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Purpose: To assess the association between tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS) samples and disease recurrence., Methods: This retrospective cohort study included women aged 18 years and older who underwent treatment between January 2007 and December 2020. Male patients, individuals diagnosed with invasive or microinvasive disease based on anatomopathological examination of surgical specimens, and those with a personal history of any other cancers were excluded. Additionally, the presence of "touching TILs" (lymphocytes in direct contact with tumor cells) and periductal desmoplasia were evaluated as complementary methods to represent the immunological microenvironment. The primary outcome was relapse-free survival based on TIL quantification adjusted for potential confounders. Pathologists assessed TILs in the sample with the highest tumor representation and quantified them as a percentage. Survival was evaluated using Kaplan‒Meier curves, log-rank tests, and Cox regression models., Results: A total of 191 patients met the eligibility criteria. The mean follow-up duration was 77.2 months, with a recurrence rate of 9.2%. Patients with TILs ≥ 17% had a greater risk of recurrence (HR 2.97, 95% CI 1.17-7.51; p = 0.02). Additionally, focal necrosis (HR 6.4, 95% CI 1.39-34.71; p = 0.018) or comedonecrosis (HR 4.53, 95% CI 1.34-15.28; p = 0.015) were associated with increased recurrence risk. According to the multivariate model, comedonecrosis and TILs ≥ 17% were significantly associated with recurrence (p = 0.034 and p = 0.035, respectively). Regarding the evaluations of "touching TILs" and periductal desmoplasia, no statistical significance was found when assessing their association with disease recurrence., Conclusion: In our cohort, a high percentage of TILs (≥ 17%) and the presence of comedonecrosis were independently associated with DCIS recurrence., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Correlation between imaging and anatomopathological breast density has been superficially explored and is heterogeneous in current medical literature. It is possible that mammographic and pathological findings are divergent. The aim of this study is to evaluate the association between breast density classified by mammography and breast density of pathological macroscopic examination in specimens of breast cancer conservative surgeries. Post-hoc, exploratory analysis of a prospective randomized clinical trial of patients with breast cancer candidates for breast conservative surgery. Breast mammographic density (MD) was analyzed according to ACR BI-RADS® criteria, and pathologic macroscopic evaluation of breast density (PMBD) was estimated by visually calculating the ratio between stromal and fatty tissue. From 412 patients, MD was A in 291 (70,6%), B in 80 (19,4%) B, C in 35 (8,5%), and D in 6 (1,5%). Ninety-nine percent (201/203) of patients classified as A+B in MD were correspondently classified in PMBD. Conversely, only 18.7% (39/209) of patients with MD C+D were classified correspondently in PMBD (p < 0.001). Binary logistic regression showed age (OR 1.06, 1.01-1.12 95% CI, p 0.013) and nulliparity (OR 0.39, 0.17-0.96 95% CI, p 0.039) as predictors of A+B PMBD., Conclusion: Mammographic and pathologic macroscopic breast density showed no association in our study for breast C or D in breast image. The fatty breast was associated with older patients and the nulliparity decreases the chance of fatty breasts nearby 60%., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 The Authors.)

DNA mismatch repair protein deficiency (MMRd) in endometrial carcinoma is associated with the risk of Lynch syndrome and response to immune checkpoint inhibitors. It is also related to microsatellite instability and corresponds to a molecular subtype of endometrial tumor with an unclear prognosis. Here, we evaluated the clinicopathological characteristics and prognosis of 312 consecutive endometrial carcinoma cases submitted to complete surgical staging at a single institution. We compared MMRd and mismatch repair protein-proficient (MMRp) tumors and examined the effects of the MMR protein loss type (MLH1/PMS2 vs. MSH2/MSH6) and influence of L1CAM and p53 expression. The median follow-up period was 54.5 (range, 0-120.5) months. No difference was observed between MMRd [ n  = 166 (37.2%)] and MMRp [ n  = 196 (62.8%)] cases in terms of age, body mass index, FIGO stage, tumor grade, tumor size, depth of myometrial infiltration, or lymph node metastasis. More MMRd than MMRp tumors had endometrioid histology (87.9% vs. 75.5%) and despite MMRd had more lymphovascular space invasion (LVSI; 27.2% vs. 16.9%), they presented fewer recurrences and no difference in lymph node metastasis and disease-related death. Relative to those with MLH1/MSH6 loss, tumors with MSH2/MSH6 loss were diagnosed at earlier FIGO stages, were smaller, and had less ≥50% myometrial invasion, LVSI and lymph node metastasis. Outcomes, however, did not differ between these groups. L1CAM positivity and mutation-type p53 expression were more common in MMRp than in MMRd tumors and did not differ between the MLH1/PMS2 and MSH2/MSH6 loss groups. In the entire cohort, L1CAM and mutation p53 expression were associated with worse prognosis, but only non-endometrioid histology, FIGO stage III/IV, and deep myometrial infiltration were significant predictors. In the subgroup of endometrioid carcinomas, only FIGO stage III/IV was associated with poor outcomes. The risk of lymph node metastasis was associated with tumor size, non-endometrioid histology, and multifocal LVSI. For MMRd tumors, only tumor size and myometrial invasion depth were predictive of lymph node involvement. In our cohort, MMRd tumors were associated with greater recurrence-free, but not overall, survival. The precise identification of MMRd status, present in a substantial proportion of endometrial cancer cases, is a challenge to be overcome for proper patient management. MMRd status serves as a marker for Lynch syndrome, and a significant number of these tumors are high risk and candidate to immunotherapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Aims: To correlate the 'Residual Cancer Burden' (RCB) index with overall survival (OS) and disease-free survival (DFS) in women undergoing neoadjuvant chemotherapy at the Cancer Institute of the State of São Paulo., Methods: We analysed the medical records of patients with breast cancer who underwent neoadjuvant chemotherapy and breast surgery, from 2011 to December 2017. Variables analysed were age, clinical and pathological staging, molecular subtype, number of recurrences or metastases, number of deaths, value and class of the RCB index. We used the Kaplan-Meier and the log-rank statistics to evaluate the possible association between RCB and OS and DFS. A regression model was used to determine the independent association of the RCB with the outcomes controlling for confounding factors., Results: 347 patients were included in the analysis with a mean age of 49.39 years. Initial clinical staging was T3 in 57.9% of patients and 43.8% of patients had N1 axillary status. Survival analysis showed a statistically significant better prognosis for the RCB 0 (pCR) subgroup compared with RCB 1, 2 and 3 (log rank p=0.01). In a multivariate analysis, only the RCB classification showed a statistically significant correlation with DFS (RCB 1, HR 6.9, CI 1.9 to 25.4, p=0.004; RCB 2, HR 4.2, CI 1.6 to 10.8, p=0.03; and RCB 3, HR 7.6, CI 2.76 to 20.8, p=0.00)., Conclusion: We demonstrated a positive and significant relationship between the RCB index and the risk of relapse and death., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study evaluated the frequency of GATA-binding protein 3 (GATA3) expression in early breast cancer and its relationship with histopathological and immunohistochemical parameters., Materials and Methods: GATA3 was analysed by immunohistochemistry in histological sections of tumors from 105 female patients, with histological diagnosis of invasive breast carcinoma (BC), at clinical stages I, II and IIIA, who underwent primary surgical treatment. GATA3 nuclear expression was determined as the percentage of positive tumor cells and further categorized as high (positive expression in more than 95% of cells) or non-high (negative or low positive expression in up to 95% of tumor cells). GATA3 expression was analysed according to the patient age, tumor and node pathological stage, histological type, histological and nuclear grade, lymphovascular invasion, and estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), human epidermal growth factor 2 (HER2) status, and Ki-67 expression., Results: GATA3 expression was positive in 103 cases (98.1%). High expression was significantly associated with low histological and nuclear grade, positive hormonal receptors, and less proliferative activity based on Ki-67 expression. A prominent feature was that 94.7% of the ER-positive/HER2-negative cases presented high-GATA3 expression, as 94.0% of the tumors showing high-GATA3 were ER-positive. In ER-negative/HER2-positive or ER-negative/HER2- negative, high-GATA3 was present in 25% while 75% were non-high-GATA3 compared with ER-positive/HER2- negative (4.1%) and ER-positive/HER2-positive (20%). Proliferative activity in triple-negative breast cancer tended to be higher among tumors with low-GATA3, irrespective of AR expression. In the group of ER-positive/HER2-negative tumors only three cases were low-GATA3 (85% and 80%), both with high proliferative activity., Conclusion: High GATA3 expression is associated with favorable histopathologic and immunohistochemical BC prognostic factors., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©Copyright 2022 by the the Turkish Federation of Breast Diseases Societies / European Journal of Breast Health published by Galenos Publishing House.)

Objectives: To assess the clinical response to and the histomorphometric effects of microablative fractional radiofrequency (MFR) in women with symptomatic vulvar lichen sclerosus (VLS)., Methods: This was a pilot study on the use of MFR for the treatment of VLS. Upon recruitment and at each treatment session, all participants were examined and each of their symptoms were rated on a visual analog scale. After the procedure, the participants completed a satisfaction questionnaire. We compared the morphometric findings of vulvar biopsies performed at enrollment and after the last treatment session. The participants were divided into three groups according to previous treatment with corticosteroids: G1, no previous treatment; G2, treated for up to 5 years; and G3, treated for >5 years., Results: This study included 26 women. After two to three sessions, most participants in all groups became either "asymptomatic" or "much better" than before treatment and were "very satisfied" or "satisfied" with the intervention. Pruritus and burning sensation were the most frequently reported symptoms. Nearly 40% of the participants in all groups reported complete remission of symptoms. The improvement was rated as moderate or higher by 80%, 76%, and 66% of the women in groups 1, 2, and 3, respectively. The improvement of symptoms persisted for 11 months (range, 7-16 months), on average, after the treatment. Type III collagen concentration significantly increased and was associated with important symptom improvement. Tissue trophism and vascularization also increased but did not reach statistical significance, probably because of the small number of cases., Conclusions: MFR may be an effective and safe treatment for symptomatic VLS.

Background: Nipple-sparing mastectomy (NSM) is increasingly performed for breast cancer (BC) treatment. To ensure local control with this procedure, it is important to obtain clear surgical margins. Here, we aimed to estimate the confidence in intraoperative evaluation of the retroareolar margin (IERM) and the necessity of removing the intra-nipple ducts., Methods: In this retrospective cohort study, we evaluated 224 BC (infiltrating carcinoma 178, ductal carcinoma in situ 46) patients, who underwent NSM. IERM was determined via cytology and frozen sections. Following gland removal, the intra-nipple ducts were excised and embedded in paraffin for analysis. The retroareolar tissue was also paraffin-embedded and reanalyzed for definitive evaluation of retroareolar margins (DERM). The IERM predictive capacity in relation to DERM and the frequency of intra-nipple duct involvement were estimated., Results: IERM classified the sub-nipple areolar complex area as cancer-free in 219 cases (97.8%). The condition of clear retroareolar margin was confirmed by DERM in 216 cases (98.6%). The IERM accuracy was estimated as 98.6%. Ductal carcinoma in situ was detected in intra-nipple ducts using paraffin sections in 1.8% of the cases, despite clear IERM (4/219)., Conclusions: In conclusion, IERM affords high accuracy and its results are suitable to manage the nipple-areolar complex. Nevertheless, some patients may retain residual disease in the intra-nipple ducts; thus, these ducts should ideally be removed during NSM., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-405). The authors have no conflicts of interest to declare., (2020 Gland Surgery. All rights reserved.)

Background: Risk stratification of endometrial carcinomas is primarily based on surgical staging that requires extensive retroperitoneal lymph node dissection. One of the most powerful predictor of lymph node involvement is the lymph vascular space invasion (LVSI). The objective of this study was to determine the potential of L1 Cell Adhesion Molecule (L1CAM) to predict LVSI and its association with other risk factors in endometrioid endometrial carcinomas., Materials and Methods: We studied 47 consecutive patients aged 37-88 (61.34±10.52). Twenty-three patients (48.9%) were submitted to complete surgical staging. Nine patients (19.1%) underwent surgical staging without para-aortic dissection. Seven (14.9%) were submitted to hysterectomy with no lymph node dissection. Eight patients (17.0%) only had the biopsy material for analysis. The 32 patients submitted to lymphadenectomy were staged according to the FIGO system and classified among the risk categories of the ESMO-ESGO-ESTRO guidelines. The following histological characteristics were analyzed: tumor size (mm), depth of myometrial infiltration, presence of microcystic, elongated, and fragmented (MELF) pattern of myoinvasion, and lymph vascular space invasion (LVSI). Immunohistochemical analyses of mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, p53, and L1CAM were performed in formalin-fixed paraffin embedded whole tumor tissue sections., Results: LVSI was identified in 26/41 (63,4%) of the cases. L1CAM was positive in 8/47 (17%) cases, all of them positive for LVSI and within the high-risk category of ESMO-ESGO-ESTRO. L1CAM-positive cases were associated with high histological grade and p53 aberrant immunohistochemical profile. Besides, it showed a trend to larger tumors, greater depth of myometrial infiltration, and with a higher frequency of the MELF pattern of myoinvasion. LVSI was also associated with FIGO stage, tumor size, depth of myometrial infiltration, and tumor grade., Conclusions: L1CAM is highly associated with LVSI and could be used as a pre-operative predictor of lymph node involvement in endometrioid endometrial carcinomas., Competing Interests: The authors have declared that no competing interests exist.

Objective: The objective of this study was to determine the impact of the use of single-photon emission computed tomography fused with computed tomography (SPECT-CT) on thoracoscopic biopsy of sentinel lymph nodes (SLNs) in the internal mammary chain in patients with breast cancer by evaluating resultant changes in staging and their clinical implications., Methods: Between September 2010 and January 2014, we performed lymphoscintigraphy-assisted thoracoscopic biopsy of the internal mammary chain SLN in 20 patients with breast cancer. Single-photon emission computed tomography fused with computed tomography was also used in 13 of these patients. The sentinel nodes were surgically identified with the aid of a gamma probe., Results: Sentinel lymph nodes were identified surgically in 19 of 20 patients. In the 13 patients in whom SPECT-CT was used, it readily identified SLNs, especially when they were located over an intercostal space. Change of staging occurred in three patients (15%), two of whom accordingly received adjuvant radiotherapy to the internal thoracic chain., Conclusions: Compared with lymphoscintigraphy alone, the use of SPECT-CT improves localization of the SLN in the internal mammary chain, allowing more accurate planning of each individual's treatment.

Introduction: In this prospective ex vivo study, we propose a new technique for the intraoperative examination of retroareolar tissue and describe both surgical excision and pathological methods. We performed a nipple-sparing mastectomy simulation in patients selected to total mastectomy, in order to evaluate the accuracy of these new technique., Materials and Methods: A total of 158 total mastectomy specimens from patients affected by ductal carcinoma in situ (n = 15) or invasive ductal carcinoma (stages I, II, or IIIA) (n = 143) were examined. To obtain the entire sample area, the terminal retroareolar milk duct bunch was isolated. Fragments approximately 1.5 cm in length were excised and sectioned in parallel at the base of the nipple using a cold bistoury. Three transverse histological sections (4 μm each) at 200 μm intervals that included the entire isolated fragments were subjected to frozen section examination. The sections were stained with hematoxylin-eosin and were evaluated. The remainder of each fragment was embedded in paraffin and 4 μm sections were subsequently stained with hematoxylin-eosin and examined., Results: There were two false-negative (1.3%) and five false-positive (3.1%) findings among the frozen and paraffin sections analyzed. A statistical analysis of the frozen section examinations showed a sensitivity of 92.0%, a specificity of 96.2%, a positive predictive value of 82.1%, a negative predictive value of 98.4%, and an accuracy of 95.4%., Conclusion: The frozen section examination technique described here detected nipple involvement in breast cancer with greater accuracy than the frozen section usually performed by most surgeons., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Ductal carcinoma in situ is the last step preceding invasive ductal carcinoma in breast carcinogenesis., Objective: We investigated the role of myoepithelial cells and epithelium characteristics as predictors of the risk of stromal invasion., Methods: We selected 236 cases with initial diagnosis of DCIS followed by surgical ressection distributed in groups 1 (without invasion) and 2 (with invasive carcinoma)., Results: The risk of stromal invasion after a DCIS diagnosis in biopsy was associated to triple-negative profile and loss of CD10 expression by myoepithelial cells, and inversely associated with CK5/6 expression by neoplastic cells and high expression of Smooth Muscle Myosin Heavy Chain (SMMHC) by myoepithelial cells., Conclusions: A combination of characteristics of epithelial and myoepithelial cells in DCIS in biopsy specimens is related to the risk of stromal invasion.

Objective: Functional polyps and chronic endometritis are among the most common abnormalities seen in the endometrium of patients with implantation failures and recurrent miscarriages. In this study we describe morphological vascular changes in endometrial samples from asymptomatic infertile patients and their association with chronic endometritis and polyp., Study Design: We selected 435 asymptomatic infertility patients submitted to office-based diagnostic hysteroscopy and endometrial biopsy. We described vascular changes and searched for histologic signs of endometritis and functional polyps in the endometrial samples. We explored the associations between these conditions., Results: Signs of endometritis, vascular changes and polyps were identified in 176 (40.5%), 168 (38.6%) and 102 (23.4%) cases, respectively. There was a significant association between endometritis and vascular changes. The more frequent vascular alteration (70%) was the hyaline thickening of vessels, a morphological pattern very similar to the thick-walled vessels of polyps. Polyps were associated with endometritis in 28 (27.4%) cases and with other vascular changes besides the vascular stalk in 14 (13.7%). All the polyps with vascular changes had histologic evidence of endometritis. There was a significant association between inflammatory phenomena and vascular changes, even among cases of polyps., Conclusions: Endometrial samples from infertile patients present a broad spectrum of vascular changes, most of them associated with endometritis. This association is also identified in functional polyps. Our results suggest that these alterations may be etiologically related. It is possible that the vessel axis of functional polyps actually may originate from the evolution of the vascular changes associated with endometritis. This would place functional polyps among the spectrum of inflammatory endometrial diseases., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Biological markers that predict the development of invasive breast cancer are needed to improve personalized therapy for patients diagnosed with ductal carcinoma in situ. We investigated the role of basal cytokeratin 5/6 in the risk of invasion in breast ductal carcinoma in situ., Methods: We constructed tissue microarrays using 236 ductal carcinoma in situ samples: 90 pure samples (group 1) and 146 samples associated with invasive carcinoma (group 2). Both groups had similar nuclear grades and were obtained from patients of similar ages. The groups were compared in terms of estrogen (ER) and progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) expression, cytokeratin 5/6 immunostaining, human epidermal growth factor receptor 1 (EGFR) membrane staining and molecular subtype, as indicated by their immunohistochemistry profiles., Results: ER/PR-negative status was predictive of invasion, whereas HER2 superexpression and cytokeratin 5/6-positive status were negatively associated with invasion. Among the high-grade ductal carcinoma in situ cases, a triple-positive profile (positive for estrogen receptor, progesterone receptor, and HER2) and cytokeratin 5/6 expression by neoplastic cells were negatively associated with invasion. In the low-grade ductal carcinoma in situ subgroup, only cytokeratin 5/6 expression exhibited a negative association with the probability of invasion., Conclusion: The immunohistochemical expression of cytokeratin 5/6 by ductal carcinoma in situ epithelial cells may provide clinically useful information regarding the risk of progression to invasive disease.

Purpose: To compare the prognostic and predictive features between in situ and invasive components of ductal breast carcinomas., Methods: We selected 146 consecutive breast samples with ductal carcinoma in situ (DCIS) associated with adjacent invasive breast carcinoma (IBC). We evaluated nuclear grade and immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6 (CK5/6), and epidermal growth factor receptor (EGFR) in both components, in situ and invasive, and the Ki-67 percentage of cells in the invasive part. The DCIS and IBC were classified in molecular surrogate types determined by the immunohistochemical profile as luminal (RE/PR-positive/ HER2-negative), triple-positive (RE/RP/HER2-positive), HER2-enriched (ER/PR-negative/HER2-positive), and triple-negative (RE/RP/HER2-negative). Discrimination between luminal A and luminal B was not performed due to statistical purposes. Correlations between the categories in the two groups were made using the Spearman correlation method., Results: There was a significant correlation between nuclear grade (p<0.0001), expression of RE/RP (p<0.0001), overexpression of HER2 (p<0.0001), expression of EGFR (p<0.0001), and molecular profile (p<0.0001) between components in situ and IBC. CK 5/6 showed different distribution in DCIS and IBC, presenting a significant association with the triple-negative phenotype in IBC, but a negative association among DCIS., Conclusions: Our results suggest that classical prognostic and predictive features of IBC are already determined in the preinvasive stage of the disease. However the role of CK5/6 in invasive carcinoma may be different from the precursor lesions.