ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease.

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

Potential histological discordance revealed by second review in the national rare gynecological cancer network (TMRG).

INTRODUCTION: Since 2010, the network of rare malignant tumors of the ovary (TMRG) was developed to optimize the management of patients, also allowing a histological second opinion of rare ovarian tumors. The aim of this work was to study the contribution of second opinion to improve histological diagnostic accuracy on ovarian rare malignant tumors included in the TMRG database. MATERIAL AND METHODS: Histological data of patients diagnosed with a rare ovarian tumor included in TMRG network over a one-year period (2018) were collected. Initial diagnoses were compared with second opinion from national gynecological pathologist experts. The modalities of histological second opinion requests were studied, as well as the histological characteristics of the tumors. The discordances were classified as minor (if the modification of histological diagnosis did not change patient management) and major (if the patient management can be modified). RESULTS: Of 1185 included patients, 937 matched the inclusion criteria. Full concordance between primary diagnosis and expert second opinion was reached in 611 cases (65,3%), minor discordance was seen in 114 (12,2%) and major discordance in 209 (22,3%) of cases. In systematic review requested by the network, 26% (n = 137) of cases were reported with a change in histological diagnosis, while the change concerned 44% (n = 186) of cases for a second opinion spontaneously requested by the initial pathologist. The discrepancies concerned all categories of ovarian tumors, with a majority of mucinous tumors (43% of major discordances), followed by stromal and sex-cord tumors (13.8% of major discordances) and clear cell tumors (12,4% of major discordances). CONCLUSION: This analysis confirms the diagnostic difficulty of ovarian tumors, due to their rarity and morphological heterogeneity. French pathologists are aware of these difficulties and spontaneously refer ovarian tumors with unusual histology for a second opinion and collaborate with rare tumor networks for systematic review.

Agenesis: pilot case report by 2.9 mm implant.

The agenesis of the upper lateral incisor is one of the most frequent aesthetic-functional problems in dentistry. The reported case concerns a 49 years old male patient with bilateral agenesis of teeth 1.2-2.2 and a root stump of tooth 5.2 temporarily rehabilitated through a Maryland bridge. Without orthodontic treatment, the only solution for implant-prosthetic rehabilitation of tooth 1.2 results therefore in the use of a 2.9 mm diameter implant. The clinical and radiographic control of the implant and the gingival stability at a distance of 1 year gives a positive result both clinically and radiographically. The use of the implant with a 2.9 mm diameter is therefore indicated in extreme cases of limited bone availability.

Tooth agenesis: part 1. Incidence and diagnosis in orthodontics.

Dental agenesis has a great clinical significance due to its frequency during daily practice and the therapeutic problems that can arise from it. This paper will explore the incidence of dental agenesis, its diagnosis and how this anomaly affects the teeth differently. The second subsequent paper will look at its treatment and management.

Adipose tissue-derived mesenchymal stromal cells for clinical application: An efficient isolation approach.

PURPOSE OF THE STUDY: Mesenchymal stromal cells (MSCs) are considered a promising tool for cell therapy approaches. The translation of research-based cell culture protocols into procedures that comply with Good Manufacturing Practice (GMP) is critical. The aim of this study was to design a new method for the expansion of MSCs from Adipose Tissue (AT-MSCs) in compliance with GMP, without enzymatic tissue digestion and without the use of animal proteins as source of growth factors. PATIENTS AND METHODS: MSCs were expanded from 10 periumbilical biopsies. Our new isolation approach is based on: (1) disruption of AT with an automated, closed system; (2) use of GMP-grade medium without the addition of fetal bovine serum or platelet lysate; (3) use of human recombinant Trypsin. AT-MSCs cultured in α-MEM and minced by scalpel were used as control. RESULTS: It was possible to expand MSCs from all the AT-samples for at least eight passages. MSCs displayed the typical spindle-shape morphology, a high viability, multilineage differentiation potential and high expression levels of the typical MSC-specific surface antigens and genes. Compared to standard method, MSCs obtained with the new method showed higher yield, up to passage 6, and higher purity in terms of percentage of CD34 and CD45 markers. All AT-MSCs exhibit in vitro immunosuppressive capacity and possess a normal karyotype. CONCLUSIONS: Our data clearly demonstrate that our new approach permits to generate AT-MSCs fully compliant for therapeutic use and better at least in terms of quantity and purity than those obtained with the standard method.

Networking for ovarian rare tumors: a significant breakthrough improving disease management.

BACKGROUND: Rare ovarian tumors represent >20% of all ovarian cancers. Given the rarity of these tumors, natural history, prognostic factors are not clearly identified. The extreme variability of patients (age, histological subtypes, stage) induces multiple and complex therapeutic strategies. METHODS: Since 2011, a national network with a dedicated system for referral, up to 22 regional and three national reference centers (RC) has been supported by the French National Cancer Institute (INCa). The network aims to prospectively monitor the management of rare ovarian tumors and provide an equal access to medical expertise and innovative treatments to all French patients through a dedicated website, www.ovaire-rare.org. RESULTS: Over a 5-year activity, 4612 patients have been included. Patients' inclusions increased from 553 in 2011 to 1202 in 2015. Expert pathology review and patients' files discussion in dedicated multidisciplinary tumor boards increased from 166 cases in 2011 (25%) to 538 (45%) in 2015. Pathology review consistently modified the medical strategy in 5-9% every year. The rate of patients' files discussed in RC similarly increased from 294 (53%) to 789 (66%). An increasing number (357 in 5 years) of gynecologic (non-ovarian) rare tumors were also registered by physicians seeking for pathological or medical advice from expert tumor boards. CONCLUSION: Such a nation-wide organization for rare gynecological tumors has invaluable benefits, not only for patients, but also for epidemiological, clinical and biological research.

HLA-G regulatory polymorphisms are associated with susceptibility to HCV infection.

BACKGROUND: Hepatitis C virus (HCV) is able to bypass the immune system modulating innate and adaptive immune response and blocking T helper 1 (Th1) cell production. Because the human leukocyte antigen (HLA)-G molecule has immunomodulatory properties inhibiting the function and production of natural killer and cytotoxic lymphocyte T cells, as well as promoting shift from Th1 toward Th2 response, we hypothesized its involvement in susceptibility to HCV infection. MATERIALS AND METHODS: Considering that HLA-G mRNA expression has been reported to be under genetic control, an association study was conducted analyzing 800 base pairs upstream the ATG at the 5'upstream regulator region (URR) and 850 base pairs from ATG to exon 3 and the 3'untranslated region (UTR) of HLA-G gene in Italian HCV-positive patients and uninfected controls. RESULTS: Four 5'URR polymorphisms (-725C>G>T, -509C>G, -400G>A and -398G>A), 7 polymorphisms at coding region (+15G>A, +36G>A, +243G>A, insC506, 531G>C, delA615 and 685G>A), the +644G>T polymorphism, and 1 haplotype (TTGTTCCIGAC) showed different frequency distributions between HCV patients and uninfected controls. CONCLUSION: The results from our study suggest a possible involvement of HLA-G in the risk modulation toward HCV infection.

MBL2 Genetic Variants in HCV Infection Susceptibility, Spontaneous Viral Clearance and Pegylated Interferon Plus Ribavirin Treatment Response.

Hepatitis C is disease that damages the liver, and it is caused by the hepatitis C virus (HCV). The pathology became chronic in about 80% of the cases due to virus persistence in the host organism. The standard of care consists of pegylated interferon plus ribavirin; however, the treatment response is very variable and different host/viral factors may concur in the disease outcome. The mannose-binding protein C (MBL) is a component of the innate immune system, able to recognize HCV and consecutively activating the immune response. MBL is encoded by MBL2 gene, and polymorphisms, two in the promoter region (H/L and X/Y) and three in exon 1 (at codon 52, 54 and 57), have been described as functionally influencing protein expression. In this work, 203 Italian HCV patients and 61 healthy controls were enrolled and genotyped for the five MBL2 polymorphisms mentioned above to investigate their role in HCV infection susceptibility, spontaneous viral clearance and treatment response. MBL2 polymorphisms were not associated with HCV infection susceptibility and with spontaneous viral clearance, while MBL2 O allele, O/O genotype, HYO haplotype and DP combined genotype (all correlated with low or deficient MBL expression) were associated with sustained virological response. Moreover, a meta-analysis to assess the role of MBL2 polymorphisms in HCV infection susceptibility was also performed: YA haplotype could be associated with protection towards HCV infection.

Transrenal E-XL stenting prior to EVAR in the case of abdominal aortic aneurysm associated to proximal aortic neck dissection.

Chronic dissection of proximal aortic neck is a rare occurrence in patients with abdominal aortic aneurysm (AAA) and a gold standard therapy has not been defined so far. Herein we report two successful cases of an original adjunctive procedure involving the transrenal placement of a self-expanding nitinol stent (E-XL aortic stent, Jotec GmbH, Germany) in order to fix a dissection flap in the aortic neck wall prior to the deployment of the bifurcated endograft. Primary technical success and midterm clinical success was achieved in both cases with freedom from any early or late reintervention. Scheduled follow-up angio-CT scans did not show any Type I endoleak, graft migration or renal/visceral arteries complications. According to these findings, patients with an AAA, presenting with a proximal neck with chronic dissection, can be safely and effectively treated by pre-emptive transrenal E-XL stenting and endovascular aneurysm repair.

[Breast cancer on a scar of excision of ectopic breast tissue: a case report]. / Cancer du sein sur la cicatrice d'exérèse d'un tissu mammaire ectopique: à propos d'un cas.

The cancerization of supernumerary breast is uncommon. So when this situation occurs, the diagnosis is often late. Cancers of ectopic breast tissue have been reported in the international literature, but to our knowledge, no cancer after excision of accessory breast gland has been published. This article describes a case of ectopic breast tissue cancer in axillary situation occurring several years after excision and details its specific diagnostic, therapeutic and prognosis.

Paraneoplastic polymyositis associated with breast cancer: a therapeutic emergency.

The association of polymyositis and cancer was first described in 1916, the most frequent cancers being mammary and gynecological for women, bronchopulmonary for men and digestive for both. This article reports a severe paraneoplastic polymyositis associated with breast cancer. The authors discuss its clinical, pathological and therapeutic particularities.

[Diabetic mastopathy: a recurrent benign breast disease]. / La mastopathie diabétique : une lésion mammaire bénigne sujette à récidive.

Diabetic mastopathy is an uncommon benign entity occurring in young women with type 1 diabetes. Its clinical and radiological signs are not specific and often mimic a breast carcinoma. However, the benign nature of this lesion is easily recognized on histological examination, visualizing dense keloid-like fibrosis, lymphocytic lobulitis and ductitis with lymphocytic perivascular inflammation, with or without epithelioid-like fibroblasts. Surgery can generally be avoided. The evolution of this entity is characterized by the risk of local growth, bilateralisation or recurrence after surgical treatment. We present a case in which the core biopsy allowed the diagnosis of a diabetic mastopathy and we discuss its clinical, diagnostic, pathological and therapeutic particularities.

[Breast fibromatosis: An uncommon benign breast disease]. / La fibromatose mammaire : une lésion bénigne peu connue.

Extra-abdominal fibromatosis is an uncommon benign breast lesion resembling an infiltrative carcinoma in its clinical and radiological presentation. Surgical excision with wide margins remains the treatment of choice to avoid recurrence of this locally aggressive tumor. We present a case in which surgical biopsy allowed the diagnosis of a breast fibromatosis and we discuss its clinical, diagnostic, pathological and therapeutic particularities.

[Most common benign epithelial breast diseases: diagnosis, treatment and cancer risk]. / Les principales lésions mammaires épithéliales bénignes et à risque. Prise en charge diagnostique et thérapeutique.

As a consequence of breast imaging development and increased interventional radiology, benign epithelial breast diseases (BEBD) represent a growing percentage of breast pathology diagnoses. BEBD include numerous entities such as cysts, fibrosis, adenosis, duct ectasia, which require neither surgery nor follow-up. Some BEBD have to be individualized (radial scars, papillomas, complex sclerosing adenosis, lobular intraepithelial neoplasia, flat epithelial atypia, atypical hyperplasia), being preinvasive lesions or markers of increased breast cancer risk, or being associated with suspect radiological aspect. BEBD should be managed in a pluridisciplinar way and correctly diagnosed by percutaneous biopsies or surgical specimens. The goals of surgery vary according to lesions. It always allows a complete surgical specimen analysis and therefore a search for atypical or cancerous cells. Surgery can also have a preventive role by reducing the risk of potential malignant transformation. Finally, it enables in some cases the excision of a radiologically suspect mass. So the aim of this review is to give a clinical and morphological description of most common BEBD, underlying their cancer risk, specific diagnosis, therapeutic, follow-up and psychological repercussions.

HBV, HCV, and TTV detection by in situ polymerase chain reaction could reveal occult infection in hepatocellular carcinoma: comparison with blood markers.

OBJECTIVE: To report a retrospective analysis on the presence of hepatitis B virus (HBV), hepatitis C virus (HCV), and transfusion transmitted virus (TTV) sequences in formalin fixed, paraffin embedded liver biopsies from eight patients with hepatocellular carcinoma, in comparison with blood markers. METHODS: A direct in situ polymerase chain reaction (PCR) technique was developed for the detection and localisation of genomic signals in the liver tissue. Conventional serological and molecular methods were used for blood evaluation. RESULTS: In situ PCR showed the presence of one of the three viruses (four HCV, two HBV, and one TTV) in seven of the eight patients. In addition, a co-infection with HBV and HCV was detected in one patient. HCV and HBV sequences were located in the cytoplasm and the nucleus, respectively. When compared with blood markers, these findings were compatible with one occult HBV and two occult HCV infections. CONCLUSIONS: These findings provide further evidence for occult HBV and HCV infections in cancerous tissues from patients with hepatocellular carcinomas. In situ PCR could be an additional tool for evaluating the viral aetiology of hepatocellular carcinoma alongside conventional diagnostic procedures.

Ultrasonographically-guided fine-needle aspiration of axillary lymph nodes: role in breast cancer management.

The knowledge of the status of axillary lymph nodes (LN) of patients with breast cancer is a fundamental prerequisite in the therapeutic decision. In the present work, we evaluated the impact of fine-needle aspiration cytology (FNAC) of ultrasonographically (US) selected axillary LN in the diagnosis of LN metastases and subsequently in the treatment of patients with breast cancer. Axillary US was performed in 298 patients with diagnosed breast cancer (267 invasive carcinomas and 31 ductal carcinoma in situ DCIS), and in 95 patients it was followed by FNAC of US suspicious LN. Smears were examined by routine cytological staining. Cases of uncertain diagnosis were stained in immunocytochemistry (ICC) with a combination of anticytokeratin and anti-HMFG2 antibodies. Eighty-five FNAC were informative (49 LN were positive for metastases, 36 were negative). In 49 of 267 patients with invasive breast carcinoma (18%), a preoperative diagnosis of metastatic LN in the axilla could be confirmed. These patients could proceed directly to axillary dissection. In addition, US-guided FNAC presurgically scored 49 out of 88 (55%) metastatic LN. Of all others, with nonsuspicious LN on US (203 cases including 31 DCIS), in which no FNAC examination was performed, 28 invasive carcinomas (16%) turned out to be LN positive on histological examination. Based on these data, US examination should be performed in all patients with breast cancer adding ICC-supported FNAC only on US-suspect LN. This presurgical protocol is reliable for screening patients with LN metastases that should proceed directly to axillary dissection or adjuvant chemotherapy, thus avoiding sentinel lymph node biopsy.

In situ polymerase chain reaction detection of transfusion-transmitted virus in liver biopsy.

The potential role of transfusion-transmitted virus (TTV) infection in determining liver damage is poorly understood and no information exists about TTV replication within hepatocytes. In this study, we assess TTV in situ PCR in liver tissue. Twenty-one patients with different degrees of liver damage were studied by both serum TTV-DNA detection and in situ TTV PCR analysis and extractive PCR in liver biopsy paraffin sections (FFPE). Extractive PCR and in situ PCR detected TTV-DNA both in serum and liver tissue of five patients. The presence of TTV in serum matched with that found in the liver and TTV sequences were never found independently in liver or serum. Four out of five TTV-DNA-positive patients have not other known cause of liver damage while in one a coinfection from HCV was observed. Our data indicate that in situ PCR appears to be a reliable tool for the detection of TTV-DNA in FFPE, and may help detecting unknown origin of liver damage.

[Rapid immunohistochemistry applied to intraoperative diagnosis: a critical analysis]. / Immunoistochimica rapida applicata alla diagnostica intraoperatoria: un'analisi critica.

A series of 1378 intra-operative frozen diagnoses performed in our department over two years (1998-1999) was studied in order to assess the agreement with the diagnosis on formalin-fixed, paraffin-embedded sections. In selected cases, a rapid immunostaining (IS) method was applied on frozen sections to solve diagnostic problems. Rapid IS allowed us to determine the histotype of poorly differentiated neoplasms, the origin of lung nodules and the presence of nests of neoplastic cells on resection margins. The method delayed the answer by about 20 minutes, and was always previously arranged with the surgeon. Rapid IS method was performed using routine reagents and was not repeated on formalin-fixed, paraffin-embedded sections of the same cases, thus avoiding additional costs.