Transcriptomic analysis of genes associated with vitamin D receptor signalling reveals differences between skin cancers.

Vitamin D activates the vitamin D receptor (VDR), which dimerizes preferentially with the retinoid X receptor-α (RXRα). This heterodimer connects with genetic elements responsive to vitamin D, inhibiting or stimulating gene activity. We performed Nanostring® analysis of VDR/RXRα to compare the mRNA expression of this heterodimer and their correlated transcriptomes in non-melanoma skin cancer (basal cell carcinomas (BCC) and squamous cell carcinomas (SCC)) and melanocytic lesions (intradermal nevi (IN), and melanomas (MM)) with control skin. To evaluate VDR, RXRα and other 22 correlated genes in BCC, SCC, IN and MM, paraffin samples had their transcriptomes analysed using Nanostring®, a platform that allows multiple mRNA analyses. There were 46 samples, including 11 BCC, 10 SCC, 10 IN, 12 MM and 3 pools of control skins. Most mRNAs differed between the lesion groups and the control group. BCC and SCC NCOR2 were upregulated; in MM and IN, RXRγ was higher than in the control group. TP53, FOXO3 and MED1 showed a significant difference when we compared the BCC group to the SCC group. Melanoma and intradermal nevi differed only in AhR. VDR and RXRα were lower than the control in all groups. The panel shows a clear difference between the non-melanocytic cancers and, on the other hand, a slight difference between the melanocytic lesions. The study of vitamin D's influence through its receptor and RXRα is an exciting issue for understanding the importance of this pathway, and the present study can impact the prevention and treatment strategies, mainly in non-melanocytic tumours.

Oral lesions of systemic lupus erythematosus: A collaborative Latin American study.

BACKGROUND: Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that may affect the oral mucosa. The variable spectrum of oral lesions observed in SLE can pose challenges in diagnosis, particularly when the lesions occur in isolation. The aim of this study was to describe the oral lesions occurring in patients with SLE from Latin America. METHODS: This collaborative record-based study involving 11 oral and maxillofacial pathology and medicine services across Venezuela, Argentina, Chile, Brazil, and Mexico describes the clinicopathological profile of SLE-related oral lesions. RESULTS: Seventy patients with SLE and oral lesions were included in the study. The majority were females (75.7%; female/male ratio: 3.1:1) and white (62.1%), with a mean age of 38.4 years (range: 11-77 years). The most common site of oral lesions was the hard/soft palate (32.0%). Clinically, oral lesions predominantly presented as ulcers (26.6%), erosions (26.6%), and white lesions (23.4%). Isolated oral lesions occurred in 65.2% of individuals, while cutaneous manifestations occurred in 80.3%. The main clinical diagnostic hypothesis in 71.4% of cases was an immune-mediated disease. Oral biopsies followed by histopathological analysis were performed in 50 cases. CONCLUSION: Oral lesions of SLE exhibit a variety of clinical and histopathological features. A key point in diagnosis is that unusual oral changes without an obvious local cause may indicate a possible systemic condition presenting with oral lesions. A multidisciplinary approach, which includes regular oral examination, is warranted to identify oral lesions and provide treatment.

The Utility of PRAME and Ki-67 as Prognostic Markers for Cutaneous Melanoma.

ABSTRACT: Cutaneous melanoma can lead to metastasis, and it is associated with high mortality. Currently, there are no widely accepted immunohistochemistry markers for melanoma prognosis in routine staging. Preferentially expressed antigen in melanoma (PRAME) is a possible biomarker for prognosis in several noncutaneous neoplasms. Ki-67 is a cell proliferation marker correlated with poor outcomes in many cancers. This study assessed PRAME and Ki-67 as potential prognostic markers for sentinel lymph node outcomes and survival among melanoma patients. This is a retrospective study analyzing cutaneous melanoma cases from a Brazilian cancer center (2005-2021). All cases were tested using immunohistochemistry to evaluate PRAME expression and Ki-67 index. Descriptive analysis, Spearman correlations, means comparison, Kaplan-Meier analysis, χ2, and Cox models were performed. In univariate analysis of 123 cutaneous melanoma cases, high extent (P = 0.0267) and elevated intensity (P = 0.043) of PRAME were associated with decreased overall survival. The Ki-67 index was associated with overall survival (P = 0.05) and sentinel lymph node status (P = 0.0403), with a positive correlation between the markers (P = 0.0004) and between Ki-67 and Breslow thickness (P = 0.0001). However, in multivariate analysis, only Breslow thickness significantly influenced overall survival (P = 0.0003). Then, the present results can suggest that elevated PRAME and Ki-67 expression are associated with poor overall survival in cutaneous melanoma; however, in multivariate analysis, only the Breslow thickness had a significant influence. These findings highlight the potential of PRAME and Ki-67 as prognostic markers, opening frontiers that could improve strategies for treating cutaneous melanoma.

Digital analyses of nuclear features can help discriminate among non-invasive follicular thyroid neoplasm with papillary-like nuclear features, papillary thyroid carcinoma follicular subtype, and follicular carcinoma in cytological specimens.

BACKGROUND: As it stands, the diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is primarily based on histological analysis. We hypothesised that computerised analysis of nuclear images of cytological specimens could be used to differentiate NIFTP from papillary thyroid carcinoma follicular subtype (PTCFS) and follicular carcinoma (FC), influencing patient management. METHODS: We employed a retrospective analytical observational study based on nuclear morphometric variables of cytological material from thyroid nodules classified as PTCFS, NIFTP, or FC. Five cases of each entity were analysed. Cytological slides were photographed, and 1170 cells for each entity were analysed digitally. The captured images were evaluated (blindly) using the ImageJ software package. The morphometric evaluation included area, perimeter, width, height, and circularity. Numerical variables were expressed as mean, median, minimum, and maximum (min; max) values. Kruskal-Wallis and Dunn's tests were used with a 5% significance level. RESULTS: Regarding nuclear analysis, all variables differed among the three groups (p < 0.001). Given the interdependence among the variables, these data indicated that nuclear size was greatest in the NIFTP group, followed by FC and PTCFS. DISCUSSION/CONCLUSION: Our analysis of the digital images, with a focus on nuclear parameters, found significantly difference among cytological specimens from cases of NIFTP, PTCFS and FC. Thus, this tool has the potential to provide additional information that may help in the diagnosis of NIFTP, even during the preoperative period. Additional studies are needed to create protocols, evaluate the applicability of nuclear morphological and morphometric parameters-focusing on digital pathology-and create algorithms and tools to assist cytopathologists with their diagnostic routines.

Depth of invasion analysis to predict acral melanoma outcomes.

BACKGROUND: Acral melanoma is a subtype with worse outcomes. The Breslow micrometric measurement is the most critical parameter in planning treatment and predicting outcomes. However, for acral lentiginous melanoma, the value of the Breslow thickness is a matter of debate. Depth of Invasion (DOI) is a well-established measure for staging oral squamous cell carcinoma. OBJECTIVE: This study compared DOI and Breslow thickness for predicting acral melanoma outcomes. METHODS: We performed a retrospective cross-sectional study of 71 acral melanoma lesions subjected to sentinel lymph node biopsy at one Brazilian referral center. RESULTS: Cox model univariate analysis showed that both DOI and Breslow thickness predicted melanoma specific survival (HR 1.12; p = 0.0255 and HR 1.144; p = 0.0006, respectively), although Kaplan Meier curve was only significant for Breslow (χ2 = 5.792; p = 0.0161) and not for DOI (χ2 = 0.2556; p = 0.6132). Sentinel lymph node status and presence or absence of ulceration also predicted specific survival in patients with acral melanoma (χ2 = 6.3514; p = 0.0117 and χ2 = 4.2793; p = 0.0386, respectively). Multivariate analysis, however, demonstrated that Breslow depth was the only independent parameter for predicting acral melanoma specific survival (HR 1.144; p = 0.0006). CONCLUSION: Even though Breslow thickness remains the main predictor for survival in acral melanoma, it is not a perfect parameter. The introduction of DOI in this context opens new perspectives for predicting acral melanoma outcomes.

Score system for cytological evaluation of fine-needle aspiration specimens to predict the diagnosis of papillary thyroid carcinomas.

INTRODUCTION: According to the World Health Organization's classification of endocrine tumors, papillary thyroid carcinoma (PTC) accounts for almost 90 % of malignant thyroid neoplasms. This study aimed to create a point system based on cytomorphological criteria for evaluating FNA products from thyroid nodules to predict the risk of papillary thyroid carcinomas. METHODS: This was an analytical observational study based on a retrospective analysis of cytological reports and surgical specimens from January 1, 2016, to December 31, 2021. Cytological slides were analyzed using the following ten variables: Nuclear Grooves; Intranuclear Pseudoinclusion; Cellularity; Colloid (Quantity); Clarified Chromatin; Overlapping nuclei; Irregular Nuclear Membrane; Multinucleated Giant Cells; Psamoma bodies; and Papillae. We categorized these variables quantitatively from zero to three points as follows: zero (absent), one (mild), two (moderate), and three (intense). RESULTS: Cytologies of 254 (4.9 %) cases were analyzed. The cut-off point was defined in this study as 6 ± 1 points. For the prediction of cases in benign, values < 5 points, malignant, values > 7 points and indeterminate, 5-7 points. Among the benign, there were 64 (69.5 %) cases <5 points, 17 (18.4 %) from 5 to 7 points and 11 (11.9 %) >7 points. Among the malignant ones, there were 12 (8.6 %) cases <5 points, 19 (13.6 %) from 5 to 7 points and 108 (77.6) >7 points. CONCLUSION: In this context, through the quantitative analysis of the ten suggested cytological variables, scored from 0 to 3, a final score > 7 is suspicious for malignancy, while a score < 5 is related to benign lesions.

Value of Immunohistochemistry to Differentiate Digital Papillary Adenocarcinoma From Acral Hidradenoma With Papillary Structures.

ABSTRACT: Digital papillary adenocarcinoma is a malignant adnexal tumor with a predilection for acral sites. Hidradenoma is a benign solid and cystic sweat gland neoplasm with focal ductal and glandular differentiation and good outcomes. Hidradenomas can occur at acral sites and show papillary structures; for this reason, they are included in the differential diagnosis of digital papillary adenocarcinoma, and immunohistochemistry is a valuable tool in this scenario. We described a case of a 43-year-old man with an epithelial tumor showing papillary structures in the intermediate phalanx of the fourth finger. There was diffuse positivity for p63 and negativity for S100 protein, suggesting that this tumor was an acral hidradenoma with papillary structures.

Dysplastic melanocytic nevus: Are molecular findings the key to the diagnosis?

The primary differential diagnosis of melanoma is dysplastic nevus. Until now, the final diagnosis is based on histological findings. With modern techniques, pathologists receive very early melanocytic lesions, which do not fit all malignant criteria. In those cases, even the concurrence between specialists and intraobserver agreement is not good. A molecular test could be developed to improve the accuracy of melanocytic lesions diagnosis and help in challenging lesions. The objective of this study is to provide a literary review looking for molecular markers that characterize dysplastic nevi and could help surgical pathologists differentiate them from melanoma. Articles from PubMed presenting case series of dysplastic nevi and melanoma genomic analyses were considered. The search was conducted in PubMed looking for papers written in English, published in the ten years preceding April 2020. This review confirmed the absence of a pathognomonic molecular marker of dysplastic nevi. This is a heterogeneous group of lesions with an uncertain risk to become a melanoma. The molecular heterogeneity of dysplastic nevi, the variation of histological diagnostic criteria among services, and the diverse molecular techniques applied are challenging features that might hamper definitive diagnoses. However, currently, there appears to be limited value for molecular testing in the diagnosis of dysplastic nevi.

Pleomorphic sarcoma of maxillary sinus: Clinical report of a patient initially diagnosed with denture-induced fibrous hyperplasia.

Undifferentiated pleomorphic sarcoma is a high-grade soft-tissue malignant tumor that is rare in the head and neck region. A 74-year-old woman displayed a large nodular lesion in the maxillary alveolar mucosa, which was initially identified as denture-related fibrous hyperplasia. Although her prosthodontist has adjusted the maxillary complete denture to relieve pressure on the lesion, it increased in size over time. Computed tomography images of the maxillary sinus showed an extensive destructive lesion. A biopsy was performed, and microscopic examination revealed a poorly differentiated malignancy with numerous spindle cells. Immunohistochemistry reactions were negative for CD45, CD30, CD68, CD34, cytokeratin, S100, desmin, and smooth muscle actin. These findings led to the diagnosis of an undifferentiated pleomorphic sarcoma of the maxillary sinus.

Thyroid nodules 1 cm or less are related to Bethesda System nondiagnostic and suspicious for malignancy categories.

OBJECTIVE: To compare the frequency of fine needle aspiration (FNA) cytological results between nodules 1 cm or less and nodules greater than 1 cm. METHODS: All FNAs performed between January 2016 and December 2019 at an institute in Brazil were analysed. For each nodule, at least two conventional slides were produced (one stained by Giemsa and the other by hematoxylin and eosin). All cases were reviewed by two cytopathologists and were reported following the Bethesda System. Clinical information (gender and age) and ultrasound data (nodule size and location) were collected. The magnitude of association was measured using the prevalence ratio (PR) with 95% confidence intervals (CIs) considering two groups of nodules: 1.0 cm or less, and greater than 1 cm. RESULTS: A total of 3703 nodules were analysed from 3265 patients (2906 women [88.48%], 359 men [11.51%], with a combined mean age of 52 years). Considering the prevalence ratio of Bethesda categories between these two groups of nodules, the nondiagnostic or unsatisfactory category (PR: 3.0, 95% CI: 2.2-4.2) and the suspicious for malignancy category (PR: 1.6, 95% CI: 1.1-2.4) were significantly associated with nodules measuring 1 cm or less. CONCLUSION: Our results demonstrated that nodules 1 cm or less are significantly associated with the nondiagnostic and suspicious for malignancy categories of the Bethesda System when compared to nodules greater than 1 cm.

Accuracy of diagnostic tests for American tegumentary leishmaniasis: a systematic literature review with meta-analyses.

OBJECTIVES: To analyse the accuracy of American tegumentary leishmaniasis (ATL) diagnostic methods and evaluate the quality of the existing publications by means of a systematic review. METHODS: Diagnostic tests evaluated in at least two studies with common reference standards were included in the sensitivity and/or specificity meta-analyses. Quality and susceptibility to bias were analysed using the QUADAS-2 and STARD tools. RESULTS: The title and abstract of 3387 publications were evaluated after deduplication resulting from database searches. Thirty-eight studies were included in the review, and 26 of them had results inserted in meta-analyses. The diagnostic methods with the highest pooled sensitivity values were ELISA, polymerase chain reaction (PCR), indirect immunofluorescence reaction and Montenegro's intradermal reaction. Cytometry was assessed in only two studies and presented 100% sensitivity in both. Smear slide microscopy and histopathology showed low pooled values of sensitivity. For specificity, the highest pooled values were identified for PCR. High values were also identified for ELISA, except for studies in which the reference standard for defining negative participants included individuals with Chagas' disease or paracoccidioidomycosis, which also occurred for cytometry. IFR had lower specificities than ELISA. There was a predominance of case-control designs of phase 1 or 2 and only four studies were strongly recommended as evidence generators. Several reference standards were adopted, and different methods were assessed in a small number of studies. CONCLUSION: PCR showed the highest accuracy for the diagnosis of ATL, and its use should be encouraged in clinical practice. ELISA is recommended for the screening of suspected individuals, but the possibility of cross-reactions should be considered. New validation studies for the tests evaluated in few publications and studies of phase 3 with appropriate methods are needed.

OBJECTIFS: Analyser l'exactitude des méthodes de diagnostic de la leishmaniose tégumentaire américaine (LTA) et évaluer la qualité des publications existantes au moyen d'une analyse systématique. MÉTHODES: Les tests diagnostiques évalués dans au moins deux études avec des étalons de référence communs ont été inclus dans les méta-analyses de sensibilité et/ou de spécificité. La qualité et la sensibilité au biais ont été analysées à l'aide des outils QUADAS-2 et STARD. RÉSULTATS: Le titre et le résumé de 3387 publications ont été évalués après déduplication résultant de recherches dans la base de données. 38 études ont été incluses dans la revue et 26 d'entre elles ont eu des résultats inclus dans des méta-analyses. Les méthodes de diagnostic avec les valeurs de sensibilité poolées les plus élevées étaient ELISA, la réaction en chaîne par polymérase (PCR), la réaction d'immunofluorescence indirecte et la réaction intradermique du Monténégro. La cytométrie a été évaluée dans seulement deux études et présentait une sensibilité de 100% dans les deux. La microscopie et l'histopathologie sur lame de frottis ont montré de faibles valeurs poolées de sensibilité. Pour la spécificité, les valeurs poolées les plus élevées ont été identifiées pour la PCR. Des valeurs élevées ont également été identifiées pour l'ELISA, à l'exception des études dans lesquelles la norme de référence pour définir les participants négatifs incluait des individus atteints de la maladie de Chagas ou de paracoccidioïdomycose, qui s'est également produite pour la cytométrie. L'IFR avait des spécificités plus faibles que l'ELISA. Il y avait une prédominance des essais cas-témoins de phases 1 ou 2 et seules quatre études étaient fortement recommandées comme génératrices de preuves. Plusieurs normes de référence ont été adoptées et différentes méthodes ont été évaluées dans un petit nombre d'études. CONCLUSION: la PCR a montré la plus grande exactitude pour le diagnostic de l'ATL et son utilisation doit être encouragée dans la pratique clinique. L'ELISA est recommandé pour le dépistage des personnes suspectées, mais la possibilité de réactions croisées doit être considérée. De nouvelles études de validation des tests évalués dans quelques publications et des études de phase 3 avec des méthodes appropriées sont nécessaires.

Usefulness of vaginal cytology tests in women with previous hysterectomy for benign diseases: assessment of 53,891 tests.

OBJECTIVE: To assess the value of vaginal screening cytology after hysterectomy for benign disease. METHODS: This cross-sectional study used cytology audit data from 2,512,039 screening tests in the metropolitan region of Campinas from 2000 to 2012; the object was to compare the prevalence of abnormal tests in women who had undergone a hysterectomy for benign diseases (n=53,891) to that of women who had had no hysterectomy. Prevalence ratios (95% confidence intervals, 95% CI) were determined, and chi-square analysis, modified by the Cochrane-Armitage test for trend, was used to investigate the effects of age. RESULTS: The prevalence of atypical squamous cells (ASC), low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion or squamous-cell carcinoma (HSIL/SCC) was 0.13%, 0.04% and 0.03%, respectively, in women who had undergone hysterectomy, and 0.93%, 0.51% and 0.26% in women who had not undergone hysterectomy. The prevalence ratios for ASC, LSIL and HSIL/SCC were 0.14 (0.11-0.17), 0.08 (0.06-0.13) and 0.13 (0.08-0.20), respectively, in women with a hysterectomy versus those without. For HSIL/SCC, the prevalence ratios were 0.09 and 0.29, respectively, for women <50 or ≥50 years. The prevalence rates in women with a previous hysterectomy showed no significant variation with age. CONCLUSION: The prevalence rates of ASC, LSIL and HSIL/SCC were significantly lower in women with a previous hysterectomy for benign disease compared with those observed in women with an intact uterine cervix. This study reinforces the view that there is no evidence that cytological screening is beneficial for women who have had a hysterectomy for benign disease.

Fine needle aspiration cytology of lobular breast carcinoma and its variants.

OBJECTIVE: To identify associations between cytological criteria in fine needle aspiration (FNA) specimens and histological subtypes of lobular breast carcinoma (classical and other types). STUDY DESIGN: FNA cytology and mastectomy specimens from 72 cases of invasive lobular breast carcinoma were consecutively retrieved from the files of the Amaral de Carvalho Hospital, Jaú-São Paulo, Brazil. All cases were reviewed regarding five cytological criteria: cellularity, cellular cohesion, presence of inflammation, nucleoli and nuclear atypia. The χ2 test or Fisher's exact tests with 95% confidence intervals (CI) were used. RESULTS: The classical type showed lower initial cytological diagnosis of malignancy compared to the other variants (p=0.017; odds ratio (OR) 0.26, 95% CI 0.89-0.80). Moderate/intense cellular cohesion (p=0.011; OR 0.18, 95% CI 0.04-0.73) and mild atypia (p=0.000; OR 16.15, 95% CI 3.20-81.48) were significantly associated with the classical type of lobular breast carcinoma, while the absence of inflammation (p=0.082; OR 0.36, 95% CI 0.12-1.15) was marginally associated with the classical type. CONCLUSIONS: In cytology, the characterization of lobular carcinoma as malignant is difficult, especially the classical type. The association between cell cohesion and the classical type of lobular breast carcinoma may be one of the factors that complicate this diagnosis.