The Spectrum of Spitz Melanocytic Lesions: From Morphologic Diagnosis to Molecular Classification.
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ABSTRACT:
SUBMITTER: Cheng TW
PROVIDER: S-EPMC9209745 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
The Spectrum of Spitz Melanocytic Lesions: From Morphologic Diagnosis to Molecular Classification.
Cheng Tiffany W TW Ahern Madeline C MC Giubellino Alessio A
Frontiers in oncology 20220607
Spitz tumors represent a distinct subtype of melanocytic lesions with characteristic histopathologic features, some of which are overlapping with melanoma. More common in the pediatric and younger population, they can be clinically suspected by recognizing specific patterns on dermatoscopic examination, and several subtypes have been described. We now classify these lesions into benign Spitz nevi, intermediate lesions identified as "atypical Spitz tumors" (or Spitz melanocytoma) and malignant Sp ...[more]
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Project description:ImportanceA standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose.ObjectiveTo revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG).Evidence reviewPracticing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0.FindingsThe new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma.Conclusions and relevanceThe implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.
| S-EPMC10375511 | biostudies-literature
Project description:BackgroundMelanoma skin cancer remains the leading cause of skin cancer-related deaths. Spitz lesions represent a subset of melanocytic skin lesions characterized by epithelioid or spindled melanocytes organized in nests. These lesions occupy a spectrum ranging from benign Spitz and atypical Spitz lesions all the way to malignant Spitz tumors. Appropriate management is reliant on accurate diagnostic classification, yet this effort remains challenging using current light microscopic techniques. The discovery of novel biomarkers such as microRNAs (miR) may ultimately be a useful diagnostic adjunct for the evaluation of Spitz lesions. miR expression profiles have been suggested for non-Spitz melanomas but have yet to be ascribed to Spitz lesions. We hypothesized that distinct miR expression profiles would be associated with different lesions along the Spitz spectrum.Materials and methodsRNAs extracted from paraffin-embedded, formalin-fixed tissues of 11 resected skin lesions including benign nevi (n = 2), benign Spitz lesions (n = 3), atypical Spitz lesions (n = 3), and malignant Spitz tumors (n = 3) were analyzed by the NanoString platform for simultaneous evaluation of over 800 miRs in each patient sample.ResultsBenign Spitz lesions had increased expression of miR-21-5p and miR-363-3p compared with those of benign nevi. Malignant Spitz lesions exhibited overexpression of miR-21-5p, miR-155-5p, and miR-1283 relative to both benign nevi and benign Spitz tumors. Notably, atypical Spitz tumors had increased expression of miR-451a and decreased expression of miR-155-5p expression relative to malignant Spitz lesions. Conversely, atypical Spitz lesions had increased expression of miR-21-5p, miR-34a-5p, miR-451a, miR-1283, and miR-1260a relative to benign Spitz tumors.ConclusionsOverall, distinct miR profiles are suggested among Spitz lesions of varying malignant potential with some similarities to non-Spitz melanoma tumors. This work demonstrates the feasibility of this analytic method and forms the basis for further validation studies.
| S-EPMC5117820 | biostudies-literature
Project description:In this article, we give an update on recent findings regarding molecular pathology in cutaneous melanocytic tumors. The focus lies on use of genetics in the diagnosis of distinct subtypes of spitzoid tumors that are often characterized by specific phenotypic-genotypic alterations that can frequently be recognized by adequate histological examination. Typical illustrating cases are given in order to increase recognition of these lesions in daily dermatopathology practice. New molecular findings in the pathogenesis of congenital melanocytic tumors and neurocutaneous melanosis are reviewed. In addition, use of mutation analysis in the differential diagnosis of melanoma metastasis is discussed. Finally, application of mutation analysis in targeted therapy in advanced melanoma with advantages of new techniques such as next generation sequencing is described.
| S-EPMC4291896 | biostudies-literature
Project description:The presence of a characteristic chimeric fusion as the initiating genomic event is one defining feature of Spitz neoplasms. Characterization of specific subtypes of Spitz neoplasms allows for better recognition facilitating diagnosis. Data on clinical outcomes of the specific tumor types may help in predicting behavior. In this study we present the largest series to date on ROS1 fusion Spitz neoplasms. We present the clinical, morphologic, and genomic features of 17 cases. We compared the morphologic features of these 17 cases to a cohort of 99 other non-ROS1 Spitz neoplasms to assess for features that may have high specificity for ROS1 fusions. These tumors consisted of ten Spitz nevi and seven Spitz tumors. None of the cases met criteria for a diagnosis of Spitz melanoma. Morphologically, the ROS1 fusion tumors of this series were characterized by a plaque-like or nodular silhouette, often densely cellular intraepidermal melanocyte proliferation, frequent pagetosis, tendency toward spindle cell cytomorphology, low grade nuclear atypia, and floating nests with occasional transepidermal elimination. However, there was a significant range in microscopic appearances, including two cases with morphologic features of a desmoplastic Spitz nevus. Different binding partners to ROS1 were identified with PWWP2A and TPM3 being the most common. No case had a recurrence or metastasis. Our findings document that most ROS1 fusion Spitz neoplasms have some typical characteristic microscopic features, while a small proportion will have features overlapping with other genomic subtypes of Spitz neoplasms. Preliminary evidence suggests that they tend to be indolent or low grade neoplasms.
| S-EPMC7855005 | biostudies-literature
Project description:BackgroundSpitz nevi, atypical Spitz tumors and spitzoid melanomas ('spitzoid lesions') represent controversial and poorly understood cutaneous melanocytic lesions that are difficult to diagnose histologically. It is unknown how these terms are used by pathologists.MethodsWe describe use of Spitz-related terminology using data from the Melanoma Pathology (M-Path) study database comprising pathologists' interpretations of biopsy slides, a nation-wide study evaluating practicing US pathologists' (N = 187) diagnoses of melanocytic lesions (8976 independent diagnostic assessments on 240 total test cases, with 1 slide per case).ResultsMost pathologists (90%) used the Spitz-related terminology. However, significant variation exists in which specific lesions were diagnosed as spitzoid and in the corresponding treatment recommendations. Recommendations ranged from 'no further treatment' to 'wide excision of 10 mm or greater' with no category capturing more than 50% of responses. For spitzoid melanoma diagnoses, 90% of pathologists recommended excision with ≥10 mm margin. Pathologists report less confidence in diagnosing these lesions compared with other melanocytic proliferations and are more likely to request second opinions and additional clinical information (all p < 0.05).ConclusionsSpitzoid lesions are often not classified in any standardized way, evoke uncertainty in diagnosis by pathologists, and elicit variability in treatment recommendations.
| S-EPMC5177484 | biostudies-literature
Project description:Bacterial vaginosis (BV) is caused by the excessive and imbalanced growth of bacteria in vagina, affecting 30 to 50% of women. Gram staining followed by Nugent scoring based on bacterial morphotypes under the microscope is considered the gold standard for BV diagnosis; this method is often labor-intensive and time-consuming, and results vary from person to person. We developed and optimized a convolutional neural network (CNN) model and evaluated its ability to automatically identify and classify three categories of Nugent scores from microscope images. The CNN model was first established with a panel of microscopic images with Nugent scores determined by experts. The model was trained by minimizing the cross-entropy loss function and optimized by using a momentum optimizer. The separate test sets of images collected from three hospitals were evaluated by the CNN model. The CNN model consisted of 25 convolutional layers, 2 pooling layers, and a fully connected layer. The model obtained 82.4% sensitivity and 96.6% specificity with the 5,815 validation images when altered vaginal flora and BV were considered the positive samples, which was better than the rates achieved by top-level technologists and obstetricians in China. The capability of our model for generalization was so strong that it exhibited 75.1% accuracy in three categories of Nugent scores on the independent test set of 1,082 images, which was 6.6% higher than the average of three technologists, who are hold bachelor's degrees in medicine and are qualified to make diagnostic decisions. When three technologists ran one specimen in triplicate, the precision of three categories of Nugent scores was 54.0%. One hundred three samples diagnosed by two technologists on different days showed a repeatability of 90.3%. The CNN model outperformed human health care practitioners in terms of accuracy and stability for three categories of Nugent score diagnosis. The deep learning model may offer translational applications in automating diagnosis of bacterial vaginosis with proper supporting hardware.
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Project description:Early diagnosis when melanoma is still small and thin is essential for improving mortality and morbidity. However, the diagnosis of small size melanoma might be particularly difficult, not only clinically but also dermoscopically. This study aimed to define clinical and dermatoscopic parameters in the diagnosis of suspicious pigmented cutaneous lesions with a diameter of ≤ 6mm and determine the sensitivity, specificity, positive and negative predictive values as well as the accuracy of each clinical and dermatoscopic criterion. This is a transversal, descriptive and analytical study of dermatoscopic analysis with the gold standard being the pathologic examination obtained from the excisional biopsy of suspicious melanocytic lesions with a diameter of ≤ 6mm. Trunk and limb lesion data from a public health service and a private clinic were prospectively collected from 2011 to 2017 by a unique observer. In total, 481 melanocytic lesions were included, with 73.8% being ≤ 4mm in diameter. Overall, 123 were diagnosed as melanoma, 56.0% in situ and 22.0% as thin melanomas (Breslow index 0.1 to 1.0mm). Melanoma presented symmetry in 53.7% of cases, regular borders in 54.5% and a single color in 60.2%. Regarding evolution, 13.8% of melanomas versus 10.9% of benign lesions (p = 0.116) were new by comparing photos from baseline with photos from the follow-up. The majority of melanomas (65%) were found on the limbs compared to 37.2% of the benign lesions at this location (p<0.001). A multiple logistic regression model adjusted for age, gender and location was created. The independent variables associated with the diagnosis of melanoma ≤ 6mm, adjusted for age, gender and location, were: streaks (adjusted Odds Ratio [aOR] 2.5; 95% CI 1.3-4.7; p = 0.006), and the presence of a structureless area (aOR 2.2, 95% CI 1.2-4.0, p = 0.011). Conversely, a symmetric typical pigment network was a protection variable (aOR 0.4, 95% 0.7-0.9, p = 0.040). In conclusion, dermatoscopic criteria have been identified which help to diagnose cases of small size melanoma. These include streaks and structureless areas that can be taken, particularly in consideration for the diagnosis of this subset of small difficult melanomas.
| S-EPMC8186794 | biostudies-literature
Project description:BackgroundDiagnostic terms used in histopathology reports of cutaneous melanocytic lesions are not standardized. We describe dermatopathologists' views regarding diverse diagnostic terminology and the utility of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) for categorizing melanocytic lesions.MethodsJuly 2018-2019 survey of board-certified and/or fellowship-trained dermatopathologists with experience interpreting melanocytic lesions.ResultsAmong 160 participants, 99% reported witnessing different terminology being used for the same melanocytic lesion. Most viewed diverse terminology as confusing to primary care physicians (98%), frustrating to pathologists (83%), requiring more of their time as a consultant (64%), and providing necessary clinical information (52%). Most perceived that adoption of the MPATH-Dx would: improve communication with other pathologists and treating physicians (87%), generally be a change for the better (80%), improve patient care (79%), be acceptable to clinical colleagues (68%), save time in pathology report documentation (53%), and protect from malpractice (51%).ConclusionsMost dermatopathologists view diverse terminology as contributing to miscommunication with clinicians and patients, adversely impacting patient care. They view the MPATH-Dx as a promising tool to standardize terminology and improve communication. The MPATH-Dx may be a useful supplement to conventional pathology reports. Further revision and refinement are necessary for widespread clinical use.
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Project description:Renal cell carcinomas (RCCs) with the t(6;11)(p21;q12) chromosome translocation are low-grade RCC which often occur in young patients. They typically feature an unusual biphasic morphology characterized by nests of larger epithelioid cells surrounding intraluminal collections of smaller cells clustered around basement membrane material. The t(6;11)(p21;q12) translocation fuses the Alpha (MALAT1) gene with the TFEB transcription factor gene, resulting in upregulated expression of intact native TFEB that drives the aberrant expression of melanocytic markers which is a hallmark of this distinctive neoplasm. We now report 8 cases of RCC, which demonstrate TFEB gene amplification (6 without TFEB rearrangement, 2 with concurrent TFEB rearrangement) and demonstrate downstream consequences of TFEB overexpression. Like the unamplified t(6;11) RCC, all TFEB-amplified RCC were associated with aberrant melanocytic marker expression. However, several differences between TFEB-amplified RCC and the usual unamplified t(6;11) RCC are evident. First, TFEB-amplified RCC occurred in older patients (median age, 64.5 y) compared with unamplified t(6;11) RCC (median age, 31 y). Second, the morphology of TFEB-amplified RCC is not entirely distinctive, frequently featuring nests of high-grade epithelioid cells with eosinophilic cytoplasm associated with pseudopapillary formation and necrosis, or true papillary formations. These patterns raise the differential diagnosis of high-grade clear cell and papillary RCC. Third, TFEB and melanocytic marker expression was more variable within the TFEB-amplified RCC. TFEB protein expression by immunohistochemistry was detectable in 6 of 8 cases. While all 8 cases expressed melan-A, only 5 of 8 expressed cathepsin K and only 3 of 8 expressed HMB45. Fourth, the TFEB-amplified RCC were associated with a more aggressive clinical course; 3 of 8 cases presented with advanced stage or metastatic disease, 2 subsequently developed metastatic disease, whereas the other 3 cases had minimal/no follow-up. Our results are corroborated by scant data reported on 6 TFEB-amplified RCC in the literature, gleaned from 1 case report, 1 abstract, and 4 individual cases identified within 2 genomic studies of large cohorts of RCC. In summary, TFEB-amplified RCC represent a distinct molecular subtype of high-grade adult RCC associated with aggressive clinical behavior, variable morphology, and aberrant melanocytic marker expression.
| S-EPMC5069163 | biostudies-literature
Project description:We performed exome sequencing of 77 melanocytic specimens composed of Spitz nevi (n=29), Spitzoid melanomas (n=27), and benign melanocytic nevi (n=21), and compared the results with published melanoma sequencing data. Our study highlights the prominent similarity between Spitzoid and conventional melanomas with similar copy number changes and high and equal numbers of ultraviolet-induced coding mutations affecting similar driver genes. Mutations in MEN1, PRKAR1A, and DNMT3A in Spitzoid melanomas may indicate involvement of the protein kinase A pathway, or a role of DNA methylation in the disease. Other than activating HRAS variants, there were few additional mutations in Spitz nevi, and few copy number changes other than 11p amplification and chromosome 9 deletions. Similarly, there were no large-scale copy number alterations and few somatic alterations other than activating BRAF or NRAS mutations in conventional nevi. A presumed melanoma driver mutation (IDH1Arg132Cys) was revealed in one of the benign nevi. In conclusion, our exome data show significantly lower somatic mutation burden in both Spitz and conventional nevi compared with their malignant counterparts, and high genetic similarity between Spitzoid and conventional melanoma.
| S-EPMC5413430 | biostudies-literature