The Role of Oncogenic Viruses in the Pathogenesis of Sporadic Breast Cancer: A Comprehensive Review of the Current Literature.

Breast cancer is the most common malignancy in the female sex; although recent therapies have significantly changed the natural history of this cancer, it remains a significant challenge. In the past decade, evidence has been put forward that some oncogenic viruses may play a role in the development of sporadic breast cancer; however, data are scattered and mostly reported as sparse case series or small case-control studies. In this review, we organize and report current evidence regarding the role of high-risk human papillomavirus, mouse mammary tumor virus, Epstein-Barr virus, cytomegalovirus, bovine leukemia virus, human polyomavirus 2, and Merkel cell polyomavirus in the pathogenesis of breast cancer.

Identification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms.

The existing Intraductal Papillary Mucinous Neoplasm (IPMN) risk stratification relies on clinical and histological factors, resulting in inaccuracies and leading to suboptimal treatment. This is due to the lack of appropriate molecular markers that can guide patients toward the best therapeutic options. Here, we assess and confirm subtype-specific markers for IPMN across two independent cohorts of patients using two Spatial Transcriptomics (ST) technologies. Specifically, we identify HOXB3 and ZNF117 as markers for Low-Grade Dysplasia, SPDEF and gastric neck cell markers in borderline cases, and NKX6-2 and gastric isthmus cell markers in High-Grade-Dysplasia Gastric IPMN, highlighting the role of TNFα and MYC activation in IPMN progression and the role of NKX6-2 in the specific Gastric IPMN progression. In conclusion, our work provides a step forward in understanding the gene expression landscapes of IPMN and the critical transcriptional networks related to PDAC progression.

Ovarian endometrioid carcinoma with a sex cord-like pattern: a morphological, immunohistochemical, and molecular analysis.

Sex cord-like endometrioid carcinoma (SCLEC) is an uncommon entity which may constitute a diagnostic challenge. This study aimed to perform a clinicopathological, immunohistochemical, and molecular reappraisal of ovarian SCLEC. Consecutive ovarian SCLECs cases from a single institution were reviewed during a 13-year period. Twenty-three immunohistochemical markers were tested; 10 genes were analyzed by next-generation sequencing. Nine cases of ovarian SCLEC were identified. Mean patient age was 65.7 years; three cases showed extraovarian extension. Architectural pattern included sertoliform (n = 2), granulosa-like (n = 2), and mixed granulosa-like/sertoliform (n = 5). Eosinophilic changes accompanied by increased nuclear atypia were observed in four tumors. Endometrioid features (glands, squamous/morular differentiation) were observed in six cases. Most tumors were positive for cytokeratin-7 (8/9), EMA (9/9), estrogen and progesterone receptor (9/9), CD10 (7/9, including a luminal pattern reminiscent of mesonephric neoplasms), nuclear ß-catenin (8/9), and CDX2 (8/9). A minority of cases showed block-type p16 pattern (2/9), PAX8-positivity (3/9), and non-diffuse positivity for WT1 (1/9), inhibin (1/9), chromogranin (1/9), and synaptophysin (2/9). All cases were negative for GATA3, TTF1, calretinin, and SF1. Ki67 range was 15-90%. Six cases showed CTNNB1 exon 3 mutation. Eight cases were of "no specific molecular profile" (NSMP) and one was p53-abnormal. In conclusion, SCLECs frequently exhibit a mixed sertoliform/granulosa-like architecture and express epithelial markers, hormone receptors, nuclear ß-catenin, and CDX2, with luminal CD10 positivity and CTNNB1 mutations. PAX8 expression is often lost, while other mesonephric, sex cord, and neuroendocrine markers are negative.

The emerging and challenging role of PD-L1 in patients with gynecological cancers: An updating review with clinico-pathological considerations.

Over recent years, there has been significant progress in the development of immunotherapeutic molecules designed to block the PD-1/PD-L1 axis. These molecules have demonstrated their ability to enhance the immune response by prompting T cells to identify and suppress neoplastic cells. PD-L1 is a type 1 transmembrane protein ligand expressed on T lymphocytes, B lymphocytes, and antigen-presenting cells and is considered a key inhibitory checkpoint involved in cancer immune regulation. PD-L1 immunohistochemical expression in gynecological malignancies is extremely variable based on tumor stage and molecular subtypes. As a result, a class of monoclonal antibodies targeting the PD-1 receptor and PD-L1, known as immune checkpoint inhibitors, has found successful application in clinical settings. In clinical practice, the standard method for identifying suitable candidates for immune checkpoint inhibitor therapy involves immunohistochemical assessment of PD-L1 expression in neoplastic tissues. The most commonly used PD-L1 assays in clinical trials are SP142, 28-8, 22C3, and SP263, each of which has been rigorously validated on specific platforms. Gynecologic cancers encompass a wide spectrum of malignancies originating from the ovaries, uterus, cervix, and vulva. These neoplasms have shown variable response to immunotherapy which appears to be influenced by genetic and protein expression profiles, including factors such as mismatch repair status, tumor mutational burden, and checkpoint ligand expression. In the present paper, an extensive review of PD-L1 expression in various gynecologic cancer types is discussed, providing a guide for their pathological assessment and reporting.

Invasive lobular carcinoma metastasis to pancreas mimicking pancreatic signet ring cell carcinoma: A case report and systematic review of the literature.

Metastasis to the gastrointestinal tract is a rare instance in the natural history of breast cancer, usually in association with lobular histology and widespread dissemination of disease. We report the case of a 74-year-old woman with a history of invasive lobular carcinoma presenting with a pancreatic metastasis mimicking a primary pancreatic adenocarcinoma; we also present a systematic review of the relevant literature. The presentation of pancreatic metastasis in the setting of breast cancer is unspecific, and histology is of paramount importance for a correct diagnosis; surgical metastasectomy could be of some benefit in the correct clinical setting.

Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Endometrial Cancer: A Review on Immunohistochemistry Staining Patterns and Clinical Implications.

Among the four endometrial cancer (EC) TCGA molecular groups, the MSI/hypermutated group represents an important percentage of tumors (30%), including different histotypes, and generally confers an intermediate prognosis for affected women, also providing new immunotherapeutic strategies. Immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6 and PMS2) has become the optimal diagnostic MSI surrogate worldwide. This review aims to provide state-of-the-art knowledge on MMR deficiency/MSI in EC and to clarify the pathological assessment, interpretation pitfalls and reporting of MMR status.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) Applied to Platinum-Resistant Recurrence of Ovarian Tumor: A Single-Institution Experience (ID: PARROT Trial).

BACKGROUND: We aimed to investigate the therapeutic efficacy and safety of Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in platinum-resistant recurrence of ovarian cancer and peritoneal carcinomatosis, while our secondary endpoint was to establish any changes in quality of life estimated via the EORTC QLQ-30 and QLQ-OV28 questionnaires. METHODS: In this monocentric, single-arm, phase II trial, women were prospectively recruited and every 28-42 days underwent courses of PIPAC with doxorubicin 2.1 mg/m2 followed by cisplatin 10.5 mg/m2 via sequential laparoscopy. RESULTS: Overall, 98 PIPAC procedures were performed on 43 women from January 2016 to January 2020; three procedures were aborted due to extensive intra-abdominal adhesions. The clinical benefit rate (CBR) was reached in 82% of women. Three cycles of PIPAC were completed in 18 women (45%), and 13 (32.5%) and 9 (22.5%) patients were subjected to one and two cycles, respectively. During two PIPAC procedures, patients experienced an intraoperative intestinal perforation. There were no treatment-related deaths. Nineteen patients showed no response according to the Peritoneal Regression Grading Score (PRGS) and 8 patients showed minor response according to the PRGS. Median time from ovarian cancer relapse to disease progression was 12 months (95% confidence interval [CI] 6.483-17.517), while the median overall survival was 27 months (95% CI 20.337-33.663). The EORTC QLQ-28 and EORTC QLQ-30 scores did not worsen during therapy. CONCLUSIONS: PIPAC seems a feasible approach for the treatment of this subset of patients, without any impact on their quality of life. Since this study had a small sample size and a single-center design, future research is mandatory, such as its application in addition to systemic chemotherapy.

Prognostic Value of Mandard's Tumor Regression Grade (TRG) in Post Chemo-Radiotherapy Cervical Cancer.

In locally advanced cervical cancer (LACC), definitive chemo-radiotherapy is the standard treatment, but chemo-radiotherapy followed by surgery could be an alternative choice in selected patients. We enrolled 244 patients affected by LACC and treated with CT-RT followed by surgery in order to assess the prognostic role of the histological response using the Mandard scoring system. Results: A complete pathological response (TRG 0) was observed in 118 patients (48.4%), rare residual cancer cells (TRG2) were found in 49 cases (20.1%), increased number of cancer cells but fibrosis still predominating (TRG3) in 35 cases (14.3%), and 42 (17.2%) were classified as non-responders (TRG4-5). TRG was significantly associated with both OS (p < 0.001) and PFS (p < 0.001). The survival curves highlighted two main prognostic groups: TRG1-TRG2 and TRG3-TRG4-5. Main responders (TRG1-2) showed a 92% 5-year overall survival (5y-OS) and a 75% 5-year disease free survival (5y-DFS). Minor or no responders showed a 48% 5y-OS and a 39% 5y-DFS. The two-tiered TRG was independently associated with both DFS and OS in Cox regression analysis. Conclusion. We showed that Mandard TRG is an independent prognostic factor in post-CT/RT LACC, with potential benefits in defining post-treatment adjuvant therapy.

Immunohistochemical Evaluation of the Expression of Specific Membrane Antigens in Patients with Pancreatic Ductal Adenocarcinoma.

(1) Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. The lack of validated disease biomarkers makes timely diagnosis challenging in most cases. Cell membrane and surface proteins play a crucial role in several routes of oncogenesis. The aim of this study was to evaluate the expression of six membrane antigens on PDAC (CA 19-9, mucin 1 and 4 (MUC1, MUC4), mesothelin (MSLN), Annexin A10 (ANXA10), Glypican-1 (GPC-1)) and their correlation with oncologic outcomes. (2) Methods: Immunohistochemical staining for CA 19.9, MUC1, MUC4, MSLN, ANXA10, and GPC-1 of surgical samples of 50 consecutive patients with PDAC was performed. Antigen expression for tumor, ductal, and acinar tissues was classified according to the histo-score (H-score) by two pathologists. (3) Results: Recurrence rate was 47% and 18 patients (36%) deceased (median follow-up 21.5 months). Immunostaining for CA 19-9 and MUC1 showed a significantly higher expression in the neoplastic tissue compared to non-tumor ductal and acinar tissues (p < 0.001). MUC4, MSLN, ANXA10, and GPC-1 were selectively expressed in the neoplastic tissue (p < 0.001). A CA 19-9 H-score value >270 was independently associated with a worse overall survival (p = 0.05) and disease-free survival (p = 0.05). (4) Conclusions: CA 19-9 and MUC1 are highly expressed in PDAC cells. The histological expression of CA 19-9 may predict prognosis. MUC4, MSLN, ANXA10, and GPC-1 are selectively expressed by neoplastic tissue and may represent a potential histological biomarker of disease.

The Role of Plasma Cells as a Marker of Chronic Endometritis: A Systematic Review and Meta-Analysis.

Chronic endometritis (CE) is the persistent inflammation of the endometrial lining associated with infertility and various forms of reproductive failures. The diagnosis of CE is based on the histological evidence of stromal plasma cells; however, standardized methods to assess plasma cells are still lacking. In the present paper, we aimed to determine the most appropriate plasma cell threshold to diagnose CE based on pregnancy outcomes. Three electronic databases were searched from their inception to February 2022 for all studies comparing pregnancy outcomes between patients with CE and patients without CE. The relative risk (RR) of pregnancy, miscarriage, and/or live birth rates were calculated and pooled based on the plasma cell threshold adopted. A p-value < 0.05 was considered significant. Nine studies adopting different thresholds (1 to 50 plasma cells/10 HPF) were included. In the meta-analysis, we only found a significant association between miscarriage rate and a plasma cell count ≥ 5/10 HPF (RR = 2.4; p = 0.007). Among studies not suitable for meta-analysis, CE showed an association with worsened pregnancy only when high thresholds (10 and 50/10 HPF) were adopted. In conclusion, our study suggests that the presence of plasma cells at low levels (<5/10 HPF) may not predict worsened pregnancy outcomes. Based on these findings, a threshold of ≥5 plasma cells/10 HPF may be more appropriate to diagnose CE.

Corded and hyalinized endometrioid carcinoma: Summary of clinical, histological, immunohistochemical and molecular data.

Corded and hyalinized endometrioid carcinoma (CHEC) represents a potential pitfall for pathologists. This study aimed to provide a complete overview of all clinicopathological and molecular features of CHEC. Electronic databases were searched for all published series of CHEC. Clinical, histological, immunohistochemical and molecular data about CHEC were extracted and pooled. Six studies with 62 patients were identified; mean age was 49.8 years (range 19-83). Most cases showed FIGO stage I (68%), low grade (87.5%), and a favorable outcome (78.4%), with "no specific molecular profile" (NSMP). A subset of cases showed high-grade features (12.5%), p53 abnormalities (11.1%) or mismatch repair (MMR) deficiency (20%) and occurred at an older age (mean age>60 years). Common features of CHEC were: superficial localization of the corded component (88.6%), squamous/morular differentiation (82.5%), nuclear ß-catenin accumulation (92%), partial/total loss of CKAE1/AE3 (88.9%), estrogen receptor (95.7%) and e-cadherin (100%), stromal changes such as myxoid (38.5%), osteoid (24%) and chondroid (4.5%), CTNNB1 mutations (57.9%), and POLE-wild-type (100%); 24.4% of cases showed lymphovascular space invasion. A minority of cases (16.2%) showed poor outcome despite a low-grade, NSMP phenotype; the molecular basis for the aggressiveness of these cases is still undefined. Further studies are necessary in this field.

Evaluating the Risk of Inguinal Lymph Node Metastases before Surgery Using the Morphonode Predictive Model: A Prospective Diagnostic Study in Vulvar Cancer Patients.

Ultrasound examination is an accurate method in the preoperative evaluation of the inguinofemoral lymph nodes when performed by experienced operators. The purpose of the study was to build a robust, multi-modular model based on machine learning to discriminate between metastatic and non-metastatic inguinal lymph nodes in patients with vulvar cancer. One hundred and twenty-seven women were selected at our center from March 2017 to April 2020, and 237 inguinal regions were analyzed (75 were metastatic and 162 were non-metastatic at histology). Ultrasound was performed before surgery by experienced examiners. Ultrasound features were defined according to previous studies and collected prospectively. Fourteen informative features were used to train and test the machine to obtain a diagnostic model (Morphonode Predictive Model). The following data classifiers were integrated: (I) random forest classifiers (RCF), (II) regression binomial model (RBM), (III) decisional tree (DT), and (IV) similarity profiling (SP). RFC predicted metastatic/non-metastatic lymph nodes with an accuracy of 93.3% and a negative predictive value of 97.1%. DT identified four specific signatures correlated with the risk of metastases and the point risk of each signature was 100%, 81%, 16% and 4%, respectively. The Morphonode Predictive Model could be easily integrated into the clinical routine for preoperative stratification of vulvar cancer patients.

Recent Advances in Cervical Cancer Management: A Review on Novel Prognostic Factors in Primary and Recurrent Tumors.

BACKGROUND: Several pathological parameters, including tumor size, depth of stromal invasion, lympho-vascular space invasion and lymph node status, have been proposed as prognostic predictors in cervical cancer. However, given the high mortality and recurrence rate of cervical cancer, novel parameters that are able to provide additional prognostic information are needed in order to allow a better prognostic stratification of cervical cancer patients. METHODS: A search was conducted on PubMed to identify relevant literature data regarding prognostic factors in cervical cancer. The key words "cervical cancer", "prognostic factors", "pathology", and "outcome" were used. RESULTS: The novel pathological grading system based on tumor budding and cell nest size appeared the most relevant prognostic factor in primary neoplasms. Moreover, other potentially useful prognostic factors were tumor size, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes. Prognostic factors related to advanced-stage cervical cancer, including lymph-nodes status, endometrial and cervical involvement as well as distant metastases, were also taken into consideration. CONCLUSIONS: According to our findings, tumor budding and cell nest size grading system, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes appeared the most relevant factors included in the pathology report.

Different Phases of Disease in Lymphocytic Myocarditis: Clinical and Electrophysiological Characteristics.

BACKGROUND: Endomyocardial biopsy (EMB) is required to make a definite diagnosis of lymphocytic myocarditis (LM), to identify its etiology, and to classify LM into different phases. OBJECTIVES: This study aims to characterize and compare clinical and electrophysiological characteristics of different biopsy-proven LM phases, namely acute myocarditis (AM), chronic active myocarditis (CAM), and healed myocarditis (HM). METHODS: All patients with a diagnosis of LM at 3 Italian referral centers were prospectively enrolled. According to EMB findings, LM was classified as AM, CAM, or HM; per-group comparisons of clinical presentations, noninvasive, and invasive findings are reported. RESULTS: Among the 122 enrolled patients (AM, n = 44; CAM, n = 42; HM, n = 36), complex ventricular arrhythmias were very common overall (n = 109, 89%), but ventricular fibrillation was slightly more prevalent in AM (P = 0.028). Cardiac magnetic resonance imaging showed late gadolinium enhancement in more patients with HM and CAM than AM (94.4% vs 92.9% vs 50%; P < 0.001), whereas edema was more common in AM than in CAM, being absent in HM (90.9% vs 50% vs 0%; P < 0.001). Accordingly, edema was the strongest independent clinical predictor of EMB-proven active inflammation. Electroanatomical mapping revealed a lower prevalence of low-voltage areas in AM than in CAM or HM. We observed a strong association between edema at a specific myocardial segment and normal voltages at that site (odds ratio: 0.24; 95% CI: 0.10-0.54; P < 0.01), as well as between late gadolinium enhancement and low-voltage areas (odds ratio: 2.86; 95% CI: 1.19-6.97; P = 0.019). CONCLUSIONS: LM is a highly heterogeneous disease, and its different phases are characterized by diverse clinical, morphological, and electrophysiological features. Further research is required to identify electroanatomical markers of inflammation.

One biopsy, two tumors: A case report of collision tumor consisting in breast and endometrioid carcinoma detected on bioptic sample of peritoneal carcinomatosis.

Collision tumors are rare and very few cases were described in which collision was revealed in a metastatic lesion. Herein we report a case of woman with a peritoneal carcinomatosis underwent to bioptic procedure in correspondence of a nodule of Douglas peritoneum with clinical suspect of ovarian/uterine origin. Histologic examination revealed two different colliding epithelial neoplasms: an endometrioid carcinoma and a ductal breast carcinoma, the latter not suspected at the time of biopsy. Morphology and immunohistochemistry, in particular GATA3 and PAX8, defined clearly the two different colliding carcinomas.

Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study.

BACKGROUND: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. METHODS: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. FINDINGS: 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36-2·17]; p=0·71). INTERPRETATION: This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. FUNDING: Swiss Cancer Research foundation.

Human papillomavirus independent status on pathologic response and outcomes in locally advanced cervical cancer managed with chemoradiotherapy followed by surgery.

OBJECTIVE: While human papillomavirus (HPV) has been shown to play a significant role in cervical cancer carcinogenesis (HPV associated cases), a considerable percentage of cervical cancers occur independently of HPV status (HPV independent). METHODS: In this retrospective study of 254 locally advanced cervical cancer patients treated with chemoradiotherapy and radical surgery, HPV genotypes were determined using the Anyplex II HPV28 kit that uses multiplex, real time polymerase chain reaction technology. The primary endpoints of this study were to evaluate the complete response to chemoradiotherapy (pathologic complete response), the presence of microscopic (<3 mm, pathologic micro partial response, group 1) and macroscopic (>3 mm, pathologic macro partial response, group 2) residual carcinoma in the cervix, and the persistence of metastatic lymph nodes (group 3) in HPV independent cervical cancers. Secondary endpoints were evaluation of disease-free survival and overall survival. RESULTS: Of 254 patients studied, 21 cases (8.3%) of cervical cancer were determined to be HPV independent. The percentage of pathologic complete response was found to be higher in the HPV associated group compared with the HPV independent group (p<0.001). In the HPV associated cervical cancer group, 5 year disease free survival was found to be 80.8% versus 59.9% in the HPV independent group (p=0.014). Overall survival was also higher in the HPV associated group (87.9%) compared with the HPV independent patients (69.4%) (p=0.023). In the multivariate analysis, the International Federation of Gynecology and Obstetrics (FIGO) stage and HPV genotypes maintained their relevant impact on pathologic complete response to chemoradiotherapy: FIGO stages IIIC1 and IIIC2 were associated with a 13-fold increased risk for the presence of metastatic lymph nodes compared with group 1 (p<0.001). HPV independent cervical cancers showed the highest risk for the development of macroscopic/stable disease (p=0.007), and persistence of metastatic lymph nodes (p=0.004) versus group 1, respectively. CONCLUSIONS: This study showed that HPV status at diagnosis could be a relevant factor for clinical outcomes in locally advanced cervical cancer patients.