Changes in the tumor immune microenvironment during disease progression in clear cell ovarian cancer.

OBJECTIVE: The tumor immune microenvironment in ovarian clear cell carcinoma has not been clearly defined. We analyzed the immunological changes from treatment-naive to recurrence to correlate them with clinical outcomes. METHOD: We compared the changes in immune infiltration of advanced-stage ovarian clear cell carcinoma samples before treatment and at the time of recurrence via immunohistochemistry (Programmed Cell Death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8+), forkhead box P3 (Foxp3+)), tumor-infiltrating lymphocytes (TIL), and next-generation sequencing (54 patients). We analyzed the association between platinum sensitivity status and tumor immune microenvironment. RESULTS: Immunohistochemistry revealed significantly increased PD-L1 (p=0.048) and CD8+T cells (p=0.022) expression levels after recurrence. No significant differences were observed in TIL density or Foxp3+T cells. There was no significant correlation between TIL, PD-L1, CD8+T cell, and Foxp3+T cell levels in treatment-naive tumors and survival outcomes. The most common genomic alterations were PIK3CA (41.7%) and ARID1A (41.7%) mutations. There were no differences in the immunological changes or survival outcomes according to PIK3CA and ARID1A mutations. Patients with recurrent platinum-sensitive disease showed higher TIL expression levels. There were no significant differences in PD-L1, CD8+T cells, or Foxp3+T cells between platinum-sensitive and platinum-resistant diseases. CONCLUSION: We characterized the tumor immune microenvironment in patients with advanced-stage ovarian clear cell carcinoma. PD-L1 and CD8+T cell expression significantly increased after recurrence. Whether this could be used to select patients for immunotherapy in the recurrence setting should be investigated.

Lung and lymph node metastases from hepatocellular carcinoma: Comparison of pathological aspects.

BACKGROUND & AIMS: Extrahepatic metastasis from hepatocellular carcinoma (HCC) is a catastrophic event, yet organ-specific pathological characteristics of metastatic HCC remain unclear. We aimed to characterize the pathological aspects of HCC metastases to various organs. METHODS: We collected intrahepatic HCC (cohort 1, n = 322) and extrahepatic metastatic HCC (cohort 2, n = 130) samples. Clinicopathological evaluation and immunostaining for K19, CD34, αSMA, fibroblast-associated protein (FAP), CAIX, VEGF, PD-L1, CD3, CD8, Foxp3, CD163 and epithelial-mesenchymal transition (EMT)-related markers were performed. RESULTS: Independent factors for extrahepatic metastasis included BCLC stage B-C, microvascular invasion (MVI), vessels encapsulating tumour clusters (VETC)-HCC, K19 and FAP expression, and CD163+ macrophage infiltration (cohort 1, P < .05 for all). Lung metastases (n = 63) had the highest proportion of VETC-HCC and macrotrabecular-massive (MTM)-HCC. Lymph node metastases (n = 19) showed significantly high rates of EMT-high features, K19 expression, fibrous tumour stroma with αSMA and FAP expression, high immune cell infiltration, PD-L1 expression (combined positive score), CD3+, CD8+, Foxp3+ T cell and CD163+ macrophage infiltration (adjusted P < .05 for all). In both cohorts, EMT-high HCCs showed higher rates of K19 expression, fibrous tumour stroma, high immune cell infiltration, PD-L1 expression and CD3+ T cell infiltration, whereas EMT-low HCCs were more frequent among VETC-HCCs (P < .05 for all). Overall phenotypic features were not significantly different between paired primary-metastatic HCCs (n = 32). CONCLUSIONS: Metastatic HCCs to various organs showed different pathological features. VETC and MTM subtypes were related to lung metastasis, whereas K19 expression, EMT-high features with fibrous tumour stroma and high immune cell infiltration were related to lymph node metastasis.

Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma.

We investigated the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the vessels that encapsulate tumor clusters (VETC), previously linked to HCC metastatic dissemination. VETC was assessed in a large multi-institutional cohort of 541 resected HCCs from Italy, Korea and Japan, and matched against a full spectrum of clinical and pathological variables. The VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small-sized tissues of tissue microarray. VETC HCCs represented 18.9% of the whole series, the lowest proportion occurring in the cohort with smallest tumors (8.7%, Japanese series). VETC was significantly associated with several clinical and pathological features such as high alfa-fetoprotein (AFP) level, tumor size greater than 5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion. VETC was associated with early recurrence (hazard ratio [HR]: 1.52 [1.06-2.19], P = 0.023), disease-free survival (HR: 1.66 [1.21-2.27], P = 0.002), and overall survival (HR: 2.26 [1.37-3.72], P = 0.001) at multivariable analysis. VETC affected the survival in HCC patients stratified for etiology (hepatitis C virus/hepatitis B virus), vascular invasion, and specific molecular phenotypes (ß-catenin/GS+). This distinct vascular pattern was enriched in the recently reported macrotrabecular massive HCC subtype, which was seen in 7.8% (42 of 541) of patients and associated with high AFP levels and poor differentiation. Conclusion: The VETC pattern was found to be easily detectable in a consistent fraction of HCC and a powerful pathological finding affecting survival. This study suggests that the heterogeneous pattern of angiogenesis is involved in HCC behavior.

PD-L1 tumour expression is predictive of pazopanib response in soft tissue sarcoma.

BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy. METHODS: Tumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%. RESULTS: Among the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8-5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1-9% (n = 3, 4.5%), 10-49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45-5.56, P = 0.006). CONCLUSION: We identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.

Mismatch repair status influences response to fertility-sparing treatment of endometrial cancer.

BACKGROUND: Patients younger than 40 years usually present with early-stage endometrial cancer with favorable prognosis. However, such patients are usually in their childbearing age and may desire fertility-sparing options. The identification of biomarkers may improve the clinical outcomes in these patients and aid in fertility-sparing management; however, there has been no reports on biomarker analysis so far. OBJECTIVE: This study aimed to evaluate the prognostic significance of Proactive Molecular Risk Classifier for Endometrial Cancer in the fertility-sparing management of endometrial cancer. STUDY DESIGN: A total of 57 endometrial biopsy specimens obtained before hormone therapy were evaluated, and patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer molecular subtypes (mismatch repair deficiency, DNA polymerase epsilon mutation, wild-type p53, and abnormal p53). The primary endpoint was the response rate after hormone therapy. The secondary endpoint was the recurrence rate after the complete response, hysterectomy rate owing to treatment failure, and upstaged diagnosis rate after hysterectomy. RESULTS: Of 57 patients, 9 (15.8%) had mismatch repair deficiency, 2 (3.5%) had DNA polymerase epsilon mutation, 45 (78.9%) had wild-type p53, and 1 (1.8%) had abnormal p53. Overall, the complete response rate was 75.4% after hormone therapy. Patients with mismatch repair deficiency had a significantly lower complete response or partial response rate than those with wild-type p53 in terms of the best overall response (44.4% [95% confidence interval, 4.0-85.0] vs 82.2% [95% confidence interval, 71.0-94.0]; P=.018) and complete response rate at 6 months (11.1% [95% confidence interval, 0.2-37.0] vs 53.3% [95% confidence interval, 38.0-68.0]; P=.010). Among patients with mismatch repair deficiency, 4 underwent immediate hysterectomy because of treatment failure and 3 presented upstaged diagnosis after hysterectomy. CONCLUSION: The Proactive Molecular Risk Classifier for Endometrial Cancer molecular classification has prognostic significance in the fertility-sparing management of endometrial cancer, thereby enabling early stratification and risk assignment to direct care. Mismatch repair status could be used as a predictive biomarker for selecting patients who could benefit from hormone therapy. These findings need to be validated in larger studies.

Characterization of novel genetic alterations in salivary gland secretory carcinoma.

Secretory carcinoma is a salivary gland tumor with a characteristic chromosomal translocation that results in an ETV6-NTRK3 fusion gene. Secretory carcinoma shows relatively frequent rates of lymph-node metastasis and tumor recurrence and has a characteristic histology. Except for the ETV6 translocation, genomic alterations in secretory carcinoma have not been reported. In the present study, we characterized the novel recurrent genetic mutations of secretory carcinoma. On the basis of histology, immunohistochemistry, and ETV6 gene break-apart fluorescence in situ hybridization assays, 22 tumors were classified as secretory carcinomas (19 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) and their clinicopathologic characteristics were reviewed. Targeted deep sequencing analyses were performed on 20 secretory carcinomas (17 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) to investigate their genetic alterations. The A16V (C→T) mutation in PRSS1, which encodes a cationic trypsinogen and has a mutation associated with hereditary pancreatitis and pancreatic adenocarcinoma, was observed in 40% (8/20) (7/17 of ETV6 translocation-positive and 1/3 of ETV6 translocation-negative secretory carcinomas). Pathogenic variants of MLH1, MUTYH, and STK11 were also identified. Variants of uncertain significance included mutations in KMT5A. These novel characteristic genetic alterations may advance current understandings of secretory carcinoma tumorigenesis and progression, leading to improved diagnoses and treatment strategies.

Distinct expression profile of key molecules in crawling-type early gastric carcinoma.

BACKGROUND: Gastric "crawling-type" adenocarcinoma (CRA) is a tumor histologically characterized by irregularly fused glands with low-grade cellular atypia that tends to spread laterally in the mucosa. To date, the expression characteristics of the key molecules involved in CRA, including receptor tyrosine kinases (RTKs), mismatch repair (MMR) proteins, phosphatase and tensin homolog (PTEN), as well as the Epstein-Barr virus (EBV) status, have yet to be uncovered. METHODS: We constructed tissue microarrays of 94 CRAs, 72 conventional-type differentiated adenocarcinomas (CDAs), and 71 intramucosal poorly cohesive adenocarcinomas (PCAs) from early gastric cancers to evaluate and compare the pathological and expression profiles of potential key molecules for molecular classification (EBV; four MMR proteins-MLH1, MSH2, PMS2, and MSH6; three RTKs-HER2, MET, and EGFR; PTEN; and p53). RESULTS: None of the CRAs showed MMR deficiency (0.0 % vs. 5.6 %, CRA vs. CDA, p = 0.036), HER2 overexpression (0.0 % vs. 12.5 %, p = 0.001), or loss of PTEN expression (0.0 % vs. 9.7 %, p = 0.003). Moreover, MET overexpression (4.4 % vs. 19.4 %, p = 0.004), and a mutant p53 pattern (12.4 % vs. 62.5 %, p < 0.001) were significantly less common in CRAs than in CDAs. However, clinicopathological features and all the profile of the molecules of CRAs were close to those of the PCA group. CONCLUSIONS: CRA demonstrated unique clinicopathological characteristics and showed a distinct expression profile of key molecules, which was close to that of a null phenotype. These results support the classification of CRA as a distinct subgroup of gastric adenocarcinoma.

Biphasic synovial sarcoma with a striking morphological divergence from the main mass to lymph node metastasis: A case report.

RATIONALE: Synovial sarcoma accounts for 5% to 10% of all soft tissue sarcomas and involves almost any anatomic site, particularly the deep soft tissue of the extremities of young adults. The incidence rate of lymph node metastases in synovial sarcoma is 3% to 7%, but the detailed morphological features of the metastatic tumors in the lymph node have not been documented. PATIENT CONCERNS: A 64-year-old Korean man presented with a huge mass in the left lower thorax and multiple hypermetabolic lymph nodes along the mediastinal, supraclavicular, internal mammary, and retrocrural regions. DIAGNOSES: The patient was diagnosed with primary pleuropulmonary biphasic synovial sarcoma with lymph node metastases, where the main mass mostly comprised spindle cells (>95%) and the metastatic lymph nodes comprised only epithelial cells. INTERVENTIONS: Left lower lobe lobectomy with the resection of the chest wall (including left ribs 8-10) and diaphragm and mediastinal lymph node dissection were performed. OUTCOMES: In the 2-month follow-up period, there have been no complications so far, and the attending physician is currently planning for the adjuvant chemotherapy. LESSONS: The main mass and the metastatic lesion can be clearly different morphologically. In tumors with biphasic differentiation, such as synovial sarcoma, cells that constitute only a small fraction of the main mass may appear as the dominant cells in metastatic lesions.

Nevus Comedonicus Syndrome Associated with Psychiatric Disorder.

Nevus comedonicus (NC) is a rare hamartoma of the pilosebaceous unit origin. The association with extracutaneous abnormalities defines NC syndrome (NCS). Fewer than 50 cases of NCS have been reported in the English literature. A 31-year-old woman presented with grouped and linear comedonal papules present from birth and located on the left buttock along Blaschko's lines. She had a history of pediatric mood disorder combined with attention-deficit hyperactivity disorder (ADHD) from 5 years of age and was recently diagnosed with sinus bradycardia. Her skin lesion was surgically removed and microscopic findings revealed the aggregation of dilated follicular infundibula filled with prominent laminated keratin plugs, a characteristic finding of NC. This is the first report presenting NCS associated with mood disorder and ADHD. Psychiatric symptoms may represent systemic manifestation of NCS.

Local and Metastatic Relapses in a Young Woman with Papillary Squamous Cell Carcinoma of the Uterine Cervix.

Papillary squamous cell carcinoma (PSCC) is a rare histological type of cervical carcinoma whose biological behavior has not been fully established. A 33-year-old woman with an exophytic cervical mass underwent radical hysterectomy and bilateral pelvic lymph node dissection. Histological examination of the tumor revealed numerous papillary fronds lined by atypical stratified squamous cells, resembling high-grade squamous intraepithelial lesions or urothelium. She was diagnosed with stage IB1 PSCC. Three months postoperatively, a 5.7 cm vaginal stump mass was detected. She received chemoradiotherapy, which helped her achieve a complete response. However, nine months postoperatively, she developed pelvic lymph node metastases. We present a rare case of recurrent cervical PSCC in a young woman. PSCC of the uterine cervix can recur rapidly within just a few months and become aggressive, as in the present case.

Combination of GATA3, SOX-10, and PAX8 in a Comprehensive Panel to Diagnose Breast Cancer Metastases.

BACKGROUND/AIM: It can be difficult to establish the origin of a tumor in metastatic breast cancer (MBC), especially with triple-negative breast cancer (TNBC) or high-grade features. We evaluated the diagnostic utility of GATA3, SOX10, and PAX8 panels in MBC by comparing their expression in each molecular subtype of MBC. PATIENTS AND METHODS: We evaluated 84 MBC and 37 primary TNBC cases using GATA3, SOX10, and PAX8 staining in whole tissue sections. RESULTS: GATA3 was least sensitive in the detection of metastatic TNBC (metastatic non-TNBC, 0.95; metastatic TNBC, 0.37). SOX10 had the lowest overall sensitivity (0.12) but was elevated in metastatic TNBC, even higher than GATA3 (0.59 vs. 0.37). The combination of GATA3, SOX10, and PAX8 expression showed the highest detection rate (MBC, 0.94; metastatic non-TNBC, 0.95; metastatic TNBC, 0.93). CONCLUSION: We recommend combining GATA3, SOX10, PAX8 expression profiling to confirm breast as the site of origin in metastatic MBC.

Alveolar Soft Part Sarcoma of the Uterus: Clinicopathological and Molecular Characteristics.

Alveolar soft part sarcoma (ASPS) is a rare malignant mesenchymal tumor mainly affecting adolescents and young adults, with a predilection for the deep soft tissues of extremities. ASPS arising in the female genital tract is extremely rare and poses a significant diagnostic challenge. We herein present two rare cases of ASPS, one occurring in the uterine corpus of a 27-year-old woman, and the other in the uterine cervix of a 10-year-old girl. We described the clinical, histological, immunophenotypical, and molecular characteristics of primary uterine ASPS. We performed immunostaining for transcription factor E3 (TFE3), human melanoma black 45 (HMB45), melan-A, desmin, pan-cytokeratin (CK), paired box 8 (PAX8), CD10, hormone receptors, and S100, and targeted RNA and DNA sequencing using commercially available cancer gene panel. In case 1, a 27-year-old woman was referred to our hospital after laparoscopic uterine myomectomy at an outside hospital. Imaging studies revealed a residual tumor in the uterine corpus. In case 2, a 10-year-old girl underwent surgical excision for the cervical mass and was diagnosed as having ASPS. She was then referred to our hospital for further management. Both patients received total hysterectomy. Histologically, they displayed characteristic histological features of ASPS. Strong nuclear TFE3 immunoreactivity, periodic acid-Schiff-positive, diastase-resistant intracytoplasmic rod-shaped crystalloids or granules, and the identification of ASPSCR1-TFE3 fusion confirmed the diagnosis of ASPS in both cases. Lack of immunoreactivity for HMB45, melan-A, desmin, pan-CK, PAX8, and S100 excluded the possibility of perivascular epithelioid cell tumor, clear cell sarcoma, metastatic renal cell carcinoma, granular cell tumor, and paraganglioma. Our observations can help pathologists make an accurate diagnosis of uterine ASPS and suggest that pathologists should include primary uterine ASPS in the differential diagnosis of uterine mesenchymal tumors.

Clinicopathological Characterization of Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System.

BACKGROUND/AIM: Primary central nervous system diffuse large B-cell lymphoma (CNS DLBCL) is a rare entity, accounting for 3-4% of intracranial neoplasms. This study aimed to investigate the clinicopathological characteristics of primary CNS DLBCL patients and their prognostic implication. PATIENTS AND METHODS: We collected 74 cases of clinically and pathologically confirmed primary CNS DLBCL from two institutions. Disease-free survival (DFS) and overall survival (OS) were analyzed based on various clinicopathological parameters. RESULTS: Most cases (83.8%) were classified as activated B-cell immunophenotype by Hans algorithm and cell-of-origin classification did not influence the clinical outcome. On univariate analysis, age (>60 years) and ECOG performance status (≥2) were significantly associated with shorter DFS and OS, and MYC/BCL2 co-expression significantly impacted poor DFS. An anaplastic variant was diagnosed in only 2 cases, but it raised possible association with poor outcome. On multivariate analysis, ECOG performance status and age was associated with poor prognosis. CONCLUSION: In primary CNS DLBCL, age and performance status revealed the most significant association with prognosis. Cell-of-origin classification was not a significant prognostic factor in contrast to systemic DLBCL.

Dynamics of the Tumor Immune Microenvironment during Neoadjuvant Chemotherapy of High-Grade Serous Ovarian Cancer.

The dynamic changes in the tumor immune microenvironment (TIME) triggered by neoadjuvant chemotherapy (NAC) have not been clearly defined in advanced-stage ovarian cancer. We analyzed the immunologic changes induced by NAC to correlate them with clinical outcomes. We compared the changes in the immune infiltration of high-grade serous carcinoma biopsies before and after NAC via immunohistochemistry (147 paired samples) and whole transcriptome sequencing (35 paired samples). Immunohistochemistry showed significantly increased PD-L1 levels and TIL levels after NAC. Whole transcriptome sequencing revealed that the stromal score, immune score, and cytolytic activity score significantly increased after NAC. An increased tumor-infiltrating lymphocyte (TIL) level in response to NAC was associated with shorter progression-free survival compared with decreased TIL level after NAC. In tumors with increased TIL levels after NAC, the relative fraction of CD8 T cells and regulatory T cells significantly increased with immunohistochemistry. Post-NAC tumors were enriched in gene sets associated with immune signaling pathways, such as regulatory T cell and JAK/STAT signaling pathways. NAC induced dynamic changes in the TIME that increased TIL levels, but their high abundance did not impart any survival benefit. Our data may provide therapeutic strategies to improve the survival benefit from immunotherapies in ovarian cancer.

p53 Immunohistochemistry and Mutation Types Mismatching in High-Grade Serous Ovarian Cancer.

High-grade serous carcinoma (HGSCa) of the ovary is featured by TP53 gene mutation. Missense or nonsense mutation types accompany most cases of HGSCa that correlate well with immunohistochemical (IHC) staining results-an all (missense) or none (nonsense) pattern. However, some IHCs produce subclonal or mosaic patterns from which TP53 mutation types, including the wild type of the gene, cannot be clearly deduced. We analyzed a total of 236 cases of ovarian HGSCa and tumors of other histology by matching the results of p53 IHC staining and targeted next-generation sequencing (TruSight Tumor 170 panel). Ambiguous IHCs that do not belong to the conventional "all or none" groups were reviewed to distinguish the true wild type (WT) from potentially pathogenic subclonal or mosaic patterns. There were about 9% of sequencing-IHC mismatching cases, which were enriched by the p53 c-terminal encoding nuclear localization signal and oligomerization domain, in which the subcellular locations of p53 protein were affected. Indeed, mutations in the oligomerization domain of the p53 protein frequently revealed an unmatched signal or cytosolic staining (L289Ffs*57 (Ins), and R342*). We conclude that both mutation types and IHC patterns of p53 are important sources of information to provide a precise diagnosis of HGSCa.

Clinicopathological Characteristics of Microscopic Tubal Intraepithelial Metastases from Adenocarcinoma and Small Cell Neuroendocrine Carcinoma of the Uterine Cervix.

BACKGROUND/AIM: Some metastatic tumors that involve the fallopian tube show intraepithelial spread, mimicking primary tubal neoplasm and representing a potential diagnostic pitfall. In this study, we aimed to investigate the clinicopathological characteristics of tubal intraepithelial metastasis (IEM) from cervical carcinoma. PATIENTS AND METHODS: We analyzed the clinical features, histological features, and immunophenotypes of IEMs in five patients with cervical carcinoma. RESULTS: This study included usual-type (1/5), mucinous-type (1/5), and gastric-type (2/5) endocervical adenocarcinomas and small cell neuroendocrine carcinoma (1/5) cases. None of the patients had ovarian metastasis, but metastatic tumor cells spread along the tubal mucosal surface and partially replaced the lining epithelium. Histological features of metastatic tumors closely resembled those of the primary tumors in all cases. CONCLUSION: Tubal IEM can mimic various tubal lesions including serous tubal intraepithelial carcinoma. Morphological consistency between the primary and metastatic tumors and immunostaining help guide the differential diagnosis of challenging intraepithelial lesions of the fallopian tube.

Clinicopathological features of 70 desmoid-type fibromatoses confirmed by ß-catenin immunohistochemical staining and CTNNB1 mutation analysis.

Desmoid-type fibromatosis (DF) is a locally aggressive neoplasm characterized by mutations in the CTNNB1 gene, which encodes the ß-catenin protein. We reviewed 85 cases of DF and performed Sanger sequencing for detecting mutations in CTNNB1 and immunostaining for detecting ß-catenin localization. We included 70 DF samples, of which 56 cases demonstrated nuclear ß-catenin localization and 43 cases harboured CTNNB1 mutations. CTNNB1-mutant DF samples consistently displayed nuclear ß-catenin expression and were derived from larger-sized tumours compared to samples with wild-type CTNNB1. When we further classified DF cases into 2 subgroups based on the type of specimen, excised specimens with nuclear ß-catenin expression frequently displayed CTNNB1 mutation and no statistical correlation between nuclear ß-catenin expression and CTNNB1 mutation was observed in biopsies. When we classified CTNNB1 mutation cases into 2 subgroups (DF with T41A or T41I, and DF with S45F or S45P), T41A or T41I mutations were observed more frequently in males than in females. Additionally, DF tumours harbouring S45F or S45P mutations were located more frequently in the abdominal wall than tumours with T41A or T41I mutations. In conclusion, CTNNB1 mutation correlates with nuclear ß-catenin expression in larger or excised DF tumours, and DF harbouring CTNNB1 mutations manifest variable clinical presentations.

Mesonephric-like Differentiation of Ovarian Endometrioid and High-grade Serous Carcinomas: Clinicopathological and Molecular Characteristics Distinct from Those of Mesonephric-like Adenocarcinoma.

BACKGROUND/AIM: Ovarian endometrioid carcinoma (EC) and high-grade serous carcinoma (HGSC) may exhibit various growth patterns and mimic mesonephric-like adenocarcinoma (MLA). We investigated the clinicopathological and molecular features of ovarian carcinomas with mesonephric-like differentiation (MLD). PATIENTS AND METHODS: We analyzed the electronic medical records and pathology slides of two EC-MLD and three HGSC-MLD patients, and conducted immunostaining and targeted sequencing of their samples. RESULTS: All cases showed architectural diversity, compactly aggregated small tubules and ducts, and eosinophilic intraluminal secretions, indicating the possibility of an ovarian MLA. However, the following histological and immunophenotypical features confirmed the diagnoses of EC-MLD and HGSC-MLD: squamous, tubal, and sertoliform differentiation; serous tubal intraepithelial carcinoma; solid, endometrioid, transitional (SET) feature; solid, transitional, endometrioid, mucinous-like (STEM) feature; diffuse expression of hormone receptors and Wilms tumor 1; mutant p53 immunostaining pattern; and wild-type v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog gene. CONCLUSION: A subset of ovarian ECs and HGSCs can display MLD and mimic an MLA. A thorough histological examination combined with ancillary tests is crucial to differentiate between these ovarian neoplastic entities.

Placental Site Plaque of the Uterine Cervix Misinterpreted as Low-Grade Squamous Intraepithelial Lesion in Liquid-Based Cervicovaginal Cytology: Usefulness of Inhibin-α Immunocytochemistry.

Cytological features of placental site plaques in liquid-based cervicovaginal preparations have been seldom documented in the literature. We present a rare case of endocervical placental site plaque misinterpreted as a low-grade squamous intraepithelial lesion in a liquid-based cytological preparation. A 32-year-old woman with polycystic ovarian syndrome gave birth 7 months previously. After delivery, she was diagnosed with cervical low-grade squamous intraepithelial lesion during routine cytological examination. Cytologically, many atypical cells showed large hyperchromatic nuclei with irregular membranes. The perinuclear cytoplasmic clearing closely resembled koilocytosis. Histologically, the endocervix showed typical histological features of a placental site plaque. Immunohistochemically, the trophoblasts were positive for p63, CD10, and inhibin-α but negative for p16. Based on genotyping, both the cytological and biopsied specimens tested negative for human papillomavirus. We re-examined the liquid-based preparation cytology slides thoroughly and concluded that the atypical cells initially misinterpreted as low-grade squamous intraepithelial lesion were actually trophoblasts. Immunocytochemical staining revealed uniform cytoplasmic inhibin-α expression in the trophoblasts. In summary, we demonstrated that endocervical placental site plaques can mimic low-grade squamous intraepithelial lesions in liquid-based cytological preparations. Immunocytochemical staining results and negative results on human papillomavirus genotyping further support that atypical cells resembling koilocytes are trophoblasts obtained from the placental site plaque.

Glioblastomas harboring gene fusions detected by next-generation sequencing.

Oncogenic gene fusions have been reported in diffuse gliomas and may serve as potential therapeutic targets. Here, using next-generation sequencing analysis (Illumina TruSight Tumor 170 panel), we analyzed a total of 356 diffuse gliomas collected from 2017 to 2019 to evaluate clinical, pathological, and genetic features of gene fusion. We found 53 cases of glioblastomas harboring the following oncogenic gene fusions: MET (n = 18), EGFR (n = 14), FGFR (n = 12), NTRK (n = 5), RET (n = 2), AKT3 (n = 1), and PDGFRA fusions (n = 1). Gene fusions were consistently observed in both IDH-wildtype and IDH-mutant glioblastomas (8.8% and 9.4%, p = 1.000). PTPRZ1-MET fusion was the only fusion that genetically resembled secondary glioblastomas (i.e., high frequency of IDH mutation, ATRX loss, TP53 mutation, and absence of EGFR amplification), whereas other gene fusion types were similar to primary glioblastomas (i.e., high frequency of IDH-wildtype, TERT mutation, EGFR amplification, and PTEN mutation). In IDH-wildtype glioblastoma patients, multivariable analysis revealed that the PTPRZ1-MET fusion was associated with poor progression-free survival (HR [95% CI]: 5.42 (1.72-17.05), p = 0.004). Additionally, we described two novel cases of CCDC6-RET fusion in glioma. Collectively, our findings indicate that targetable gene fusions are associated with aggressive biological behavior and can aid the clinical treatment strategy for glioma patients.