To improve the precision of epithelial ovarian cancer histotyping, Köbel et al. (2016) developed immunohistochemical decision-tree algorithms. These included a six- and four-split algorithm, and separate six-split algorithms for early- and advanced stage disease. In this study, we evaluated the efficacy of these algorithms. A gynecological pathologist determined the hematoxylin and eosin (H&E)-based histotypes of 230 patients. Subsequently, the final histotypes were established by re-evaluating the H&E-stained sections and immunohistochemistry outcomes. For histotype prediction using the algorithms, the immunohistochemical markers Napsin A, p16, p53, progesterone receptor (PR), trefoil factor 3 (TFF3), and Wilms\' tumor 1 (WT1) were scored. The algorithmic predictions were compared with the final histotypes to assess their precision, for which the early- and advanced stage algorithms were assessed together as six-split-stages algorithm. The six-split algorithm demonstrated 96.1% precision, whereas the six-split-stages and four-split algorithms showed 93.5% precision. Of the 230 cases, 16 (7%) showed discordant original and final diagnoses; the algorithms concurred with the final diagnosis in 14/16 cases (87.5%). In 12.4%-13.3% of cases, the H&E-based histotype changed based on the algorithmic outcome. The six-split stages algorithm had a lower sensitivity for low-grade serous carcinoma (80% versus 100%), while the four-split stages algorithm showed reduced sensitivity for endometrioid carcinoma (78% versus 92.7-97.6%). Considering the higher sensitivity of the six-split algorithm for endometrioid and low-grade serous carcinoma compared with the four-split and six-split-stages algorithms, respectively, we recommend the adoption of the six-split algorithm for histotyping epithelial ovarian cancer in clinical practice.

UNASSIGNED: Adenoid cystic carcinoma of minor salivary glands (AdCCmSG) represents a \'rarity in the rarity,\' posing a clinical challenge in lack of standardized, evidence-based recommendations. At present, AdCCmSG management is mostly translated from major salivary gland cancers (MSGCs). Ideally, AdCCmSG diagnostic-therapeutic workup should be discussed and carried out within a multidisciplinary, high-expertise setting, including pathologists, surgeons, radiation oncologists and medical oncologists.
UNASSIGNED: The present review provides an overview of epidemiology and pathologic classification. Moreover, the most recent, clinically relevant updates in the treatment of AdCCmSG (Pubmed searches, specific guidelines) are critically discussed, aiming to a better understanding of this rare pathologic entity, potentially optimizing the care process, and offering a starting point for reflection on future therapeutic developments.
UNASSIGNED: The management of rare cancers is often hindered by limited data and clinical trials, lack of evidence-based guidelines, and hardly represented disease heterogeneity, which cannot be successfully tackled with a \'one-size-fits-all\' approach. Our goal is to address these potential pitfalls, providing an easy-to-use, updated, multidisciplinary collection of expert opinions concerning AdCCmSG management as of today\'s clinical practice. We will also cover the most promising future perspectives, based on the potential therapeutic targets highlighted within AdCCmSG\'s molecular background.

This study investigated the incidence, mortality, and 5-year survival rates of testicular cancers diagnosed in a northern Italian province, which were eventually associated with previous or subsequent extratesticular neoplasms. Cases from 1996 to 2020 were examined by age and histotype (seminoma vs. non-seminoma). The standardized incidence rate was calculated using the European population, and the annual percent change (APC) was reported. The five-year relative survival was estimated using the Pohar Perme method. The association with the second neoplasm was also evaluated. In our study, 385 patients with testicular cancer were included, most of whom were aged between 30 and 40 years. The non-seminoma and seminoma groups accounted for 44% and 18% of younger adults, respectively. The incidence rate increased during the study period (APC 1.6*); however, it increased in seminomas (APC 2.3*) but not in non-seminomas (APC -0.1). Conversely, the mortality rate remained constantly low either overall or in each of the two groups. The overall 5-year survival rate of testicular cancer patients was 95% (99% and 88% for seminomas and non-seminomas, respectively). Primary extratesticular tumors were documented in 37 cases, 18 after and 19 before the testicular cancer diagnosis. Our study confirms that the increased incidence and excellent survival rate are the prerogative of seminomas.

A better understanding of the mechanisms generating tumour heterogeneity will allow better targeting of current therapies, identify potential resistance mechanisms and highlight new approaches for therapy. We have previously shown that in genetically modified mouse models carrying conditional oncogenic alleles, mammary tumour histotype varies depending on the combination of alleles, the cell type to which they are targeted and, in some cases, reproductive history. This suggests that tumour heterogeneity is not a purely stochastic process; rather, differential activation of signalling pathways leads to reproducible differences in tumour histotype. We propose the NOTCH signalling pathway as one such pathway. Here, we have crossed conditional knockout Notch1 or Notch2 alleles into an established mouse mammary tumour model. Notch1/2 deletion had no effect on tumour-specific survival; however, loss of Notch alleles resulted in a dose-dependent increase in metaplastic adenosquamous carcinomas (ASQCs). ASQCs and adenomyoepitheliomas (AMEs) also demonstrated a significant increase in AKT signalling independent of Notch status. Therefore, the NOTCH pathway is a suppressor of the ASQC phenotype, while increased PI3K/AKT signalling is associated with ASQC and AME tumours. We propose a model in which PI3K/AKT and NOTCH signalling act interact to determine mouse mammary tumour histotype.

The MV1 and MV2 subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) are linked to the heterozygous methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene. MV2 is phenotypically heterogeneous, whereas MV1, due to its low prevalence, is one of the least well characterized subtypes. In this study, we investigated the biochemical properties of PrPSc and phenotypic expression of cases diagnosed as sCJD MV1 and MV2. We describe four MV2 histotypes: 2C, with cortical (C) coarse pathology; 2K, with kuru (K) plaque deposits; 2C-K, with co-existing C and K histotypic features; and the novel histotype 2C-PL that mimics 2C in the cerebral cortex and cerebellum, but exhibits plaque-like (PL) PrP deposits in subcortical regions (e.g., basal nuclei, thalamus and midbrain). Histotype prevalence is highest for 2C-K (55%), intermediate for 2C (31%), and lowest for 2C-PL and 2K (7%). Nearly every MV2 case expressed both PrPSc types, with T2 being the predominant type (\"MV2-1\"). MV1 cases typically show a rapid disease course (≤ 4 months), and feature the 1C histotype, phenotypically identical to sCJDMM1. Co-existing PrPSc types, with T1 significantly exceeding T2 (\"MV1-2\"), are detected in patients diagnosed as MV1 with longer disease courses. We observed four histotypes among MV1-2 cases, including two novel histotypes: 1V, reminiscent of sCJDVV1; 1C-2C, resembling sCJDMM1-2 with predominant MM1 histotypic component; and novel histotypes 1C-2PL and 1C-2K, overall mimicking 1C in the cerebral cortex, but harboring T2 and plaque-like PrP deposits in subcortical regions (1C-2PL), and T2 and kuru plaques in the cerebellum (1C-2K). Lesion profiles of 1C, 1V, and 1C-2C are similar, but differ from 1C-2PL and 1C-2K, as the latter two groups show prominent hippocampal and nigral degeneration. We believe that the novel \"C-PL\" histotypes are distinct entities rather than intermediate forms between \"C\" and \"C-K\" groups, and that 1C-2PL and 1C-2K histotypes may be characterized by different T1 variants of the same size.

Contemporary population-based data on ovarian cancer survival using current subtype classifications and by surgical status are sparse. We evaluated 1-, 3-, 5- and 7-year relative (and overall) survival, and excess hazards in patients with borderline tumors or invasive epithelial ovarian cancer diagnosed 2012 to 2021 in a nationwide registry-based cohort in Norway. Outcomes were evaluated by histotype, FIGO stage, cytoreduction surgery and residual disease. Overall survival was evaluated for non-epithelial ovarian cancer. Survival of women with borderline ovarian tumors was excellent (≥98.0% 7-year relative survival). Across all evaluated invasive epithelial ovarian cancer histotypes, 7-year relative survival for cases diagnosed with stages I or II disease was ≥78.3% (stage II high-grade serous). Survival for ovarian cancers diagnosed at stage ≥III differed substantially by histotype and time since diagnosis (eg, stage III, 5-year relative survival from 27.7% [carcinosarcomas] to 76.2% [endometrioid]). Overall survival for non-epithelial cases was good (91.8% 5-year overall survival). Women diagnosed with stage III or IV invasive epithelial ovarian cancer and with residual disease following cytoreduction surgery had substantially better survival than women not operated. These findings were robust to restriction to women with high reported functional status scores. Patterns for overall survival were similar to those for relative survival. We observed relatively good survival with early stage at diagnosis even for the high grade serous histotype. Survival for patients diagnosed at stage ≥III invasive epithelial ovarian cancer was poor for all but endometrioid disease. There remains an urgent need for strategies for risk reduction and earlier detection, together with effective targeted treatments.

(1) Background: Ovarian cancer (OC) and Parkinson\'s disease (PD) represent a huge public health burden. The relationship of these two diseases is suggested in the literature while not fully understood. To better understand this relationship, we conducted a bidirectional Mendelian ran-domization analysis using genetic markers as a proxy. (2) Methods: Utilizing single nucleotide polymorphisms associated with PD risk, we assessed the association between genetically predicted PD and OC risk, overall and by histotypes, using summary statistics from previously conducted genome-wide association studies of OC within the Ovarian Cancer Association Consortium. Similarly, we assessed the association between genetically predicted OC and PD risk. The inverse variance weighted method was used as the main method to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations of interest. (3) Results: There was no significant association between genetically predicted PD and OC risk: OR = 0.95 (95% CI: 0.88-1.03), or between genetically predicted OC and PD risk: OR = 0.80 (95% CI: 0.61-1.06). On the other hand, when examined by histotypes, a suggestive inverse association was observed between genetically predicted high grade serous OC and PD risk: OR = 0.91 (95% CI: 0.84-0.99). (4) Conclusions: Overall, our study did not observe a strong genetic association between PD and OC, but the observed potential association between high grade serous OC and reduced PD risk warrants further investigation.

UNASSIGNED: Ovarian cancer (OC) is the leading cause of gynecological cancer-related death. Of the main OC histologic subtypes, invasive mucinous carcinomas (MC) account for only 3% of OC cases and are frequently associated with favorable prognosis. Nevertheless, MCs differ greatly from the other OC histotypes in clinical, pathological, and biological behavior. However, the origin and molecular pathogenesis of MC are not yet fully understood. Therefore, identification of novel diagnostic markers could potentially facilitate early diagnosis of OC, particularly the MC histotype, thereby leading to the development of histotype-specific treatment regimens and improved survival rates.
UNASSIGNED: In the present study, Trefoil factor gene family members (TFF1, TFF2 and TFF3) were identified as MC histotype-specific biomarkers using RNA sequencing (RNA-seq) data for 95 stage I-II OCs. The diagnostic value of TFF1, TFF2 and TFF3 was then evaluated by immunohistochemistry on 206 stage I-II OCs stratified by histotype (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], clear cell carcinoma [CCC], and MC).
UNASSIGNED: We showed significantly elevated intracytoplasmic protein expression levels for TFF1, TFF2 and TFF3 in MC samples, thereby revealing an association between expression of Trefoil factor gene family members and the MC histotype. Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype.
UNASSIGNED: Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Moreover, these novel histotype-specific diagnostic biomarkers may not only improve patient stratification of early-stage ovarian carcinomas but may also be candidates for the development of molecular targeted therapies.

Pilomatrix-like high-grade endometrioid carcinoma (PiMHEC) has recently been described as an aggressive variant of endometrial carcinoma. Herein, we described a case of ovarian PiMHEC, comparing it to endometrial PiMHEC and assessing previously published cases of putative ovarian PiMHEC. A 65-year-old woman underwent hysterectomy for an ovarian tumor characterized by solid nests of basaloid cells with prominent ghost cell keratinization. Immunohistochemistry showed nuclear β-catenin and CDX2 expression and loss of estrogen and progesterone receptors and PAX8. These features were consistently observed in all previously published cases and may represent diagnostic criteria of PiMHEC. Other frequent features were geographic necrosis and a low-grade endometrioid component. CK7, neuroendocrine, and basal/squamous markers were inconsistently expressed. All cases with available follow-up showed poor prognosis. PiMHEC should be distinguished from mimickers, such as high-grade endometrioid carcinoma with geographic necrosis, low-grade endometrioid carcinoma with ghost cell keratinization, and undifferentiated/dedifferentiated carcinoma. In conclusion, PiMHEC can also occur in the ovary and shows several consistent clinical, morphological, and immunophenotypical features. These features support that PiMHEC is a distinct entity requiring an aggressive management.

isomiRs, the sequence-variants of microRNA, are known to be tissue and cell type specific but their physiological role is largely unknown. In our study, we explored for the first time the expression of isomiRs across different Stage I epithelial ovarian cancer (EOC) histological subtypes, in order to shed new light on their biological role in tumor growth and progression. In a multicentric retrospective cohort of tumor biopsies (n = 215) we sequenced small RNAs finding 971 expressed miRNAs, 64% of which are isomiRs. Among them, 42 isomiRs showed a clear histotype specific pattern, confirming our previously identified miRNA markers (miR192/194 and miR30a-3p/5p for mucinous and clear cell subtypes, respectively) and uncovering new biomarkers for all the five subtypes. Using integrative models, we found that the 38% of these miRNA expression alterations is the result of copy number variations while the 17% of differential transcriptional activities. Our work represents the first attempt to characterize isomiRs expression in Stage I EOC within and across subtypes and to contextualize their alterations in the framework of the large genomic heterogeneity of this tumor.