Vaginal Intraepithelial Neoplasia (VaIN) after Hysterectomy Is Strongly Associated with Persistent HR-HPV Infection.

The data from the literature show that women undergoing a LEEP due to CIN3 have a greater risk of having subsequent high-grade anogenital intraepithelial neoplasia or cancer, and the risk is greater for vaginal cancer than for anal and vulvar cancers. It is hypothesized that the laparoscopic hysterectomy procedure may cause a higher incidence of VaIN in hysterectomized women. There are few studies addressing this issue, and they show mixed results. This study aimed to investigate the incidence of high-grade or severe VaIN in the population of women undergoing hysterectomy for CIN3 or benign uterine disease and illustrate the treatment options and follow-up. METHODS: This retrospective study was conducted on 170 women who underwent a laparoscopic hysterectomy due to high-grade cervical intraepithelial neoplasia (CIN3) or benign gynecological disease. The follow-up strategy included performing a cotest and colposcopy with biopsy if necessary. The median time between primary treatment and a diagnosis of high-grade VaIN was 18 months. RESULTS: High-grade or severe VaIN was found in eight patients after hysterectomy (4.7%). All cases of high-grade VaIN occurred in women with persistent HPV infection. The most frequent genotype was 16. Women hysterectomized due to CIN3 showed an eight-fold greater risk than women hysterectomized due to benign disease of developing high-grade VaIN. The risk of VaIN is low in women hysterectomized due to benign disease. The risk of developing VaIN is greater in women with viral persistence. CONCLUSION: All these elements suggest that it is a history of HPV-related disease of the lower genital tract and viral persistence, rather than hysterectomy itself, that should be considered risk factors for the development of high-grade VaIN. After hysterectomy, patients with a history of CIN should undergo annual screening with vaginal dome cytology and HPV testing.

Extended Genotyping to Stratify the Risk of CIN2+ in Women with Persistent HPV Infection, Negative Cytology and Type 3 Transformation Zone.

Persistent human papillomavirus (HPV) infection is recognized as a major risk factor for cervical cancer. Women with persistent HPV and negative cytology are at greater risk of CIN2+ than women with negative infection. The diagnosis becomes more complicated when the woman has a type 3 transformation zone at colposcopy. The aim of this study was to determine the prevalence of CIN2+ in women with persistent HPV, negative cytology and TZ3; how to stratify the risk of CIN2+; and what the best diagnostic strategy is, given TZ3. METHODS: In a multicenter retrospective cohort study, we enrolled women with negative cytology and TZ3 among the 213 women referred for colposcopy for persistent HPV. The average age of the women was 53 years; in particular, 83% were postmenopausal women. In the presence of a TZ3, the entire transformation zone cannot be explored, making colposcopy and targeted biopsy useless and inadequate, with great risks of underdiagnosis or missed diagnosis. Women with TZ3 underwent diagnostic LEEP to ensure correct diagnoses. RESULTS: The study highlighted 19% (16/84) of CIN2+ lesions, a higher frequency of non-HPV 16/18 genotypes (76.2%), and 50% of CIN2+ lesions being due to non-HPV 16/18 genotypes. Furthermore, more than half of the women (80.9%) had normal histopathological results in the LEEP sample. CONCLUSION: Women with viral persistence, negative cytology, and TZ3 have a 19% risk of CIN2+; genotyping helps stratify risk, but extensive genotyping is necessary instead of partial genotyping (16/18), referring to a population of women over 50 years old in which the prevalence of genotypes 16,18 decreases and the prevalence of other genotypes increases; diagnostic LEEP is excessive (only 16 cases of CIN2+ out of 48 cases treated), even though 83% of women had viral clearance after LEEP; p16/Ki67 double staining could be a potential risk marker, which would only highlight women at risk of CIN2+ to undergo LEEP. To individualize the diagnostic workup and treatment and minimize the risk of under diagnosis and overtreatment, future studies should explore the use of extended genotyping and new biomarkers for individual risk stratification.

Tumor-associated microenvironment, PD-L1 expression and their relationship with immunotherapy in glioblastoma, IDH-wild type: A comprehensive review with emphasis on the implications for neuropathologists.

Although novel knowledge has been acquired on the molecular landscape of glioblastoma (GBM), a relatively few steps forward have been made regarding its therapy. With the increasing use of novel immunotherapeutic drugs capable of stimulating the antitumor inflammatory response, in the last decades numerous studies aimed to characterize the tumor-associated microenvironment (TME) and its relationship with the immunogenicity of GBM. In this regard, although the tumor-associated microglia and macrophages (TAMs) and PD-L1/PD-1 axis have been emerged as one of the most relevant components of the GBM TME and one of the potential molecular pathways targetable with immunotherapy, respectively. It has been supposed that TAMs may acquire different phenotypes, switching from M1 to M2 phenotypes, with tumor-suppressive and tumor-stimulating role depending on the different surrounding conditions. PD-L1 is a type 1 transmembrane protein ligand expressed by T-cells, B-cells and antigen-presenting cells, with a main inhibitory checkpoint role on tumor immune regulation. While PD-L1 immunohistochemical expression has been extensively investigated in many cancers, its usefulness in the evaluation of GBM response rates to immunotherapy and its standardized evaluation by immunohistochemistry are still debated. The present review paper focuses on the current "state of the art" about the relationship between TME, PD-L1/PD-1 pathway and immunotherapy in GBM, also providing neuropathologists with an updated guide about the clinical trials conducted with PD-L1 and PD-1 inhibitors.

Brain Metastases from Breast Cancer Histologically Exhibit Solid Growth Pattern with at Least Focal Comedonecrosis: A Histopathologic Study on a Monocentric Series of 30 Cases.

Since there are no morphological clues capable of making a pathologist suspect a possible mammary origin of a metastatic lesion without adequate clinical information, the histologic diagnosis of brain metastasis from BC is still based on the immunohistochemical expression of mammary gland markers such as GATA-3, ERs, PgRs and HER-2. The present retrospective study aimed to select purely morphological features capable of suggesting the mammary origin of a metastatic carcinoma in the brain. The following histological features were collected from a series of 30 cases of brain metastases from breast cancer: (i) a solid growth pattern; (ii) the presence of comedonecrosis; and (iii) glandular differentiation. Our results showed that most cases histologically exhibited a solid growth pattern with at least focal comedonecrosis, producing an overall morphology closely reminiscent of mammary high-grade ductal carcinoma in situ. Although the above-mentioned morphological parameters are not strictly specific to a mammary origin, they may have an important diagnostic utility for leading pathologists to suspect a possible breast primary tumor and to include GATA-3, ERs, PgRs and HER-2 in the immunohistochemical panel.

Tumor Infiltrating Lymphocytes (TILS) and PD-L1 Expression in Breast Cancer: A Review of Current Evidence and Prognostic Implications from Pathologist's Perspective.

With the rise of novel immunotherapies able to stimulate the antitumor immune response, increasing literature concerning the immunogenicity of breast cancer has been published in recent years. Numerous clinical studies have been conducted in order to identify novel biomarkers that could reflect the immunogenicity of BC and predict response to immunotherapy. In this regard, TILs have emerged as an important immunological biomarker related to the antitumor immune response in BC. TILs are more frequently observed in triple-negative breast cancer and HER2+ subtypes, where increased TIL levels have been linked to a better response to neoadjuvant chemotherapy and improved survival. 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 breast cancer is observed in about 10-30% of cases and is extremely variable based on tumor stage and molecular subtypes. Briefly, TNBC shows the highest percentage of PD-L1 positivity, followed by HER2+ tumors. On the other hand, PD-L1 is rarely expressed (0-10% of cases) in hormone-receptor-positive BC. The prognostic role of PD-L1 expression in BC is still controversial since different immunohistochemistry (IHC) clones, cut-off points, and scoring systems have been utilized across published studies. In the present paper, an extensive review of the current knowledge of the immune landscape of BC is provided. TILS and PD-L1 expression across different BC subtypes are discussed, providing a guide for their pathological assessment and reporting.

Eosinophilic Angiocentric Fibrosis of the Nasal Cavities: A Report of an Uncommon Lesion with Emphasis on the Etiology and Differential Diagnosis.

Background and Objectives: Eosinophilic angiocentric fibrosis (EAF) is an indolent but sometimes locally destructive lesion with a predilection for the sinonasal tract. Although it was first described in 1983, its etiology remains unknown. Some authors initially attributed EAF to trauma, hypersensitivity, and/or surgical manipulation, while it has been recently suggested to include EAF within the spectrum of IgG4-related systemic diseases. Materials and Methods: We report an uncommon case of idiopathic EAF in a 76-year-old male who developed two bilateral tumefactive masses in the nasal cavities. Results: As the histological examination showed a subepithelial proliferation of fibroblasts along with sclero-hyaline fibrosis around small-sized vessels (an "onion skin-like" pattern) and an eosinophils-rich inflammatory infiltrate, a diagnosis of EAF was rendered. The differential diagnosis included granuloma faciale, Wegener's granulomatosis, and Churg-Strauss syndrome. Conclusions: Pathologists should be aware of the possibility that this lesion can be part of the wide spectrum of IgG4-related systemic diseases by performing IgG4 investigations to assess adherence to IgG4-related systemic disease criteria.

Reporte de un caso: Co-infección dengue­COVID-19 / Case report: ¿Dengue ­ covid-19 co-infection?

Introducción: El primer caso registrado de COVID-19 en el Paraguay fue en marzo 2020. La infección por el virus del dengue es endémica en el Paraguay. La confección dengue ­COVID-19 podría tener una mayor gravedad. Se describe un caso de un paciente con neumonía por COVID -19 con probable co-infección con el virus del dengue internado en diciembre 2020 en el Servicio de Medicina Interna del Hospital distrital de Ñemby. Caso clínico: Varón de 63 años de edad, procedente de Villeta, consulta en diciembre 2020 por cuadro de 9 días de evolución, con dolor de garganta, tos seca y fiebre de 38 °C, 2 días antes del ingreso presenta dificultad respiratoria progresiva hasta llegar a mínimos esfuerzos. El examen pulmonar indica murmullo vesicular disminuido, crepitantes bibasales, sibilancias aisladas. Las pruebas laboratoriales muestran recuento de glóbulos blancos: 4200 por mm3, linfocitos: 42%, LDH: 883 UI/L, ferritina: >1000. Tanto el test inmunocromatográfico IgM para dengue como el antígeno SARS-COV2 fueron positivos. En el día 21 de enfermedad, presenta empeoramiento de la disnea, necesidad de asistencia respiratoria mecánica, ingreso a la unidad de cuidados intensivos, y fallece 5 días después de una falla multiorgánica. Conclusión: la coinfección dengue COVID -19 no puede descartarse en este paciente; tampoco una serología falsa positiva para dengue pues para el diagnóstico de dengue se utilizó una prueba rápida.

Introduction: The first registered case of COVID-19 in Paraguay was in March 2020. Dengue virus infection is endemic in Paraguay. The dengue -COVID-19 confection could be more severe. A case of a patient with COVID-19 pneumonia with probable co-infection with the dengue virus hospitalized in December 2020 at the Internal Medicine Service of the Ñemby District Hospital is decribed. Clinical case: 63-year-old man from Villeta, consulting in December 2020 due to a 9-day history, with sore throat, dry cough and fever of 38 °C, 2 days before admission he presents progressive respiratory distress until reach minimal efforts. Pulmonary examination indicates decreased vesicular murmur, bibasal crackles, isolated wheezing. Laboratory tests show white blood cell count: 4200 per mm3, lymphocytes: 42%, LDH: 883 IU/L, ferritin: >1000. Both, IgM immunochromatographic test for dengue and the SARS-COV2 antigen were positive. On the 21st day of illness, he presented worsening of dyspnea, need for mechanical ventilation, admission to the intensive care unit, and died 5 days after multiple organ failure. Conclusion: dengue and COVID -19 co-infection cannot be ruled out in this patient; nor was a false positive serology for dengue, since a rapid test was used for the diagnosis of dengue.