Systematic assessment of HER2 status in ductal carcinoma in situ of the breast: a perspective on the potential clinical relevance.

In many countries, hormone receptor status assessment of ductal carcinoma in situ (DCIS) is routinely performed, as hormone receptor-positive DCIS patients are eligible for adjuvant anti-hormonal treatment, aiming to reduce the ipsilateral and contralateral breast cancer risk. Although HER2 gene amplification and its associated HER2 protein overexpression constitute a major prognostic and predictive marker in invasive breast carcinoma, its use in the diagnosis and treatment of DCIS is less straightforward. HER2 immunohistochemistry is not routinely performed yet, as the role of HER2-positivity in DCIS biology is unclear. Nonetheless, recent data challenge this practice. Here, we discuss the value of routine HER2 assessment for DCIS. HER2-positivity correlates strongly with DCIS grade: around four in five HER2-positive DCIS show high grade atypia. As morphological DCIS grading is prone to interobserver variability, HER2 immunohistochemistry could render grading more robust. Several studies showed an association between HER2-positive DCIS and ipsilateral recurrence risk, albeit currently unclear whether this is for overall, in situ or invasive recurrence. HER2-positive DCIS tends to be larger, with a higher risk of involved surgical margins. HER2-positive DCIS patients benefit more from adjuvant radiotherapy: it substantially decreases the local recurrence risk after lumpectomy, without impact on overall survival. HER2-positivity in pure biopsy-diagnosed DCIS is associated with increased upstaging to invasive carcinoma after surgery. HER2 immunohistochemistry on preoperative biopsies might therefore provide useful information to surgeons, favoring wider excisions. The time seems right to consider DCIS subtype-dependent treatment, comprising appropriate local treatment for HER2-positive DCIS patients and de-escalation for hormone receptor-positive, HER2-negative DCIS patients.

Significance of Crypt Atypia in Barrett's Esophagus: A Clinical, Molecular, and Outcome Study.

BACKGROUND & AIMS: The aim of this study was to characterize baseline morphologic features of crypts in nondysplastic Barrett's esophagus and correlate them with DNA content abnormalities and risk of progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC). METHODS: The morphologic features of nondysplastic crypts in baseline biopsy specimens from 212 BE patients (2956 biopsy specimens) were graded histologically using a 4-point scale (crypt atypia levels, 0-3). DNA content abnormalities were detected using flow cytometry. RESULTS: In patients who had dysplasia in their baseline biopsy specimens, dysplasia was associated significantly with increasing grades of crypt atypia in the background nondysplastic Barrett's esophagus (P < .001). In a subset of patients without dysplasia at baseline (N = 149), a higher grade of crypt atypia was associated with longer Barrett's esophagus segment length (5.5 vs 3.3 cm; P = .0095), and a higher percentage of cells with 4N DNA content (3.67 ± 1.27 vs 2.93 ± 1.22; P = .018). Crypt atypia was associated with the development of any neoplasia (low-grade dysplasia and HGD/EAC). Although no significant association was noted between the grade of crypt atypia and increased 4N, aneuploidy, or progression to HGD/EAC, only patients with grade 2 or 3 crypt atypia showed increased 4N, aneuploidy, or progression to HGD/EAC. CONCLUSIONS: Patients with Barrett's esophagus likely develop dysplasia via a progressive increase in the level of crypt atypia before the onset of dysplasia, and these changes may reflect some alteration of DNA content.

Grading Cytologic Epithelial Atypia in Pancreatic Mucinous Cysts Predicts Patient Survival: Correlation With Histologic, Molecular, and Clinical Follow-Up.

Cytologic examination of epithelial cells in cyst fluids from pancreatic mucinous cysts is the optimal method for identifying high-grade atypia (HGA), which may represent histologic high-grade dysplasia (HGD) or invasive carcinoma and thereby classify the cyst as high risk, warranting surgical resection. Cytologic features of HGA were previously described at our institution in 2013 and implemented thereafter, but performance of grading with these criteria has not yet been reported. In total, 1322 pancreatic cyst fluid specimens (2014-2021) were identified; all pathology reports and relevant clinical data were reviewed in detail; and 230 unique cysts (217 patients) contained neoplastic mucinous epithelium. Of the 230 cysts, 178 had low-grade atypia (LGA), and 52 had HGA. Ninety-seven cysts had histologic follow-up: 77 (79%) were resections and 20 (21%) were diagnostic surgical biopsies only. Moreover, 92 (95%) were confirmed neoplastic mucinous cysts, 3 were adenocarcinomas, and 2 were benign entities. Among histologically confirmed neoplastic mucinous cysts, 58 had low-grade dysplasia (LGD); 34 had HGD, of which 14 also had invasive carcinoma. A significantly higher proportion of cysts with HGA (63%) demonstrated at least HGD on follow-up compared to those with LGA (26%, P < .001). The sensitivity and specificity of HGA for accurately classifying a high-risk cyst were 54% and 81%, respectively. Of the 230 cysts, 146 (64%) cysts had corresponding next-generation sequencing results; 31% of HGA cysts harbored a high-risk mutation (TP53, CDKN2A, and/or SMAD4) vs 7% of LGA cysts (P < .001). Among cysts without histologic confirmation, 25% of HGA cysts had high-risk mutation vs 7% of LGA cysts. The grade of cytologic atypia was predictive of overall survival and recurrence-free survival (P < .001 and P = .020, respectively). Implementation of cytologic criteria for HGA in pancreatic mucinous cysts has relatively low sensitivity but modest specificity for classifying a high-risk cyst. Although high-risk mutations were more commonly found in cysts with HGA, their frequency is overall low. Thus, evaluating the degree of cytologic atypia, which is predictive of patient survival, provides significant value and informs patient outcomes.

Trajectory of Subsequent Breast Cancer Diagnoses in a Diverse Patient Cohort with Breast Atypia.

BACKGROUND: Proliferative breast atypical lesions, including atypical ductal hyperplasia (ADH) and lobular intraepithelial neoplasms (LIN), represent benign entities that confer an elevated risk of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC). However, the timing of disease progression is variable and risk factors associated with the trajectory of disease are unknown. METHODS: Patients diagnosed with ADH or LIN from 1992 to 2017 at an academic center were identified. Early progression was defined as DCIS or IBC diagnosed within 5 years following the initial atypia diagnosis. Unadjusted cancer-free survival was estimated using the Kaplan-Meier method. Demographics, clinicopathologic features, and use of chemoprevention were compared between the early and late development groups. RESULTS: Overall, 418 patients were included-73.7% with ADH and 26.3% with LIN. Over a median follow up of 92.1 months, 71/418 (17.0%) patients developed IBC (57.7%) or DCIS (42.3%). Almost half (47.9%, 34/71) were diagnosed within 5 years of their initial atypia diagnosis, and 52.1% (37/71) were diagnosed after 5 years. Patient and atypia characteristics were not associated with rate of events or time to events. There was a trend of early events being more often ipsilateral (76.5% early vs. 54.1% late; p = 0.13) versus contralateral. CONCLUSIONS: In a large cohort of patients with breast atypia and long-term follow up, 17% experienced subsequent breast events, with approximately half of the events occurring within the first 5 years following the initial atypia diagnosis. Clinical features were not associated with the trajectory to subsequent events, supporting that atypia signals both local and overall malignancy risk.

Positive Nipple Margins in Nipple-Sparing Mastectomy: Management of Nipples Containing Cancer or Atypia.

BACKGROUND: Nipple-sparing mastectomy (NSM) is an oncologically safe approach for breast cancer treatment and prevention; however, there are little long-term data to guide management for patients whose nipple margins contain tumor or atypia. METHODS: NSM patients with tumor or atypia in their nipple margin were identified from a prospectively maintained, single-institution database of consecutive NSMs. Patient and tumor characteristics, treatment, recurrence, and survival data were assessed. RESULTS: A total of 3158 NSMs were performed from June 2007 to August 2019. Nipple margins contained tumor in 117 (3.7%) NSMs and atypia only in 164 (5.2%) NSMs. Among 117 nipple margins that contained tumor, 34 (29%) margins contained invasive cancer, 80 (68%) contained ductal carcinoma in situ only, and 3 (3%) contained lymphatic vessel invasion only. Management included nipple-only excision in 67 (57%) breasts, nipple-areola complex excision in 35 (30%) breasts, and no excision in 15 (13%) breasts. Only 23 (24%) excised nipples contained residual tumor. At 67 months median follow-up, there were 2 (1.8%) recurrences in areolar or peri-areolar skin, both in patients with nipple-only excision. Among 164 nipple margins containing only atypia, 154 (94%) nipples were retained. At 60 months median follow-up, no patient with atypia alone had a nipple or areola recurrence. CONCLUSIONS: Nipple excision is effective management for nipple margins containing tumor. No intervention is required for nipple margins containing only atypia. Our results support broad eligibility for NSM with careful nipple margin assessment.

High-risk human papillomavirus infection and cervical cytopathology: relationship with cervical nitric oxide levels.

BACKGROUND: Nitric oxide (NO) may contribute to the persistence of high-risk human papillomavirus (hrHPV) infection, which has been linked to the development of premalignant lesions and cervical cancer. Our study aimed to examine the relationship between cervical NO metabolite (NOx) levels, hrHPV infection, and cytopathological findings. Additionally, we assessed cervical NOx levels as a biomarker for predicting hrHPV infection and epithelial atypia. METHODS: The study involved 74 women who attended the Gynecology and Obstetrics outpatient clinics at Cairo University Hospitals between November 2021 and August 2022. Cervical samples were subjected to Pap testing, assessment of NOx levels by the Griess method, and detection of hrHPV DNA by real-time polymerase chain reaction. RESULTS: High-risk HPV was detected in 37.8% of women. EA was found in 17.1% of cases, with a higher percentage among hrHPV-positive than negative cases (35.7% vs. 4.3%, p = 0.001). The most prevalent hrHPV genotype was HPV 16 (89.3%). The cervical NOx level in hrHPV-positive cases was significantly higher (37.4 µmol/mL, IQR: 34.5-45.8) compared to negative cases (2.3 µmol/mL, IQR: 1.2-9.8) (p = < 0.001). Patients with high-grade atypia showed significantly higher NOx levels (38.0 µmol/mL, IQR: 24.6-94.7) in comparison to NILM and low-grade atypia cases (5.0 µmol/mL, IQR: 1.6-33.3 and 34.5 µmol/mL, IQR: 11.7-61.7, respectively) (p = 0.006). Although the NOx levels among hrHPV-positive cases with low-grade atypia (40.4 µmol/mL, IQR: 33.3‒61.8) were higher than those with NILM (36.2 µmol/mL, IQR: 35.7‒44.0) and high-grade atypia (38.0 µmol/mL, IQR: 24.6‒94.7), the difference was not significant (p = 0.771). ROC curve analysis indicated that the cervical NOx cut-off values of > 23.61 µmol/mL and > 11.35 µmol/mL exhibited good diagnostic accuracy for the prediction of hrHPV infection and EA, respectively. CONCLUSIONS: The high prevalence of hrHPV infection, particularly HPV 16, in our hospital warrants targeted treatment and comprehensive screening. Elevated cervical NOx levels are associated with hrHPV infection and high-grade atypia, suggesting their potential use as biomarkers for predicting the presence of hrHPV and abnormal cytological changes.

Retained Biopsy Site Markers After Breast Lesion Surgical Resection: Associations With Residual Malignancy.

BACKGROUND. Biopsy site markers (BSMs) placed during image-guided core needle biopsy (CNB) are typically targeted for surgical excision, along with the breast imaging abnormality. Retained BSMs raise concern of incomplete resection of the breast abnormality. OBJECTIVE. The purpose of our study was to assess the frequency of residual malignancy in patients with retained BSMs identified on the initial mammography performed after breast lesion surgical excision. METHODS. This retrospective study included 30 patients (median age, 59 years) who underwent surgical resection between August 2015 and April 2022 of a borderline, high-risk, or malignant breast lesion after CNB and technically adequate preoperative image-guided localization, in whom the initial postoperative mammography report described a retained nonmigrated BSM. EMR data were extracted. The index pathology from CNB and initial surgical resection was classified as malignant or nonmalignant. The presence of residual malignancy after initial surgical resection required pathologic confirmation from subsequent tissue sampling; the absence of residual malignancy required 2 years of benign imaging follow-up. RESULTS. Thirteen specimen radiographs were interpreted intraoperatively by a surgeon with later radiologist interpretation, and 17 underwent real-time radiologist interpretation. Eighteen patients had malignant index pathology from the initially resected lesion. The frequency of residual malignancy on subsequent follow-up after initial surgical resection was higher in patients with malignant than nonmalignant index pathology (39% [7/18] vs 0% [0/12], respectively; p = .02). Among patients with malignant index pathology, the frequency of residual malignancy was higher in those without, than with, malignancy in the initial surgical specimen (80% [4/5] vs 23% [3/13]; p = .047). Also in these patients, the frequency of a positive interpretation of the initial postoperative mammography (BI-RADS category 4 or 6) was not significantly different between those with and without residual malignancy (57% [4/7] vs 55% [6/11]; p > .99). CONCLUSION. Patients with retained BSMs associated with malignant index lesions are at substantial risk of having residual malignancy. Initial postoperative mammography is not sufficient for excluding residual malignancy. CLINICAL IMPACT. Retained BSMs associated with index malignancy should be considered suspicious for residual malignancy. In this scenario, timely additional tissue sampling targeting the retained BSM is warranted, given the greater-than-2% chance of malignancy. Active surveillance is a reasonable management strategy in patients with retained BSMs from nonmalignant index lesions.

Evolving approaches in paediatric thyroid cytopathology: A review.

The guidelines for the workup of thyroid nodules have been established in adult populations and secondarily applied to paediatric populations. In particular, The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is commonly applied to both adult and paediatric thyroid nodules. However, as paediatric nodules have distinct molecular drivers and behavioural trajectories, there is renewed interest in diagnostic and management strategies that are paediatric specific. Here, we review key differences between paediatric and adult thyroid cancer and recent literature evaluating the use of TBSRTC in paediatric populations.

Next-generation sequencing has diagnostic utility in challenging small/flat urothelial lesions.

Small/flat urothelial lesions are challenging and currently available ancillary immunohistochemistry testing often cannot reliably distinguish between reactive lesions and urothelial carcinoma (UCa). UCa has a characteristic molecular profile, but small/flat urothelial lesions are typically considered too small to perform next generation sequencing (NGS). Herein, we present our institution's experience with utilizing comprehensive DNA-based NGS to evaluate small/flat urothelial lesions (n = 13 cases). NGS was ordered on 7/13 small/flat urothelial lesions initially diagnosed as urothelial atypia, ordered by the pathologist to aid in further diagnosis; the remaining 6/13 cases were diagnosed as urothelial carcinoma in situ (uCIS), ordered by a treating oncologist. The test was considered as adding value if it yielded pathogenic or likely pathogenic alterations previously associated with urothelial carcinoma in the literature. Macroscopic dissection was determined necessary in all cases and obtained either by scraping (7), punch biopsy (5) or scooping (1) of paraffin tissue blocks. In 4/13 cases, tumor content was considered low (<25%); in 2/13 cases, DNA quantity yield was considered below optimal (<250 ng); all cases met required DNA quantity for testing (>50 ng). Mean target coverage ranged: 498 to 985 (optimal >500 reads). NGS testing identified mutations compatible with urothelial carcinoma in all 7 cases initially diagnosed as atypical; and in one case, the tumor recurred as a lung metastasis. All 6 uCIS had NGS testing results concordant with UCa. In conclusion, despite small sample quantity with low tumor content and DNA concentration yield, NGS testing with appropriate methodology can be considered in the setting of small/flat urothelial lesions to aid in diagnosis or per oncologist request and yield interpretable results.

Diagnostic Challenges during Inflammation and Cancer: Current Biomarkers and Future Perspectives in Navigating through the Minefield of Reactive versus Dysplastic and Cancerous Lesions in the Digestive System.

In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.

[Molecular and other ancillary tests proposed by The Bethesda system for reporting thyroid cytopathology 2023]. / Les tests moléculaires et autres techniques ancillaires en cytologie thyroïdienne selon Bethesda 2023.

For the first time the 2023 version of The Bethesda System for Reporting Thyroid Cytology dedicates a whole chapter (chapter 14) to ancillary studies almost exclusively represented by molecular testing. The latest data reported bring some evidence that molecular testing could help to optimize the diagnostic performance of « indeterminate ¼ categories (AUS and NF). Other studies suggest a promising role to guide the management of suspicious of malignancy and malignant categories. Indeed, the recognition of prognostic and predictive biomarkers analyzed on cytological samples, regardless of how it is collected, has progressed thanks to advances in our knowledge of molecular abnormalities of thyroid tumors. The chapter 14 is presented here highlighting the current and emerging roles of « in-house ¼ and commercialized molecular testing as presented by TSBRTC.

Prognostic value of nuclear morphometry in myxoid liposarcoma.

Myxoid liposarcoma (MLS) accounts for 20%-30% of liposarcoma and the round cell component (RCC) is believed to be a specific poor prognostic factor. However, the RCC assessment criteria are vaguely defined and, therefore, are inconsistently employed by pathologists. In this study, we modified and applied two established grading systems to evaluate nuclear atypia (namely, the World Health Organization/International Society of Urological Pathology and the Fuhrman grading in renal cell carcinoma) in 64 MLS cases. Detailed software-based assessments of the morphology and the cellularity were performed. DNA mutation analysis, comprehensive mRNA expression analysis, and immunohistochemistry were also performed. Our findings revealed that the high-nuclear-grade group according to the modified Fuhrman grading system exhibited a significantly poor disease-free survival (hazard ratio: 4.43; 95% confidence interval: 0.9-22.6; p = 0.047). On the other hand, the cellularity was significantly higher in the modified Fuhrman high-grade group (p = 0.010 at the percentage of the hypercellular area; p = 0.003 at the maximum cell density) but did not qualify per se as a poor prognostic factor in the survival analyses. Furthermore, the modified Fuhrman high-grade group significantly expressed the cell cycle-related genes (such as FOXM1, PLK1, and CDK1). In conclusion, our analyses suggest that an evaluation focusing on nuclear morphology (rather than on cellular density) can be more reliable in predicting the MLS prognosis.

Degree of crypt atypia correlates with progression to high-grade dysplasia/adenocarcinoma in non-dysplastic Barrett's oesophagus.

AIMS: Patients with non-dysplastic Barrett's oesophagus (BE) often show a wide range of 'atypical' histological features in the bases of the crypts. However, the significance of crypt atypia has never been evaluated, despite prior studies showing the presence of DNA content and other molecular abnormalities in this epithelium. The aim of this study was to evaluate whether the degree of crypt atypia in BE patients without dysplasia correlates with progression to high-grade dysplasia/adenocarcinoma (HGD/EAC). METHODS AND RESULTS: Baseline biopsies from 114 BE patients without dysplasia, 57 who progressed to HGD/EAC (progressors) and 57 who did not progress (non-progressors), were included in the study. Biopsies were evaluated for the degree of basal crypt atypia on a three-point scale according to discrete histological criteria. In non-progressors, 64.9, 31.6 and 3.5% of biopsies had a crypt atypia score of 1, 2 and 3, respectively, with a mean score of 1.39 ± 0.56. The percentage of biopsies with an atypia score of 2 or 3 increased in progressors [42.1, 42.1 and 15.8% of biopsies scored 1, 2 or 3, respectively, with a mean score of 1.74 ± 0.72 (P = 0.004)]. The odds ratio of grade 3 crypt atypia for progression to HGD/EAC was 5.2 (95% confidence interval = 1.1-25.0, P = 0.04) and the findings did not change significantly when the data were analysed according to progression to either HGD or EAC. CONCLUSIONS: This study shows that non-dysplastic crypts in BE are biologically abnormal, suggesting that neoplastic progression begins prior to the onset of dysplasia. The degree of crypt atypia in BE patients without dysplasia correlates with progression.

Cytologic atypia of benign inflammatory versus neoplastic cutaneous squamous lesions.

BACKGROUND: Cytologic atypia encompasses several features of abnormal cellular morphology. We sought to quantify these features in benign and premalignant/malignant squamous cell lesions to better characterize criteria for malignancy. METHODS: We conducted a rater-blinded observational study in which histopathology slides were evaluated under light microscopy, and the presence and relative quantity of 24 distinct cytological features were recorded, along with respective diagnoses. Each slide was evaluated, and the ratings were recorded and analyzed. RESULTS: The most helpful findings, whose presence in high numbers indicates an increased likelihood that the tissue sample is premalignant/malignant, were: (1) pleomorphic parakeratosis; (2) pleomorphic nuclei in the epithelium; (3) irregular nuclei; (4) thick refractile nuclear envelope; (5) presence of nuclear hyperchromasia (dark gray); (6) peripheral nucleoli; and (7) nucleolar stems. Higher values of round or oval nuclear shape and vesicular nuclei increase the likelihood that the tissue sample is benign. CONCLUSIONS: Certain nuclear features have a higher association with premalignancy/malignancy and may guide histologic evaluation of a given lesion. These findings can be used in combination with architectural features and clinical history to add to a complete diagnostic picture.

Real-life data of adjuvant IFN-α2b and MMC in conjunctival melanocytic lesions.

PURPOSE: We herein compare topical interferon alpha 2b (IFN-α2b) to topical mitomycin C (MMC) in the adjuvant management after excision of primary acquired melanosis with atypia (PAM) and melanoma of the conjunctiva/cornea (CM). METHODS: We included 25 tumors from 25 patients (six with PAM and 19 with CM). After surgical excision, four patients started with adjuvant IFN-α2b (two in combination with radiotherapy), 19 with MMC, and two with radiotherapy alone. Five patients were switched from initial MMC/radiotherapy to IFN-α2b during follow-up. Efficacy was assessed via time to tumor recurrence and initial therapy response. RESULTS: With initial IFN-α2b, three patients (3/4, two with additional radiotherapy) showed complete remission (follow-up: 1478-1750 days) and one recurrence (1/4) was noted after 492 days. With initial MMC, no recurrence was recorded in 15 of the 19 patients (follow-up: 99-4732 days). Five patients were switched from MMC or radiotherapy to IFN-α2b: two patients showed complete remission (2/5), while another two (2/5) experienced recurrences and remained without recurrence after repeated courses of IFN-α2b (follow-up: 1798 and 1973 days). Only one patient showed incomplete response. Adverse effects were recorded in five patients, all received MMC. CONCLUSION: Topical IFN-α2b (arguably together with radiotherapy) may be a viable alternative to MMC in PAM and CM. We observed fewer side effects at similar response rates. However, when response to MMC was poor, IFN-α2b may also be of limited utility.

An artificial neural network for the prediction of the risk of malignancy in category III Bethesda thyroid lesions.

BACKGROUND: The diagnosis of cases of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) by fine needle aspiration cytology (FNAC) is challenging for both cytopathologists and clinicians. It is extremely difficult to predict the risk of malignancy based on cytological features alone. AIMS AND OBJECTIVES: In this study, we attempted to construct an artificial neural network (ANN) model to predict the risk of malignancy in FNAC cases of AUS/FLUS in thyroid lesions based on cytological features. MATERIALS AND METHODS: We included two groups of AUS/FLUS cases: (1) 29 cases of histopathologically proven malignancy, and (2) 32 cases that had either been histopathologically proven to be benign, or for which no progress of malignancy on follow-up had been observed in the last 2 years. Cytological characteristics were analysed semi-quantitatively by two independent observers (TS and PD). Based on these data, we tried to generate an artificial neural network (ANN) model to differentiate between malignant and benign cases. The performance of the ANN was assessed using the confusion matrix and receiving operator curve. RESULTS: There were 29 malignant cases of AUS/FLUS (histopathologically proven) and 32 benign/follow-up cases in this study. There were 41 cases in the training set, 9 cases in the validation set and 11 cases in the test set. In the test group, the ANN model successfully distinguished between all benign (5/5) and malignant cases (6/6). The area under the receiver operating curve was 1. CONCLUSION: The present ANN model is well structured and coherent to distinguish malignant from benign outcomes in AUS/FLUS cases on cytology smears with no error. This is an open-ended ANN model, and additional parameters and more cases could be included to make the model more robust.

Dienogest versus norethisterone acetate in management of endometrial hyperplasia without atypia.

OBJECTIVES: To compare the effectiveness of dienogest (DIE) and norethisterone acetate (NETA) regimens in the treatment of endometrial hyperplasia (EH) without atypia. METHODS: Participants were premenopausal women with irregular uterine bleeding, and endometrial hyperplasia without atypia on endometrial biopsy. Enrolled patients were randomly allocated into two groups: group I got DIE 2 mg/day (orally Visanne) for 14 days (10th to the 25th day of cycle) while group II received between the 16th and 25th day of the cycle, norethisterone acetate (NETA) 15 mg/d (orally Primolut Nor) was administered for 10 days. Both groups continued the therapy for six months. RESULTS: The DIE group showed a higher resolution (32.7%) and regression (57.7%) than NETA group (31% & 37.9%, respectively) with significant regression (p = 0.039). No progression in DIE group while four (6.9%) women in NETA group were recorded a progression to complex type without a significance. Also, NETA group showed a significant persistence rate (22.5%) than DIE group (3.8%) (p = 0.005). Also number in NETA group managed by hysterectomy with significant difference (p = 0.042). CONCLUSION: If used as first-line treatment, Dienogest produces a better rate of regression and a lower incidence of hysterectomy than Norethisterone Acetate does when used in EH without atypia.

Weighty Matters: The Obesity-Thyroid Nodule Connection Unveiling the Impact of Obesity on Thyroid Cancer Risk.

Background and Objectives: The effect of obesity on the development/progression of thyroid nodules with uncertain cytology is unknown. Therefore, our objective was to assess the role of body mass index (BMI) in predicting malignancy in patients with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) nodules. Materials and Methods: We retrospectively analyzed 113 patients with available BMI data and final histopathology of benign or differentiated thyroid cancer. Patients were classified into four groups based on BMI: <18.5 (underweight), 18.5-24.9 (normal weight), 25-29.9 (overweight), and ≥30 (obesity) kg/m2. The association between risk of malignancy and BMI was examined for all data and subgroups based on nodule size, sex, and age. Results: Overall, 44.2% were obese, 36.3% were ≥45 years, and 75.4% were women. Final pathological results showed malignant nodules in 52 patients (46%) and benign nodules in 61 patients (54%) (mean age: 41 ± 11.6 vs. 39.9 ± 11.7 years; p = 0.62). Men had more malignant nodules than benign nodules (32.7% vs. 16.4%, p < 0.05). Overall, no significant correlation was identified between the risk of thyroid cancer and BMI, and the risk of malignancy was not significantly different between obese men and women (p = 0.4). However, in individuals with BMI < 30 kg/m2 (non-obese group), malignant nodules were more frequent in men than in women (71% vs. 41%, p = 0.04). No significant difference was observed in mean nodule size between the benign and malignant groups. Furthermore, BMI was not related to increased risk of malignancy in multiple logistic regression models using all data, even after controlling for confounding variables (odds ratio, 0.99, 95% confidence interval: 0.93-1.06, p = 0.87) or when stratifying by sex. Conclusions: Our study showed no correlation between obesity and thyroid cancer in patients with AUS/FLUS. Moreover, men had more malignant nodules than benign nodules. Further well-designed prospective studies are required to confirm our findings.

The effect of delay of excisional biopsy on upstage rate for atypical ductal hyperplasia, flat epithelial atypia, intraductal papilloma, and radial scar.

PURPOSE: When Core Needle Biopsy (CNB) demonstrates Atypical Ductal Hyperplasia (ADH), Flat Epithelial Atypia (FEA), Intraductal Papilloma (IDP), or Radial Scar/Complex Sclerosing Lesion (RS), excisional biopsy (EB) is often performed to rule out underlying malignancy with upstage rates (UR) ranging between 1 and 20%. The COVID-19 pandemic led to delayed EB for many patients. We sought to evaluate whether this delay was associated with higher UR. METHODS: We performed a retrospective analysis of women who underwent CNB and then EB for ADH, FEA, IDP, or RS between 2017 and 2021 using an IRB-approved repository. UR was evaluated by days between CNB and EB. RESULTS: 473 patients met inclusion. 55 were upstaged to cancer (11.6%). 178 patients had pure ADH on CNB and 37 were upstaged (20.8%). 50 patients had pure FEA and 3 were upstaged (6%). 132 had pure IDP and 7 were upstaged (5.3%). 98 had pure RS and 1 was upstaged (1%). 7/15 (46.7%) had a combination of diagnoses or diagnosis with palpable mass and were upstaged. Days between CNB and EB were < 60 for 275 patients (58.1%), 60-90 for 108 (22.8%), 91-120 for 43 (9.1%), and > 120 for 47 (9.9%). There was no significant difference in UR (10.9% for < 60, 14.8% for 60-90, 7% for 90-120, and 12.8% for > 120, p = 0.54). UR for ADH was clinically increased after 60 days (27.8 vs. 17.5%), but this did not reach statistical significance (p = 0.1). CONCLUSION: Surgical delay was not associated with an increased UR.

Lessons learnt from MDM2 fluorescence in-situ hybridisation analysis of 439 mature lipomatous lesions with an emphasis on atypical lipomatous tumour/well-differentiated liposarcoma lacking cytological atypia.

AIMS: Amplification of the murine double minute-2 (MDM2) gene, which is usually detected with fluorescence in-situ hybridisation (FISH), is the key driving event for atypical lipomatous tumours (ALTs)/well-differentiated liposarcomas (WDLs). We sought to determine the concordance between the histopathological findings and MDM2 FISH in the diagnosis of ALT/WDL, and to identify the histological features of MDM2-amplified tumours lacking classic atypia. METHODS AND RESULTS: We performed a retrospective analysis of all mature lipomatous lesions subjected to MDM2 FISH analysis at our institution. MDM2 FISH analysis was performed on 439 mature lipomatous lesions: 364 (82.9%) were negative and 75 (17%) were positive. In 17 of 75 (22.6%) ALTs/WDLs, cytological atypia was not identified on initial histological assessment, thus favouring lipoma. On review, these cases shared common histological features, consisting of a very low number of relatively small stromal cells within the tumour lobules, with mildly coarse chromatin and oval nuclei, admixed with unremarkable adipocytes in a tumour background devoid of fibroconnective septa, areas of fibrosis, or blood vessels. These cells matched the cells in which FISH showed MDM2 amplification. In contrast, 13 cases (3.5%) regarded as suspicious for ALT/WDL on the basis of histology lacked MDM2 amplification and were reclassified following the FISH findings. CONCLUSIONS: We conclude that a subset of lipoma-like ALTs/WDLs are not associated with any of the features typically described in ALT/WDL. Our study also showed that tumours >100 mm are more likely to be ALT/WDL; however, a history of recurrence or concerning clinical/radiological features was not significantly associated with classification as ALT/WDL.