseous standard is reported. The progressively implemented FA generation techniques, together with commercially-available instruments, are herein described, classified, and compared.
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http://dx.doi.org/10.1080/10408347.2021.1913090DOI Listing
June 2021

Videodermoscopic folliculotropism as a sign of lentigo maligna in the fluorescence-advanced videodermatoscopy (FAV).

Skin Res Technol 2021 Jun 3. Epub 2021 Jun 3.

Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy.

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http://dx.doi.org/10.1111/srt.13072DOI Listing
June 2021

Impact of Circulating and Tissue Biomarkers in Adjuvant and Neoadjuvant Therapy for High-Risk Melanoma: Ready for Prime Time?

Am J Clin Dermatol 2021 Jul 25;22(4):511-522. Epub 2021 May 25.

Unit of Medical Oncology, Department of Surgery and Medicine, University of Perugia, Perugia, Italy.

The prognosis of patients with metastatic melanoma has substantially improved over the last years with the advent of novel treatment strategies, mainly immune checkpoint inhibitors and BRAF and MEK inhibitors. Given the survival benefit provided in the metastatic setting and the evidence from prospective clinical trials in the early stages, these drugs have been introduced as adjuvant therapies for high-risk resected stage III disease. Several studies have also investigated immune checkpoint inhibitors, as well as BRAF and MEK inhibitors, for neoadjuvant treatment of high-risk stage III melanoma, with preliminary evidence suggesting this could be a very promising approach in this setting. However, even with new strategies, the risk of disease recurrence varies widely among stage III patients, and no available biomarkers for predicting disease recurrence have been established to date. Improved risk stratification is particularly relevant in this setting to avoid unnecessary treatment for patients who have minimum risk of disease recurrence and to reduce toxicities and costs. Research for predictive and prognostic biomarkers in this setting is ongoing to potentially shed light on the complex interplay between the tumor and the host immune system, and to further personalize treatment. This review provides an insight into available data on circulating and tissue biomarkers, including the tumor microenvironment and associated gene signatures, and their predictive and prognostic role during neoadjuvant and adjuvant treatment for cutaneous high-risk melanoma patients.
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http://dx.doi.org/10.1007/s40257-021-00608-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200339PMC
July 2021

Disseminated Talaromyces infection in an AIDS patient.

Clin Microbiol Infect 2021 Apr 2. Epub 2021 Apr 2.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Infectious and Tropical Diseases Unit, Careggi University and Hospital, Florence, Italy.

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http://dx.doi.org/10.1016/j.cmi.2021.03.017DOI Listing
April 2021

Digital Immunophenotyping Predicts Disease Free and Overall Survival in Early Stage Melanoma Patients.

Cells 2021 02 17;10(2). Epub 2021 Feb 17.

Division of Pathological Anatomy, Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy.

Background: the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and spatial distribution of immune cells in early stage intermediate/thick PCM.

Materials And Methods: digital image acquisition and quantitative analysis of tissue immune biomarkers (CD3, CD4, CD8, CD68, PD-L1, CD163, FOX-P3, and PD-1) was carried out in a training cohort, which included patients with primary PCM ≥ 2 mm diagnosed, treated, and followed-up prospectively in three Italian centers. Results were validated in an independent Italian cohort.

Results: in the training cohort, 100 Stage II-III melanoma patients were valuable. At multivariable analysis, a longer disease free survival (DFS) was statistically associated with higher levels of CD4 intratumoral T-cells (aHR [100 cell/mm increase] 0.98, 95%CI 0.95-1.00, = 0.041) and CD163 inner peritumoral (aHR [high vs. low] 0.56, 95%CI 0.32-0.99, = 0.047). A statistically significant longer DFS (aHR [high-high vs. low-low] 0.52, 95%CI 0.28-0.99, = 0.047) and overall survival (OS) (aHR [high-high vs. low-low] 0.39, 95%CI 0.18-0.85, = 0.018) was found in patients with a high density of both intratumoral CD8 T-cells and CD68 macrophages as compared to those with low density of both intratumoral CD8 T-cells and CD68 macrophages. Consistently, in the validation cohort, patients with high density of both intratumoral CD8 and CD3 T-cells were associated to a statistically better DFS (aHR[high-high vs. low-low] 0.24, 95%CI 0.10-0.56, < 0.001) and those with high density of both intratumoral CD8 and CD68 were associated to a statistically longer OS (aHR[high-high vs. low-low] 0.28, 95%CI 0.09-0.86, = 0.025).

Conclusion: our findings suggest that a specific preexisting profile of T cells and macrophages distribution in melanomas may predict the risk of recurrence and death with potential implications for the stratification of stage II-III melanoma patients.
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http://dx.doi.org/10.3390/cells10020422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922113PMC
February 2021

Multitarget fluorescence in situ hybridization diagnostic applications in solid and hematological tumors.

Expert Rev Mol Diagn 2021 Feb 22;21(2):161-173. Epub 2021 Feb 22.

Department of Mental and Physic Health and Preventive Medicine, Pathology Unit, University of Campania Luigi Vanvitelli, Napoli, Italy.

: Multitarget FISH (mFISH) is a technique allowing for simultaneous detection of multiple targets sequences on the same slide through the choice of spectrally distinct fluorophore labels. The mFISH could represent a useful tool in the field of precision oncology.: This review discusses the potential applications of mFISH technology in the molecular diagnosis of different solid and hematological tumors, including non-small cell lung cancers, melanomas, renal cell carcinomas, bladder carcinomas, germ cell tumors, and multiple myeloma, as commonly required in the clinical practice.: In this emerging era of the tailored therapies and newer histo-molecular classifications, there are increasing numbers of predictive and diagnostic biomarkers required for effective clinical care. The mFISH approach may have several applications in the common clinical practice, improving the molecular diagnosis in terms of time, cost and preservation of biomaterial for tumors with a limited amount of tumor available. The mFISH provides several advantages compared to other high-throughput technologies; however, it requires high level of expertise required to interpret complex results.
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http://dx.doi.org/10.1080/14737159.2021.1887733DOI Listing
February 2021

Clinical and dermoscopic polymorphisms in agminated Spitz nevi: Ugly presentation but benign behavior.

Pediatr Dermatol 2021 Mar 2;38(2):461-463. Epub 2021 Feb 2.

Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.

Agminated Spitz nevi are an uncommon entity, and their management is challenging due not only the young age of the patients but also the tumor's uncertain malignant potential and the variability in the dermoscopic and clinical presentation. We report a case of a 6-year-old boy with multiple agminated Spitz nevi on a café au lait macule with different atypical clinical patterns and dermoscopic features.
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http://dx.doi.org/10.1111/pde.14535DOI Listing
March 2021

Germline MC1R variants and frequency of somatic BRAF, NRAS, and TERT mutations in melanoma: Literature review and meta-analysis.

Mol Carcinog 2021 03 14;60(3):167-171. Epub 2021 Jan 14.

Department of Experimental Oncology, European Institute of Oncology, IRCCS, Milan, Italy.

Germline variants of the melanocortin-1-receptor (MC1R) gene are the most common genetic trait predisposing to cutaneous melanoma (CM). Here, we performed a literature review and meta-analysis of the association between MC1R gene variants and the frequency of somatic mutations of the BRAF, NRAS, and TERT genes in CM patients. We included studies published until January 2020 in MEDLINE, EMBASE, Ovid Medline, and two grey literature databases. Random effect models were used to pool study-specific estimates into summary odds ratio (SOR) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity and assess the robustness of pooled estimates. Twelve studies published between 2006 and 2018 (encompassing 3566 CM, mostly on nonacral sites) were included. MC1R gene variants were not significantly associated with the frequency of somatic mutations of the BRAF and NRAS genes. Only three studies focused on somatic mutations of the TERT gene promoter, all of which reported moderate-to-strong positive associations with MC1R germline variants. MC1R gene variants appear to make only moderate changes, if any, to the risk of BRAF- or NRAS-mutant CM. The association with TERT promoter mutations is suggestive, yet it warrants confirmation as it is based on a still limited number of studies.
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http://dx.doi.org/10.1002/mc.23280DOI Listing
March 2021

ESP, EORTC, and EURACAN Expert Opinion: practical recommendations for the pathological diagnosis and clinical management of intermediate melanocytic tumors and rare related melanoma variants.

Virchows Arch 2021 Jul 12;479(1):3-11. Epub 2021 Jan 12.

Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.

The recent WHO classification of skin tumors has underscored the importance of acknowledging intermediate grade melanocytic proliferations. A multistep acquisition of oncogenic events drives the progressive transformation of nevi into melanomas. The various pathways described are modulated by the initial oncogenic drivers that define the common, blue, and Spitz nevi groups. Intermediate lesions are most often the result of a clonal evolution within such nevi. Based on this established classification, we have suggested for each pathway a practical diagnostic approach, benefiting from the recently developed molecular tools, both in the setting of general pathology labs and expert centers. Moreover, recommendations regarding the re-excision and clinical follow-up are given to support decision-making in multidisciplinary tumor boards.
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http://dx.doi.org/10.1007/s00428-020-03005-1DOI Listing
July 2021

Formalin safety in anatomic pathology workflow and integrated air monitoring systems for the formaldehyde occupational exposure assessment.

Int J Occup Med Environ Health 2021 Jun 24;34(3):319-338. Epub 2020 Nov 24.

University of Florence, Florence, Italy (Department of Experimental and Clinical Medicine).

The potential carcinogenicity of formaldehyde (FA) has prompted increasing preventive measures in anatomic pathology (AP) laboratories and new strategies aimed at innovating airborne FA monitoring systems. This review provides an updated overview of the most recent improvements in preventive measures, safe practices, and exposure monitoring tools in the FA usage and handling. A computer-based search of scientific and non-scientific sources was performed on PubMed, Web of Science, Google and Google Patents databases, querying the main topics of real-time, in-continuous FA monitoring instruments for sale, and commercially available tools for improving preventive measures in formalin management. In order to simplify the sampling process and to choose a better analytic solution to FA assessment, the main characteristics of each FA monitoring instrument were described. The novel technical tools recently introduced on the global market, aimed at reducing FA emissions in AP laboratories, were summarized. This review is directed at anatomic pathologists to draw their attention to the rapidly growing field of safe formalin practices. A repeated exposure assessment is recommended to evaluate technical changes in air monitoring programs to keep FA emissions low, in compliance with the limit value; thus, evolved monitoring devices are needed. Int J Occup Med Environ Health. 2021;34(3):319-38.
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http://dx.doi.org/10.13075/ijomeh.1896.01649DOI Listing
June 2021

Folliculotropism in head and neck lentigo maligna and lentigo maligna melanoma.

J Dtsch Dermatol Ges 2021 02 9;19(2):223-229. Epub 2020 Nov 9.

Dermatology Department, University of Modena and Reggio Emilia, Modena, Italy.

Background: Lentigo maligna (LM) and lentigo maligna-melanoma (LMM) are histotypes of melanoma arising in skin with cumulative solar radiation damage. The extension of atypical melanocytes to the hair follicle (folliculotropism) is a histopathological feature of LM/LMM. Its role has not been totally clarified, but it may be correlated to treatment response in LM or to progression in LMM.

Objective: This retrospective, multicentric study aims to identify dermatoscopic features associated with folliculotropism in LMs/LMMs.

Patients And Methods: We analyzed cases of head and neck LMs/LMMs diagnosed between 2005-2014 at Melanoma Units, University of Bologna/Modena/Florence/Siena (Italy), Nice (France): 25 LMs and 73 LMMs were included.

Results: Grey circles (44 %) indicated an isthmic/bulb level of involvement, which were completely absent in the infundibular LM lesions (P = 0.041). In the group of LMMs, light/dark brown pseudonetwork and light brown structureless areas were an indicator of diffuse distribution of malignant melanocytes in the follicular units (P < 0.001 and P = 0.001, respectively), while grey circles indicated focal or diffuse distribution (P < 0.001).

Conclusions: A better understanding of the extension of malignant melanocytes is helpful, aiding clinicians in their decision to perform a radical excision or obtaining a biopsy in the most invasive area of the lesion, which includes potential folliculotropism.
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http://dx.doi.org/10.1111/ddg.14311DOI Listing
February 2021

TRPA1 Expression in Synovial Sarcoma May Support Neural Origin.

Biomolecules 2020 10 15;10(10). Epub 2020 Oct 15.

Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, 50139 Florence, Italy.

Synovial sarcoma (SS) is a malignant mesenchymal soft tissue neoplasm. Despite its name, the cells of origin are not synovial cells, but rather neural, myogenic, or multipotent mesenchymal stem cells have been proposed as possible cells originators. Unlike other sarcomas, an unusual presentation of long-term pain at the tumor site has been documented, but the exact mechanisms have not been fully clarified yet. The transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel mainly expressed in primary sensory neurons, where it functions as a pain sensor. TRPA1 have also been described in multiple non-excitable cells, including those derived from neural crest stem cells such as glial cells and, in particular, Schwann cell oligodendrocytes and astrocytes. We evaluated TRPA1 expression in SS. We selected a cohort of 41 SSs, and by immunohistochemistry, we studied TRPA1 expression TRPA1 was found in 92.6% of cases. Triple TRPA1/pS100/SOX10 and TRPA1/SLUG/SNAIL staining strongly supports a neural origin of SS. TRPA1 positivity was also observed in a subset of cases negative with pS100, SOX10 and/or SLUG/SNAIL, and these divergent phenotypes may reflect a process of tumor plasticity and dedifferentiation of neural-derived SSs. Given the functional diversity of TRPA1 and its expression in neuronal and non-neuronal multipotent neural crest stem cells, it remains to be determined whether TRPA1 expression in SSs neoplastic cells plays a role in the molecular mechanism associated with premonitory pain symptoms and tumor progression.
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http://dx.doi.org/10.3390/biom10101446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602570PMC
October 2020

How improvements in monitoring and safety practices lowered airborne formaldehyde concentrations at an Italian university hospital: a summary of 20 years of experience.

Arh Hig Rada Toksikol 2020 Sep 6;71(3):178-189. Epub 2020 Oct 6.

University of Florence, Department of Experimental and Clinical Medicine, Florence, Italy.

The last two decades have been crucial for the assessment of airborne formaldehyde (FA) exposure in healthcare environments due to changes in limits and reference values, definition of carcinogenicity, and new monitoring methods. The aim of this study was to analyse twenty years (1999-2019) of experience in automatic, continuous airborne FA monitoring in the Pathology Laboratory and operating rooms at the Careggi University Hospital, Florence, Italy. These 20 years saw gradual improvements in FA monitoring of exposed employees considered at maximum risk, including improvements in analytical methods of detection and sampling strategies, which came with changes in procedures and workflow operations. In 2019, after the adoption of safe practices, including a closed-circuit system using pre-loaded containers and a vacuum sealing, 94 % of the total measurements (FA concentrations) were lower than 16 μg/m3, and only 6 % ranged from 21 to 75 μg/m3. In the studied work units, the ratio between area and personal readings ranged from 0.9 to 1.0, both for long and short-term sampling. Personal sampling was simplified with a new workstation, which integrated different monitoring systems into an innovative ergonomic armchair equipped with personal sampling devices. Area monitoring was also improved with a real-time, continuous photoacoustic instrument. Over these 20 years, FA exposure significantly dropped, which coincided with optimised histology workflow and implementation of safety practices. For high-throughput screening and cost savings we propose an innovative ergonomic armchair station which allows remote continuous monitoring.
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http://dx.doi.org/10.2478/aiht-2020-71-3406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968499PMC
September 2020

Granulomatous Dermatitis and Systemic Disease: An Association to Consider.

Biomed Res Int 2020 30;2020:3281380. Epub 2020 Sep 30.

Dermatology Unit, Department of Health Sciences, University of Florence, Florence, Italy.

Granuloma annulare (GA) and interstitial granulomatous dermatitis (IGD) are granulomatous dermatoses with variable clinical appearances. GA is associated with diabetes mellitus, metabolic syndrome, chronic infections, and malignancies, while two Japanese reports described unusual cases of interstitial-type GA in setting of Sjogren syndrome. IGD was associated with rheumatoid arthritis, systemic lupus erythematosus, and autoantibodies. We report a case series of six patients with GA or IGD. Half of the patients were diagnosed with Sjogren syndrome, while all of them presented ANA positivity and the majority reported arthralgia. In many cases, GA showed interstitial-type histology, arising challenges in differential diagnosis with IGD. The overlap of clinical and histological features of GA and IGD can be explained considering them as a broad disease spectrum, including also the other forms of reactive granulomatous dermatitis. These conditions should be considered as an indicator of possible systemic disorders or other immunological dyscrasias, for which patients must be screened. Sjogren syndrome may be associated to GA also in Caucasians.
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http://dx.doi.org/10.1155/2020/3281380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545450PMC
May 2021

BRAF as a positive predictive biomarker: Focus on lung cancer and melanoma patients.

Crit Rev Oncol Hematol 2020 Dec 3;156:103118. Epub 2020 Oct 3.

Department of Public Health, University of Naples Federico II, Naples, Italy. Electronic address:

In the era of personalized medicine, BRAF mutational assessment is mandatory in advanced-stage melanoma and non-small cell lung cancer (NSCLC) patients. The identification of actionable mutations is crucial for the adequate management of these patients. To date various drugs have been implemented in clinical practice. Similarly, various methods may be adopted for the identification of BRAF mutations. Here, we briefly review the current literature on BRAF in melanoma and NSCLC, focusing attention in particular on the different methods and drugs adopted in these patients. In addition, an overview of the real-world practice in different Italian laboratories with high expertise in molecular predictive pathology testing is provided.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103118DOI Listing
December 2020

Eyelid skin metastasis as first sign of breast cancer recurrence.

Breast J 2020 12 9;26(12):2416-2417. Epub 2020 Oct 9.

Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.

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http://dx.doi.org/10.1111/tbj.14077DOI Listing
December 2020

Recognition of Cutaneous Melanoma on Digitized Histopathological Slides Artificial Intelligence Algorithm.

Front Oncol 2020 20;10:1559. Epub 2020 Aug 20.

Institute of Clinical Physiology, National Research Council, Pisa, Italy.

Increasing incidence of skin cancer combined with a shortage of dermatopathologists has increased the workload of pathology departments worldwide. In addition, the high intraobserver and interobserver variability in the assessment of melanocytic skin lesions can result in underestimated or overestimated diagnosis of melanoma. Thus, the development of new techniques for skin tumor diagnosis is essential to assist pathologists to standardize diagnoses and plan accurate patient treatment. Here, we describe the development of an artificial intelligence (AI) system that recognizes cutaneous melanoma from histopathological digitalized slides with clinically acceptable accuracy. Whole-slide digital images from 100 formalin-fixed paraffin-embedded primary cutaneous melanoma were used to train a convolutional neural network (CNN) based on a pretrained Inception-ResNet-v2 to accurately and automatically differentiate tumoral areas from healthy tissue. The CNN was trained by using 60 digital slides in which regions of interest (ROIs) of tumoral and healthy tissue were extracted by experienced dermatopathologists, while the other 40 slides were used as test datasets. A total of 1377 patches of healthy tissue and 2141 patches of melanoma were assessed in the training/validation set, while 791 patches of healthy tissue and 1122 patches of pathological tissue were evaluated in the test dataset. Considering the classification by expert dermatopathologists as reference, the trained deep net showed high accuracy (96.5%), sensitivity (95.7%), specificity (97.7%), F score (96.5%), and a Cohen's kappa of 0.929. Our data show that a deep learning system can be trained to recognize melanoma samples, achieving accuracies comparable to experienced dermatopathologists. Such an approach can offer a valuable aid in improving diagnostic efficiency when expert consultation is not available, as well as reducing interobserver variability. Further studies in larger data sets are necessary to verify whether the deep learning algorithm allows subclassification of different melanoma subtypes.
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http://dx.doi.org/10.3389/fonc.2020.01559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508308PMC
August 2020

Scalp spiradenocylindroma: A challenging dermoscopic diagnosis.

Dermatol Ther 2020 11 29;33(6):e14307. Epub 2020 Sep 29.

Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy.

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http://dx.doi.org/10.1111/dth.14307DOI Listing
November 2020

Melanoma brain metastases: review of histopathological features and immune-molecular aspects.

Melanoma Manag 2020 Jun 8;7(2):MMT44. Epub 2020 Jun 8.

Section of Pathological Anatomy, Department of Health Sciences, University of Florence, Florence, Italy.

Patients with melanoma brain metastases (MBM) have a dismal prognosis, but the unprecedented advances in systemic therapy alone or in combination with local therapy have now extended the 1-year overall survival rate from 20-25% to nearing 80-85%, mainly in asymptomatic patients. The histopathological and molecular characterization of MBM and the understanding of the microenvironment are critical to more effectively manage patients with advanced melanoma and to design biologically driven clinical trials. This review aims to give an overview of the main histopathological features and the immune-molecular aspects of MBM.
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http://dx.doi.org/10.2217/mmt-2019-0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426753PMC
June 2020

Clinical and Dermoscopic Features of Vulvar Melanosis Over the Last 20 Years.

JAMA Dermatol 2020 11;156(11):1185-1191

Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.

Importance: Vulvar melanosis is a common pigmentary change that accounts for most pigmented vulvar lesions. It presents as single or multiple asymptomatic macules or patches of varying size and color that may be asymmetric with poorly defined borders. The differential diagnosis of melanocytic lesions includes melanoma, which creates anxiety for patients and the physicians who diagnose the condition and treat the patients.

Objective: To evaluate the clinical and dermoscopic features of vulvar melanosis and their changes over time.

Design, Setting, And Participants: In this cohort study, patients with vulvar melanosis were recruited and followed up in the Department of Dermatology, University of Florence, Florence, Italy, between January 1, 1998, and June 30, 2019. Data on patient characteristics and on both the clinical and dermoscopic features of the vulvar lesions were collected. Each lesion was photographed clinically and dermoscopically at initial evaluation and at annual follow-up visits.

Main Outcomes And Measures: The clinical, dermoscopic, and histopathologic features of vulvar melanosis and their changes over time.

Results: This cohort study included 129 women (mean age at diagnosis, 46 years [range, 19-83 years]) with vulvar melanosis. A total of 87 patients (67%) with vulvar melanotic lesions were premenopausal, and 84 patients (65%) had received some type of hormone therapy. The most frequent location for vulvar melanosis was the labia minora (55 [43%]), followed by the labia majora (33 [26%]). In 39 of 129 cases (30%), the lesions increased in size and changed color after initial evaluation but ultimately stabilized. No malignant evolution was documented in any patient during a median follow-up of 13 years (range, 5-20 years).

Conclusions And Relevance: This study suggests that vulvar melanosis was a benign entity, and changes in lesions over time did not signify malignant transformation. An association between hormonal status and vulvar melanosis may be hypothesized.
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http://dx.doi.org/10.1001/jamadermatol.2020.2528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658736PMC
November 2020

SOX10 is as specific as S100 protein in detecting metastases of melanoma in lymph nodes and is recommended for sentinel lymph node assessment.

Eur J Cancer 2020 09 8;137:175-182. Epub 2020 Aug 8.

Section of Pathological Anatomy, Department of Health Sciences, University of Florence, Florence, Italy.

Background: Sentinel lymph node (SLN) biopsy remains crucial for melanoma staging. The European Organisation for Research and Treatment of Cancer Melanoma Group recommends performing immunohistochemical stainings for reproducible identification of melanoma metastases. S100 protein (pS100) is a commonly used melanocytic antigen because of its high sensitivity in spite of relatively low specificity. SRY-related HMG-box 10 protein (SOX10) is a transcription factor characterising neural crest-derived cells. It is uniformly expressed mostly in the nuclei of melanocytes, neural, and myoepithelial cells. Pathologists sometimes prefer SOX10 as a melanoma marker, but it has not yet been investigated on a large-scale to confirm that it is reliable and recommendable for routine SLN evaluation.

Methods: Four hundred one treatment-naïve lymph node (LN) metastatic melanomas were included in high-density tissue microarrays and were assessed for the presence of SOX10 and pS100 by immunohistochemistry. The slides were digitalised, shared and evaluated by a panel of experienced melanoma pathologists.

Results: The vast majority of melanomas were double-positive for pS100 and SOX10 (93.2%); a small percentage of the cases (3.9%) were double-negative melanomas. Discordance between the two markers was observed: 1.9% pS100(-)/SOX10(+) and 0.75% pS100(+)/SOX10(-). SOX10 was not expressed by immune cell types in the LN, resulting in a less controversial interpretation of the staining.

Conclusions: SOX10 is as equally specific as pS100 for the detection of melanoma metastases in LNs. The interpretation of SOX10 staining is highly reproducible among different centres and different pathologists because of the absence of staining of immune cells.
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http://dx.doi.org/10.1016/j.ejca.2020.06.037DOI Listing
September 2020

Timing of sentinel node biopsy independently predicts disease-free and overall survival in clinical stage I-II melanoma patients: A multicentre study of the Italian Melanoma Intergroup (IMI).

Eur J Cancer 2020 09 30;137:30-39. Epub 2020 Jul 30.

Melanoma and Sarcoma Unit, Department of Surgery, IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, Italy.

Background: Sentinel lymph node biopsy (SNB) still remains a key procedure to appropriately stage melanoma patients and to select those who are candidate to novel treatments with immunotherapy and targeted therapy in the adjuvant setting. The impact of timing of SNB on disease-free survival (DFS) and overall survival (OS) is still unclear.

Material And Methods: The study was conducted at 6 Italian Melanoma Intergroup (IMI) centres and included 8953 consecutive clinical stage I-II melanoma patients who were diagnosed, treated, and followed up between November 1997 and March 2018. All patients were prospectively included in dedicated IMI database. Multivariable Cox regression analyses were performed to investigate how baseline characteristics and time interval until SNB are related to DFS and OS.

Results: Considering the whole population, at multivariable analysis, after adjusting for age, gender, Breslow thickness, site, ulceration, and the SNB status, a delay in the timing of SNB was associated with a better DFS (adjusted hazard ratio [aHR, delayed versus early SNB] 0.98, 95% confidence interval [CI] 0.97-0.99, p < 0.001) and OS (aHR 0.98, 95% CI 0.97-0.99, p = 0.001). Specifically, in patients with a negative SNB status, a beneficial impact of delayed SNB (i.e. at least 32 days after primary excision) was confirmed for DFS (aHR 0.70, 95%CI 0.63-0.79, p < 0.001) and OS (aHR 0.69, 95%CI 0.61-0.78, p < 0.001), whereas in those with a positive SNB status, DFS (aHR 0.96, 95%CI 0.84-1.09, p = 0.534) and OS (aHR 0.94 95%CI 0.81-1.08, p = 0.374) were not significantly different in patients with early or delayed SNB.

Conclusions: Our study does not support a strict time interval for SNB. These results may be useful for national guidelines, for counselling patients and reducing the number of high urgency referrals.
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http://dx.doi.org/10.1016/j.ejca.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391020PMC
September 2020

Dedifferentiated melanomas: Morpho-phenotypic profile, genetic reprogramming and clinical implications.

Cancer Treat Rev 2020 Aug 23;88:102060. Epub 2020 Jun 23.

Unit of Melanoma, Division of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. Electronic address:

Phenotypic plasticity of malignant melanoma is a well-known phenomenon. Several translational studies and small case series have reported this clinical and biological entity, particularly in metastatic melanoma, showing frequent aberrant expression of non-melanocytic differentiation markers of different lineages, posing remarkable challenges due to several alternative differential diagnoses including undifferentiated carcinoma and sarcomas. When melanoma loses its typical morpho-phenotype by routinely used diagnostic immunohistochemical markers, it is defined as "dedifferentiated melanoma". Historically, this process was closely related to diagnostic interpretative difficulties. In recent years, however, dedifferentiation has been increasingly recognized as an important biological phenomenon that demonstrates the phenotypic and genetic plasticity of melanoma, and specifically the non-irreversibility of the multistep cancerogenesis. Furthermore, dedifferentiation emerged as a general hallmark of cancer evolution and a common denominator of cross-resistance to both targeted and immunotherapy. In this review, we summarize the histopathological features, the genetic and epigenetic bases underlying the dedifferentiated phenotype in melanomas and provide additional support that dedifferentiation is a mechanism of resistance to immunotherapy and targeted therapy.
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http://dx.doi.org/10.1016/j.ctrv.2020.102060DOI Listing
August 2020

TRK fusion positive cancers: From first clinical data of a TRK inhibitor to future directions.

Crit Rev Oncol Hematol 2020 Aug 31;152:103011. Epub 2020 May 31.

Section of Anatomic Pathology, Department of Health Sciences, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

Genetic alterations of neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) 1/2/3 genes generate TRK fusion proteins have been reported in a variety of adult and child cancers from diverse cell/tissue lineages. Larotrectinib, a tumour-agnostic TRK inhibitor, has shown remarkable efficacy in a novel "basket" study which has enrolled patients from infants to elderly with different TRK fusion-positive cancers. In this review, we focus on the challenges and expectations on the development of "tumour-agnostic" targeted therapies in rare malignancies.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103011DOI Listing
August 2020

Congenital circumscribed plantar hypokeratosis.

Int J Dermatol 2020 Oct 9;59(10):e367-e369. Epub 2020 Jun 9.

Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1111/ijd.14967DOI Listing
October 2020
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