Pathogenesis of Penile Squamous Cell Carcinoma: Molecular Update and Systematic Review.

Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC

HPV-negative Penile Intraepithelial Neoplasia (PeIN) With Basaloid Features.

Most human papillomavirus (HPV)-independent penile squamous cell carcinomas (PSCCs) originate from an intraepithelial precursor called differentiated penile intraepithelial neoplasia, characterized by atypia limited to the basal layer with marked superficial maturation. Previous studies in vulvar cancer, which has a similar dual etiopathogenesis, have shown that about one fifth of HPV-independent precursors are morphologically indistinguishable from high-grade squamous intraepithelial lesions (HSILs), the precursor of HPV-asssociated carcinomas. However, such lesions have not been described in PSCC. From 2000 to 2021, 55 surgical specimens of PSCC were identified. In all cases, thorough morphologic evaluation, HPV DNA detection, and p16, p53, and Ki-67 immunohistochemical (IHC) staining was performed. HPV-independent status was assigned based on both negative results for p16 IHC and HPV DNA. Thirty-six of the 55 PSCC (65%) were HPV-independent. An intraepithelial precursor was identified in 26/36 cases (72%). Five of them (19%) had basaloid features, morphologically indistinguishable from HPV-associated HSIL. The median age of the 5 patients was 74 years (range: 67 to 83 y). All 5 cases were p16 and DNA HPV-negative. Immunohistochemically, 3 cases showed an abnormal p53 pattern, and 2 showed wild-type p53 staining. The associated invasive carcinoma was basaloid in 4 cases and the usual (keratinizing) type in 1. In conclusion, a small proportion of HPV-independent PSCC may arise on adjacent intraepithelial lesions morphologically identical to HPV-associated HSIL. This unusual histologic pattern has not been previously characterized in detail in PSCC. p16 IHC is a valuable tool to identify these lesions and differentiate them from HPV-associated HSIL

HPV-independent, p53-wild-type vulvar intraepithelial neoplasia: a review of nomenclature and the journey to characterize verruciform and acanthotic precursor lesions of the vulva

Vulvar squamous cell carcinomas and their precursors are currently classified by the World Health Organization based on their association with high-risk human papillomavirus (HPV). HPV independent lesions often harbor driver alterations in TP53, usually seen in the setting of chronic vulvar inflammation. However, a group of pre-invasive vulvar squamous lesions is independent from both HPV and mutant TP53. The lesions described within this category feature marked acanthosis, verruciform growth and altered squamous maturation, and over the last two decades several studies have added to their characterization. They have a documented association with verrucous carcinoma and conventional squamous cell carcinoma of the vulva, suggesting a precursor role. They also harbor recurrent genomic alterations in several oncogenes, mainly PIK3CA and HRAS, indicating a neoplastic nature. In this review, we provide a historical perspective and a comprehensive description of these lesions. We also offer an appraisal of the terminology used over the years, going from Vulvar Acanthosis with Altered Differentiation and Verruciform Lichen Simplex Chronicus to Differentiated Exophytic Vulvar Intraepithelial Lesion and Vulvar Aberrant Maturation, the latter term having been recently proposed by the International Society for the Study of Vulvovaginal Diseases. In line with the recognition of these lesions by the 2020 World Health Organization Classification of Tumours as a neoplastic precursor, we herein propose the term HPV-independent, p53-wild-type verruciform acanthotic Vulvar Intraepithelial Neoplasia (HPVi(p53wt) vaVIN), which better conveys not only the pathology but also the neoplastic nature and the biologic risk inherent to these uncommon and challenging lesions. We outline strict morphologic and immunohistochemical criteria for its diagnosis and distinction from mimickers. Immunohistochemistry for p16 and p53 should be performed routinely in the diagnostic work-up of these lesions, and the morphologic alternative term vaVIN should be reserved for instances in which p16/HPV/p53 status is unknown. We also discuss management considerations and the need to further explore precursors within and beyond the spectrum of verruciform acanthotic vulvar intraepithelial neoplasia

Microbiology in minimally invasive autopsy: best techniques to detect infection. ESGFOR (ESCMID study group of forensic and post-mortem microbiology) guidelines

This manuscript aims to: 1) provide specific guidelines on PMM techniques in the setting of minimally invasive autopsy (MIA), both for pathologists collecting samples and for microbiologists advising pathologists and interpreting the results and 2) introduce standardization in PMM sampling at MIA. Post-mortem microbiology (PMM) is crucial to identify the causative organism in deaths due to infection. MIA including the use of post-mortem (PM) computed tomography (CT) and PM magnetic resonance imaging (MRI), is increasingly carried out as a complement or replacement for the traditional PM. In this setting, mirroring the traditional autopsy, PMM aims to: detect infectious organisms causing sudden unexpected deaths; confirm clinically suspected but unproven infection; evaluate the efficacy of antimicrobial therapy; identify emergent pathogens; and recognize medical diagnostic errors. Meaningful interpretation of PMM results requires careful evaluation in the context of the clinical history, macroscopic and microscopic findings. These guidelines were developed by a multidisciplinary team with experts in various fields of microbiology and pathology on behalf of the ESGFOR (ESCMID – European Society of Clinical Microbiology and Infectious Diseases - Study Group of Forensic and Post-mortem Microbiology, in collaboration with the ESP -European Society of Pathology-) based on a literature search and the author’s expertise. Microbiological sampling methods for MIA are presented for various scenarios: adults, children, developed and developing countries. Concordance between MIA and conventional invasive autopsy is substantial for children and adults and moderate for neonates and maternal deaths. Networking and closer collaboration among microbiologists and pathologists is vital to maximize the yield of PMM in MIA

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Accuracy of verbal autopsy, clinical data and minimally invasive autopsy in the evaluation of malaria-specific mortality: an observational study

Background Global malaria mortality estimates are hindered by the low reliability of the verbal autopsy (VA) and the clinical records, the most common sources of information used to estimate malaria-specific mortality. We aimed to determine the accuracy of these tools, as well as of the minimally invasive autopsy (MIA), a needle-based postmortem sampling method, to identify malaria-specific mortality in a large series of deceased patients from Mozambique, using complete autopsy as the gold standard. Methods Observational study that included 264 deaths, occurring at a tertiary level hospital in Mozambique, from 1 November 2013 to 31 March 2015 (17 months-long period). Clinical data were abstracted, a computer coded VA was completed using the clinical data as source of information, and an MIA followed by a complete autopsy were performed. Screening for malaria infection was conducted postmortem to all participants using molecular and histological techniques (PCR and immunohistochemistry). Findings Malaria infection was considered the cause of death in 6/264 (2.3%) cases: 2/54 children (3.7%, both less than 5 years old) and 4/57 (7.0%) maternal deaths. The sensitivity and specificity of the VA, the clinical data and the MIA to identify malaria-specific deaths were 33.3% and 96.1%, 66.7% and 96.1%, and 100% and 100%, respectively. In addition, malaria was identified as a possible contributor in 14 additional patients who died of other diseases. These cases were also accurately identified by the MIA (sensitivity 82.4%, specificity 100%). Interpretation The high sensitivity and specificity of the MIA in identifying malaria may help to improve current estimates of malaria-specific mortality in endemic areas

Accuracy of verbal autopsy, clinical data and minimally invasive autopsy in the evaluation of malaria-specific mortality: an observational study

Background Global malaria mortality estimates are hindered by the low reliability of the verbal autopsy (VA) and the clinical records, the most common sources of information used to estimate malaria-specific mortality. We aimed to determine the accuracy of these tools, as well as of the minimally invasive autopsy (MIA), a needle-based postmortem sampling method, to identify malaria-specific mortality in a large series of deceased patients from Mozambique, using complete autopsy as the gold standard.Methods Observational study that included 264 deaths, occurring at a tertiary level hospital in Mozambique, from 1 November 2013 to 31 March 2015 (17 months-long period). Clinical data were abstracted, a computer coded VA was completed using the clinical data as source of information, and an MIA followed by a complete autopsy were performed. Screening for malaria infection was conducted postmortem to all participants using molecular and histological techniques (PCR and immunohistochemistry).Findings Malaria infection was considered the cause of death in 6/264 (2.3%) cases: 2/54 children (3.7%, both less than 5 years old) and 4/57 (7.0%) maternal deaths. The sensitivity and specificity of the VA, the clinical data and the MIA to identify malaria-specific deaths were 33.3% and 96.1%, 66.7% and 96.1%, and 100% and 100%, respectively. In addition, malaria was identified as a possible contributor in 14 additional patients who died of other diseases. These cases were also accurately identified by the MIA (sensitivity 82.4%, specificity 100%).Interpretation The high sensitivity and specificity of the MIA in identifying malaria may help to improve current estimates of malaria-specific mortality in endemic areas