Updates on Lymphovascular Invasion in Breast Cancer.

Traditionally, lymphovascular invasion (LVI) has represented one of the foremost pathological features of malignancy and has been associated with a worse prognosis in different cancers, including breast carcinoma. According to the most updated reporting protocols, the assessment of LVI is required in the pathology report of breast cancer surgical specimens. Importantly, strict histological criteria should be followed for LVI assessment, which nevertheless is encumbered by inconsistency in interpretation among pathologists, leading to significant interobserver variability and scarce reproducibility. Current guidelines for breast cancer indicate biological factors as the main determinants of oncological and radiation therapy, together with TNM staging and age. In clinical practice, the widespread use of genomic assays as a decision-making tool for hormone receptor-positive, HER2-negative breast cancer and the subsequent availability of a reliable prognostic predictor have likely scaled back interest in LVI's predictive value. However, in selected cases, the presence of LVI impacts adjuvant therapy. This review summarizes current knowledge on LVI in breast cancer with regard to definition, histopathological assessment, its biological understanding, clinicopathological association, and therapeutic implications.

Thyroid findings in pediatric and adult patients with PTEN hamartoma tumor syndrome: A retrospective analysis, and literature review.

PURPOSE: PTEN hamartoma tumor syndrome (PHTS) comprises a group of rare genetic conditions caused by germline mutations in PTEN gene and characterized by development of both benign and malignant lesions in many body tissues. In this study, we aimed to evaluate the incidence of thyroid findings in both adult and pediatric PHTS patients. METHODS: A retrospectively analysis conducted in 19 (13 adult and 6 pediatric) patients with PHTS, all confirmed with genetic testing, observed from 2015 to 2021 at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. RESULTS: We found a thyroid involvement in 12 adult patients (92%): 11 patients had benign lesions (85%) and the remaining developed a follicular thyroid carcinoma (8.3%). The median age at time of the first available record was 30 years. Among benign lesions, multinodular goiter was the most observed finding (10/11, 91%). Only 1 out of 6 (16%) pediatric patients was diagnosed with a thyroid lesion (unifocal lesion in mild lymphocytic thyroiditis) at the age of 8 years. CONCLUSIONS: Thyroid disorders affected nearly all adult PHTS patients, but a much lower proportion of pediatric patients. We discuss about the natural history of thyroid involvement, age of PHTS clinical onset, and optimized surveillance.

Assessment of estrogen receptor low positive status in breast cancer: Implications for pathologists and oncologists.

Estrogen receptor (ER) status assessment by immunohistochemistry (IHC) is the gold standard test for the identification of patients with breast cancer who may benefit from endocrine therapy (ET). Whilst most ER+ breast cancers have a high IHC score, about 3% of cases display a low positivity, with 1% to 10% of cells being weakly stained. These tumors are generally classified within the luminal-like category; however, their risk profile seems to be more similar to that of ER-negative breast cancers. The decision on ET for patients with a diagnosis of ER-low breast cancer should be carefully considered in light of the risks and possible benefits of the treatment. Potential pitfalls hinder pathologists and oncologists from establishing an appropriate threshold for "low positivity". Furthermore, several pre-analytical and analytical variables might trouble the pathological identification of these clinically challenging cases. In this review, we sought to discuss the adversities that can be accounted for the pathological identification of ER-low breast cancers in real-world clinical practice, and to provide practical suggestions for the perfect ER testing in light of the most updated recommendations and guidelines.

Early Breast Cancers During Pregnancy Treated With Breast-Conserving Surgery in the First Trimester of Gestation: A Feasibility Study.

Breast cancer is the most common malignancy occurring during gestation. In early-stage breast cancer during pregnancy (PrBC), breast-conserving surgery (BCS) with delayed RT is a rational alternative to mastectomy, for long considered the standard-of-care. Regrettably, no specific guidelines on the surgical management of these patients are available. In this study, we investigated the feasibility and safety of BCS during the first trimester of pregnancy in women with early-stage PrBC. All patients with a diagnosis of PrBC during the first trimester of pregnancy jointly managed in two PrBC-specialized Centers were included in this study. All patients underwent BCS followed by adjuvant radiotherapy to the ipsilateral breast after delivery. Histopathological features and biomarkers were first profiled on pre-surgical biopsies. The primary outcome was the isolated local recurrence (ILR). Among 168 PrBC patients, 67 (39.9%) were diagnosed during the first trimester of gestation. Of these, 30 patients (age range, 23-43 years; median=36 years; gestational age, 2-12 weeks; median=7 weeks; median follow-up time=6.5 years) met the inclusion criteria. The patients that were subjected to radical surgery (n=14) served as controls. None of the patients experienced perioperative surgical complications. No ILR were observed within three months (n=30), 1 year (n=27), and 5 years (n=18) after surgery. Among the study group, 4 (12.3%) patients experienced ILR or new carcinomas after 6-13 years, the same number (n=4) had metastatic dissemination after 3-7 years. These patients are still alive and disease-free after 14-17 years of follow-up. The rate of recurrences and metastasis in the controls were not significantly different. The findings provide evidence that BCS in the first trimester PrBC is feasible and reasonably safe for both the mother and the baby.

Breast Cancer Systemic Treatments and Upper Limb Lymphedema: A Risk-Assessment Platform Encompassing Tumor-Specific Pathological Features Reveals the Potential Role of Trastuzumab.

Breast cancer related lymphedema (BCRL) is frequent but strategies for an individualized risk assessment are lacking. We aimed to define whether tumor-specific pathological features, coupled with clinical and therapeutic data, could help identify patients at risk. Data from 368 patients with node-positive breast cancers were retrospectively collected, including 75 patients with BCRL (0.4⁻25.6 years follow-up). BCRL was assessed during the standard follow-up oncology visits using the circumferential measurement. Clinicopathologic and therapeutic factors associated with BCRL were integrated into a Cox proportional hazards regression model. Lymphovascular invasion (LVI) was more common in BCRL patients (n = 33, 44% vs. n = 85, 29%, p = 0.01), akin extra nodal extension (ENE) of the metastasis (n = 57, 76% vs. n = 180, 61%, p = 0.02). Sentinel lymph node excision without axillary dissection and extra-axillary radiotherapy were BCRL-unrelated. A higher number of BCRL-positive patients were treated with taxane-based chemotherapy with or without trastuzumab, compared to BCRL-negative patients (p < 0.01). Treatment with trastuzumab and/or taxanes, adjusted for systemic infections, laterality, therapy, and pathological features (i.e., LVI and ENE), had a significant impact in BCRL-free survival (p < 0.01). This work offers new insights on BCRL risk stratification, where the integration of clinical, therapeutic, and tumor-specific pathological data suggests a possible role of anti-human epidermal growth factor receptor 2 (HER2) therapy in BCRL pathogenesis.

Columnar Cell Lesion and Apocrine Hyperplasia of the Breast: Is There a Common Origin? The Role of Prolactin-induced Protein.

Noninvasive breast lesions encompass a heterogeneous group of risk indicators and nonobligate precursors of breast cancer, such as apocrine hyperplasia (AH) and columnar cell lesions (CCLs). Given the different expression of ER and ER-regulated genes in AH and CCL, these two alterations are currently considered discrete conditions. However, whether they share early biologic changes is not clear to date. Here, we sought to define the clinicopathologic and immunohistochemical features of a prospective series of combined lesions made up by CCLs and AH forming a continuum within single terminal duct-lobular units. The study group included 19 cases, whereas 25 cases of synchronous contiguous CCLs and AH served as control group. The different components of each case were subjected to immunohistochemical analysis for ER, PR, AR, HER2, BCL2, CCND1, MUC1, and PIP. Although CCLs and AHs arising in continuity showed opposite patterns of ER expression, the PIP-positive apocrine signature was consistently present in both components. In conclusion, apocrine changes are highly recurrent in CCLs growing within foci of AH, regardless of the ER activation. Our results suggest that PIP-positive and PIP-negative CCLs are likely to represent biologically distinct conditions and that apocrine changes might occur earlier than ER activation in the natural history of breast precursor lesions.

Lymphovascular invasion and extranodal tumour extension are risk indicators of breast cancer related lymphoedema: an observational retrospective study with long-term follow-up.

BACKGROUND: Breast cancer related lymphoedema (BCRL) occurs in a substantial proportion of breast cancer survivors and is a major contributor to patients' disability. Regrettably, there are no validated predictive biomarkers, diagnostic tools, and strong evidence-supported therapeutic strategies for BCRL. Here, we provide an integrative characterization of a large series of women with node-positive breast cancers and identify new bona fide predictors of BCRL occurrence. METHODS: Three hundred thirty-two cases of surgically-treated node-positive breast cancers were retrospectively collected (2-10.2 years of follow-up). Among them, 62 patients developed BCRL. To identify demographic and clinicopathologic features related to BCRL, Fisher's exact test or Chi-squared test were carried out for categorical variables; the Wilcoxon rank-sum was employed for continuous variables. Factors associated with BCRL occurrence were assessed using a Cox proportional hazards regression model. RESULTS: En-bloc dissection of the axillary lymph nodes but not the type of breast surgery impacted on BCRL development. Most of BCRL patients had a Luminal A-like neoplasm. The median number of lymph nodes involved by metastatic deposits was significantly higher in BCRL compared to the control group (p = 0.04). Both peritumoral lymphovascular invasion (LVI) and extranodal extension (ENE) of the metastasis had a negative impact on BCRL-free survival (p = 0.01). Specifically, patients with LVI and left side localization harboured 4-fold higher risk of developing BCRL, while right axillary nodes metastases with ENE increased the probability of BCRL compared to ENE-negative patients. CONCLUSIONS: Assessment of LVI and ENE should be integrated with clinical and surgical data to improve BCRL risk stratification.

Mismatch Repair Protein Loss as a Prognostic and Predictive Biomarker in Breast Cancers Regardless of Microsatellite Instability.

BACKGROUND: Breast cancers that harbor mismatch-repair (MMR) deficiency and/or microsatellite instability (MSI) might be sensitive to immune checkpoint blockade, but there are currently no specific guidelines for assessing MMR status in breast cancer. Here, we sought to define the clinical value of MMR immunohistochemistry (IHC) and MSI analysis in breast cancers. METHODS: We subjected 444 breast cancers to MMR IHC and MSI analysis. Cases were classified as MMR-proficient (pMMR), MMR-deficient (dMMR), and MMR-heterogeneous (hMMR) based on the loss of immunoreactivity; MSI was defined by instability in the five indicators recommended by the National Cancer Institute for endometrial and colorectal cancers. Correlation of MMR status with patients' survival was assessed using the Kaplan-Meier estimator. Statistical tests were two-sided. RESULTS: Loss of MMR proteins was homogeneous (dMMR) in 75 patients (17%) and heterogeneous (hMMR) in 55 (12%). Among luminal breast cancers, there were similar frequencies of dMMR and hMMR tumors. Overall, the rate of discrepancy between IHC and MSI analysis was high (91%). Women with Luminal B-like dMMR carcinomas (n = 44) showed shorter overall survival (median = 77 months, range = 0-115 months) than those with pMMR (n = 205) or hMMR (n = 35) tumors (median = 84 months, range = 0-127 months) (P = .008). On the contrary, patients with estrogen receptor-negative breast cancers treated with chemotherapy lived longer in cases of dMMR (n = 9) than pMMR (n = 33) or hMMR (n = 7) tumors, with 87 months of median survival (range = 73-123 months) for the former compared with 79 months (range = 8-113 months) for the latter two categories (P < .001). CONCLUSIONS: Immunohistochemistry and MSI are not interchangeable tests in breast carcinomas. MMR protein loss is a more common event than MSI and shows intra-tumor heterogeneity. MMR IHC allows the identification of clinically relevant subclasses of breast cancer patients, provided that multiple areas of the tumor are analyzed.

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers.

Targeted therapies against the human epidermal growth factor receptor 2 (HER2) have radically changed the outcome of patients with HER2-positive breast cancers. However, a minority of cases displays a heterogeneous distribution of HER2-positive cells, which generates major clinical challenges. To date, no reliable and standardized protocols for the characterization and quantification of HER2 heterogeneous gene amplification in large cohorts have been proposed. Here, we present a high-throughput methodology to simultaneously assess the HER2 status across different topographic areas of multiple breast cancers. In particular, we illustrate the laboratory procedure to construct enhanced tissue microarrays (TMAs) incorporating a targeted mapping of the tumors. All TMA parameters have been specifically optimized for the silver in situ hybridization (SISH) of formalin-fixed paraffin-embedded (FFPE) breast tissues. Immunohistochemical analysis of the prognostic and predictive biomarkers (i.e., ER, PR, Ki67, and HER2) should be performed using automated procedures. A customized SISH protocol has been implemented to allow a high-quality molecular analysis across multiple tissues that underwent different fixation, processing, and storage procedures. In this study, we provide a proof-of-principle that specific DNA sequences could be localized simultaneously in distinct topographic areas of multiple and heterogeneously processed breast cancers using an efficient and cost-effective method.

Videothoracoscopic approach to stage I non-small cell lung cancer.

AIM: Aim of this study is to evaluate the validity of videothoracoscopic staging and treatment in a twenty-year-long series of 286 VATS lobectomies for Clinical Stage I NSCLC. MATERIAL OF STUDY: We retrospectively reviewed 1549 candidates to resection after conventional staging from November 1991 to December 2013, and routinely submitted to videothoracoscopy immediately before the procedure. Patients deemed operable at videoexploration were resected by thoracoscopy or thoracotomy. Out of 534 VATS resections 286 thoracoscopic lobectomies for clinical stage I cancers were performed with strict indications and standardized technique; more advanced tumours were converted even when thoracoscopically resectable. Impact of preliminary videothoracoscopy and and longterm Kaplan-Meier survival was analyzed. RESULTS AND DISCUSSION: Out of 1549 patients, videothoracoscopy disclosed inoperability in 62 (4 %), mostly for pleural carcinosis (33pts.-2.1%) or mediastinal infiltration (22pts-1.4%). 534 (34.5%) patients had videothoracoscopic resection (286 lobectomies, 7 pneumonectomies, 241 wedge resections), 919 (59.3%) had thoracotomy resection, 34 (2.2%) had an exploratory thoracotomy (ET). Thoracoscopy had an accuracy rate of 72.4%, was reliable in excluding unresectability (NPV 0.95), and decreased the rate of ETs to 2.1%, ,sparing 596 (38.5%) thoracotomies. There was no intraoperative mortality or recurrence. Stage I patients had 83.8% 3-yr survival and 64.3% 5-yr survival. Five-year survival was significantly better (p=0.004) for T1N0 patients (70%) than T2N0 (55%) and for patients younger than 55 (86.4%) or with lesion < 2 cm (80.8%). CONCLUSIONS: Preliminary videothoracoscopy reliably assesses tumor resectability and feasibility of thoracoscopic resection, limiting unnecessary thoracotomies. Videolobectomies are safe and survival is comparable to open lobectomy. KEY WORDS: Lobectomy, Lung cancer, Minimally invasive surgery, Thoracoscopy, VATS.

Routine surgical videothoracoscopy as the first step of the planned resection for lung cancer.

OBJECTIVES: Notwithstanding preoperative staging, a number of procedures still end in an exploratory thoracotomy as a result of unexpected findings. The aim of this work is to evaluate the validity of routine videothoracoscopy, performed as the first step of every planned resection for non-small cell lung cancer, to assess tumor resectability and feasibility of the resection through thoracoscopy. METHODS AND RESULTS: From November 1991 to December 2007, in our department, 1306 patients with non-small cell lung cancer, judged operable at conventional staging, underwent videothoracoscopy before the operation. Thoracoscopy revealed inoperability in 58 (4.4%) patients, mostly owing to pleural dissemination (2.5%) or mediastinal infiltration (1.7%). In the remaining 1248 (95.6%), thoracoscopy did not reveal inoperability. Of these, 449 (34.4%) underwent thoracoscopic resection. The other 799 (61.2%) underwent thoracotomy: 767 underwent resection, but 32 (2.5%) had an exploratory thoracotomy. Thoracoscopy had suggested unresectability in 7 (0.5%) patients, had been incompletely carried out in 4 (0.3%), and was unfeasible in 21 (1.6%) owing to insurmountable technical reasons. In our previous series from 1980 to 1991 the exploratory thoracotomy rate had been 11.6%. In the present series, after the introduction of routine thoracoscopy in the staging process, the exploratory thoracotomy rate was 2.5%. Thoracoscopy was reliable in excluding unresectability (negative predictive value 0.97). The global percentage of correct staging was significantly better (P < .0001) by thoracoscopy (73.3%) than by computed tomography (48.7%). Considering T descriptor, video-assisted thoracic surgery correctly matched with final pathologic staging in 96.2% of patients. CONCLUSIONS: Routine preliminary videothoracoscopy ensured assessment of tumor resectability and feasibility of the resection through thoracoscopy and limited unnecessary thoracotomies.

Tracheal sleeve pneumonectomy: long-term outcome.

Selected primary lung cancers less than 2cm from the carina or invading the tracheo-bronchial angle, formerly considered inoperable, can be amenable to tracheal sleeve pneumonectomy (TSP). Such a delicate technique, can entail remarkable post-operative morbidity and mortality, and only few clinical series are reported. Purpose of this paper is to examine complications and long-term survival of our personal series and those reported in literature. At our academic department from 1983 to December 2004, out of 99 patients with NSCLC less than 2cm from the carina, 35 (35.4%) were deemed inoperable after conventional staging; the remaining 64 underwent surgery. Since 1993 in every patient with lung cancer we perform a thoracoscopic exploration as the first step of the intervention. Unexpected causes of inoperability were found at thoracotomy in nine patients (14.1%) and at thoracoscopy in two other patients. Of the remaining 53 patients, 52 had a right TSP and one a left TSP. Intraoperative mortality was nil. Perioperative mortality was 7.5%. Major complications occurred in 11.3% of the patients. Thirty (56.6) patients are alive and disease-free 23-97 months after surgery; for 18 (33.4%) of these, more than 5 years have elapsed after the operation. TSP is the only concrete option for treating lung cancer originating less than 2 cm from the carina. The review of our experience and of other reported series suggests that, with careful selection of patients and meticulous surgical technique, operative mortality and complications are acceptable. Long-term survival and prognosis are encouraging.