Uncommon Morphologic Types of Endometrial Cancer and Their Mimickers: How Much Does Molecular Classification Improve the Practice for Challenging Cases?

The previous endometrial cancer (EC) FIGO staging primarily relied on the extent of the disease spread into the anatomical sites at diagnosis. The most recent one (2023) incorporates clinicopathological features such as histological subtype, tumor grade, the extent of lymphovascular space invasion (LVI), and, when available, molecular subtypes of EC. The emphasis on accurate histological typing, tumor grading, and the molecular features of the cancer is stronger than ever. This review addresses challenging diagnostic patterns in the histologic subtyping and grading EC under five categories: 1. EC with spindle cells, 2. EC with clear cells, 3. EC with a papillary architecture, 4. EC with a biphasic morphology, and 5. EC with a microglandular architecture. The morphological features differentiating low- and high-grade cancers are discussed, along with relevant clinical work-ups. Recent molecular genetic findings regarding the diagnosis and prognosis of the disease and the results of related clinical trials are summarized. The potential challenges in the evaluation of LVI follow these sections. The final section of the review includes an overview of the literature on incorporating molecular subtypes of EC into clinical practice

Metastatic VIPoma presenting as an ovarian mass

AbstractIntroductionPancreatic VIPomas are exceedingly rare, with an annual incidence of less than 1 per million. Most VIPomas are metastatic at diagnosis, with the liver being the most common site of spread.Presentation of caseWe describe a highly unusual case of a metastatic pancreatic VIPoma to an ovary in a 54 year-old patient. She was ten years out from her initial diagnosis when routine CT scan showed an enlarging left adnexal mass. After having both ovaries removed laparoscopically the final pathology was consistent with her pancreatic primary. To our knowledge, there has been only one other such case described in the literature.DiscussionIn this case, pathology revealed metastatic neuroendocrine tumor involving both the left and right ovaries despite only the right ovary apparently enlarging. In our literature search, only two other cases of metastatic PNET to the ovaries have been reported. One case was a glucagonoma and the other a VIPoma. We recommend that clinicians consider referral of patients with metastatic NET and ovarian metastases to gynecologic surgery for consideration of surgical resection.ConclusionIn conclusion, this case proves that although uncommon, PNET can show metastases in both ovaries even a decade after initial diagnosis

Morphologic and molecular correlates of EZH2 as a predictor of platinum resistance in high-grade ovarian serous carcinoma

Abstract Background Enhancer of zesta homologue 2 (EZH2) is an essential component of polycomb repressive complex 2 (PRC2) that contributes to tumor progression and chemo-resistance. The aim of this study was to comprehensively assess the prognostic value of EZH2 across the morphologic and molecular spectra of high-grade serous ovarian carcinoma (HGSOC) by utilizing both immunohistochemistry (IHC) and proteogenomic technologies. Methods IHC of EZH2 was performed using a tissue microarray of 79 HGSOC scored (+/−) for lymphovascular invasion (LVI), tumor-infiltrating lymphocytic aggregates ≥1 mm (TIL) and architectural growth patterns. The association of EZH2 H-score with response to therapy and overall survival was evaluated by tumor features. We also evaluated EZH2 transcriptional (RNA sequencing) and protein (mass spectrometry) expression from bulk tumor samples from 336 HGSOC from The Cancer Genome Atlas (TCGA). EZH2 expression and co-expression networks were compared by clinical outcomes. Results For HGSOC without TIL (58%), EZH2 expression was almost 2-fold higher in platinum resistant tumors (P = 0.01). Conversely, EZH2 was not associated with platinum resistance among TIL+ HGSOC (P = 0.41). EZH2 expression was associated with reduced survival for tumors with LVI (P = 0.04). Analysis of TCGA found higher EZH2 expression in immunoreactive and proliferative tumors (P = 6.7 × 10− 5) although protein levels were similar across molecular subtypes (P = 0.52). Both mRNA and protein levels of EZH2 were lower in platinum resistant tumors although they were not associated with survival. Co-expression analysis revealed EZH2 networks totaling 1049 mRNA and 448 proteins that were exclusive to platinum sensitive or resistant tumors. The EZH2 network in resistant HGSOC included CARM1 which was positively correlated with EZH2 at both mRNA (r = 0.33, p = 0.003) and protein (r = 0.14, P = 0.01) levels. Further, EZH2 co-expression with CARM1 corresponded to a decreased prognostic significance of EZH2 expression in resistant tumors. Conclusions Our findings demonstrate that EZH2 expression varies based on its interactions with immunologic pathways and tumor microenvironment, impacting the prognostic interpretation. The association between high EZH2 expression and platinum resistance in TIL- HGSOC warrants further study of the implications for therapeutic strategies

Viruses and bacteria identified in tissue samples by next-generation sequencing.

<p>Viruses and bacteria identified in tissue samples by next-generation sequencing.</p

Number of next-generation sequencing (NGS) reads at each step of the SURPI bioinformatics pipeline for pathogen identification.

<p>Number of next-generation sequencing (NGS) reads at each step of the SURPI bioinformatics pipeline for pathogen identification.</p

Ranked Z-score analysis of ViroChip microarrays corresponding to dVIN samples and controls for virus identification.

<p>*Criteria: ≥5 hits out of top 50 probes (10%) and probe hits mapped to ≥3 distinct locations on the viral genome.</p><p>**Distinct locations: mapped probe locations on the viral genome separated by at least 5% of the total genome length.</p><p>Ranked Z-score analysis of ViroChip microarrays corresponding to dVIN samples and controls for virus identification.</p

Histology and p16^ink4a immunostaining patterns of high-grade dVIN and uVIN samples.

<p>(A) dVIN, showing characteristic elongation and anastomosis of rete ridges. The epithelium shows enlarged keratinoocytes with abundant eosinophilic cytoplasm. The inset displays prominent cytologic atypia localized to the lower 1/3 of the epithelium. (B) uVIN, warty subtype. A spiked surface epithelium with hyperkeratosis and hypergranulosis is visualized. The inset displays full-thickness cytologic atypia. (C) p16^ink4a immunostaining is negative in dVIN. (D) Full-thickness p16^ink4a immunopositivity is seen in high-grade uVIN. Abbreviations: dVIN, differentiated vulvar intraepithelial neoplasia; uVIN, usual-type vulvar intraepithelial neoplasia.</p

Schematic flowchart showing testing of FFPE vulvar tissues from 28 cases of high-grade differentiated VIN (dVIN) and usual-type VIN (uVIN).

<p>Histological (yellow boxes), p16^ink4a immunostaining (yellow boxes), and genomic (pink boxes) analyses were performed. Abbreviations: FFPE, formalin-fixed, paraffin-embedded; VIN, vulvar intraepithelial neoplasia; VSCC, vulvar squamous cell carcinoma; PCR, polymerase chain reaction.</p

Pan-viral analysis of high-grade dVIN samples.

<p>(A) Tissue samples (x-axis) were analyzed using the ViroChip, a pan-viral DNA detection microarray. The cluster heat map of HPV probes (y-axis) shows only one strong papillomavirus cluster corresponding to the HPV18 cervical cancer positive control (PC). Other scattered clusters corresponding to the dVIN samples (tissue samples 1–10) consisted of lower-intensity probes representing multiple papillomavirus subtypes, including HPV7, HPV34, HPV81, and HPV 83 (clusters I, II, and III). Confirmatory PCR testing from the HPV L1 region using conserved primers was negative for all of the dVIN samples (gel, left). PCR testing using primers specific for each HPV subtype was also negative (2 gels, right), with the exception of bands in dVIN sample 5 that were cloned and sequenced as <i>Pseudomonas aeruginosa</i> (asterisks), and attributed to bacterial surface contamination of the FFPE block. Thus, the dVIN samples were deemed negative for HPV infection. The red color bar denotes the normalized magnitude of hybridization intensity. (B) Mapping of 16 HPV18 probes out of the top 50 (by ranked Z-score analysis) to the HPV18 genome in the cervical cancer positive control. Abbreviations: HPV, human papillomavirus; VIN, vulvar intraepithelial neoplasia; N, normal skin vulvar biopsy; PC, positive control; ntC, no template control.</p