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Pathology May 2024Wilms tumour (WT) is the most common renal tumour in children, and studies of immune checkpoint inhibitors (ICIs) treatment and markers are limited in number. In this...
Wilms tumour (WT) is the most common renal tumour in children, and studies of immune checkpoint inhibitors (ICIs) treatment and markers are limited in number. In this study we investigated the ICIs' related immune landscape by examining the expression of PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) proteins by immunohistochemistry (IHC), tumour mutation burden (TMB), and correlations with histology and clinical outcome. Positive PD-L1 (SP263) expression was defined as modified combined positive score (CPS) ≥1. A total of 59 WTs (from 2000 to 2017), including eight (14.0%) with anaplasia, from 46 patients were analysed (45 primary and 14 metastatic). Thirteen WTs (13/59, 22%) were positive for PD-L1 (8 primary, 5 metastatic; CPS 1.11-3.42). Positive PD-L1 expression was associated with diffuse anaplasia (p<0.05) and significantly shorter progression-free survival (p<0.05) among WTs with favourable histology (n=39). CD8+ lymphocytes were present in all analysed WTs. A subset of CD8+ cells co-expressed PD-1, which was associated with favourable histology and treatment. MMR IHC stains identified two (2/18, 11%) WTs with isolated PMS2 loss. All six WTs analysed for TMB showed low mutation burden. We found CD8+ lymphocytes in all analysed WTs and identified a fraction of WT (17.8% of primary and 35.8% of metastatic) with positive PD-L1 CPS, suggesting potential response to ICIs in some patients.
PubMed: 38879422
DOI: 10.1016/j.pathol.2024.03.005 -
BioRxiv : the Preprint Server For... Jun 2024models for tumorigenesis and metastasis have revealed conserved mechanisms of signaling that are also involved in mammalian cancer. Many of these models use the...
models for tumorigenesis and metastasis have revealed conserved mechanisms of signaling that are also involved in mammalian cancer. Many of these models use the proliferating tissues of the larval stages of development, when tissues are highly mitotically active, or stem cells are abundant. Fewer tumorigenesis models use adult animals to initiate tumor formation when many tissues are largely terminally differentiated and postmitotic. The accessory glands are prostate-like tissues and a model for some aspects of prostate tumorigenesis using this tissue has been explored. In this model, oncogenic signaling was induced during the proliferative stage of accessory gland development, raising the question of how oncogenic activity would impact the terminally differentiated and postmitotic adult tissue. Here, we show that oncogenic signaling in the adult accessory gland leads to activation of a conserved pro-tumorigenic program, similar to that observed in mitotic larval tissues, but in the absence of proliferation. Oncogenic signaling in the adult postmitotic gland leads to tissue hyperplasia with nuclear anaplasia and aneuploidy through endoreduplication, which increases polyploidy and occasionally results in non-mitotic neoplastic-like extrusions. We compare gene expression changes in our model with that of endocycling prostate cancer cells induced by chemotherapy, which potentially mediate tumor recurrence after treatment. Similar signaling pathways are activated in the gland and endocycling cancer cells, suggesting the adult accessory glands provide a useful model for aspects of prostate cancer progression that do not involve cellular proliferation.
PubMed: 38853988
DOI: 10.1101/2024.05.10.593549 -
Journal of Neuropathology and... May 2024Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor,...
Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor, either at presentation or at recurrence. To date, most published cases lack molecular characterization. We describe the histologic and molecular features of 3 patients presenting with BRAF p. V600E-mutant GG (CNS WHO grade 1) with high-grade glial transformation at recurrence. The tumors occurred in pediatric patients (age 9-16 years) with time to recurrence from 20 months to 7 years. At presentation, each tumor was low-grade, with a BRAFV600E-positive ganglion cell component and a glial component resembling pleomorphic xanthoastrocytoma (PXA) or fibrillary astrocytoma. At recurrence, tumors resembled anaplastic PXA or high-grade astrocytomas without neuronal differentiation. CDKN2A homozygous deletion (HD) was absent in all primary tumors. At recurrence, 2 cases acquired CDKN2A HD; the third case showed loss of p16 and MTAP immunoexpression, but no CDKN2A/B HD or mutation was identified. By DNA methylation profiling, all primary and recurrent tumors either grouped or definitely matched to different methylation classes. Our findings indicate that malignant progression of the glial component can occur in GG and suggest that CDKN2A/B inactivation plays a significant role in this process.
Topics: Humans; Ganglioglioma; Adolescent; Child; Brain Neoplasms; Male; Female; Proto-Oncogene Proteins B-raf; Epigenesis, Genetic; Neoplasm Recurrence, Local; Cell Transformation, Neoplastic
PubMed: 38699943
DOI: 10.1093/jnen/nlae038 -
Pediatric Blood & Cancer Jul 2024The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic...
INTRODUCTION
The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials.
METHODS
Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed.
RESULTS
Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months.
CONCLUSION
Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.
Topics: Humans; Wilms Tumor; Male; Female; Kidney Neoplasms; Child, Preschool; Infant; Anaplasia; Child; Prognosis; Survival Rate; Follow-Up Studies; Nephrectomy
PubMed: 38637871
DOI: 10.1002/pbc.30981 -
Genes, Chromosomes & Cancer Apr 2024The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification...
The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.
Topics: Male; Humans; Adult; Child; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Rhabdomyosarcoma, Alveolar; Epigenomics; Genomics; Ribonuclease III; DEAD-box RNA Helicases; Receptor, Fibroblast Growth Factor, Type 1
PubMed: 38607246
DOI: 10.1002/gcc.23232 -
Pediatric Blood & Cancer Jul 2024Anaplasia in Wilms tumor is recognized as the most important prognostically unfavorable histological feature. It is subtyped as focal anaplastic Wilms tumor (FAWT) and... (Review)
Review
Anaplasia in Wilms tumor is recognized as the most important prognostically unfavorable histological feature. It is subtyped as focal anaplastic Wilms tumor (FAWT) and diffuse anaplastic Wilms tumor (DAWT). Outcomes of patients with DAWT remain poor in patients with stage III and IV tumors. Important issues relevant to anaplasia in Wilms tumor, including prevalence, treatment, outcomes, biomarkers, anaplasia, and chemotherapy, and the concept of tumor aggressiveness, are reviewed and discussed here. We also consider the differences in clinical approaches to anaplasia in Wilms tumor between the two major renal tumor clinical research groups: the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group and the Children's Oncology Group (COG) Renal Tumor Group. We emphasize the importance and implications of recognizing FAWT and DAWT as separate clinico-pathological entities.
Topics: Wilms Tumor; Humans; Kidney Neoplasms; Anaplasia; Prognosis
PubMed: 38605554
DOI: 10.1002/pbc.31000 -
Current Issues in Molecular Biology Mar 2024There is an ongoing need for biomarkers that could reliably predict the outcome of BC and that could guide the management of this disease. In this setting, we aimed to...
There is an ongoing need for biomarkers that could reliably predict the outcome of BC and that could guide the management of this disease. In this setting, we aimed to explore the prognostic value of the transcription factor P63 in patients with muscle-invasive bladder cancer (MIBC) having undergone radical cystectomy. The correlation between P63 expression and clinicopathological features (tumor stage, nodes involvement, patterns of muscularis propria invasion, papillary architecture, anaplasia, concomitant carcinoma in situ, lymphovascular invasion, perineural invasion, necrosis) and molecular subtyping (basal and luminal type tumors) was tested in 65 radical cystectomy specimens and matched with cancer-specific survival (CSS) and overall survival (OS). P63-negative tumors displayed significantly higher rates of pattern 2 of muscularis propria invasion (50% vs. 14%, = 0.002) and variant histology (45% vs. 19%, = 0.022) compared to P63-positive ones. According to the combined expression of CK5/6 and CK20 (Algorithm #1), P63-positive and P63-negative tumors were mostly basal-like and double-negative, respectively ( = 0.004). Using Algorithm #2, based on the combined expression of CK5/6 and GATA3, the vast majority of tumors were luminal overall and in each group ( = 0.003). There was no significant difference in CSS and OS between P63-positive and P63-negative tumors, but the former featured a trend towards longer OS. Though associated with pathological features harboring negative prognostic potential, P63 status as such failed to predict CSS and OS. That said, it may contribute to better molecular subtyping of MIBC.
PubMed: 38534771
DOI: 10.3390/cimb46030155 -
Cancer Management and Research 2024The determination of the presence or absence of anaplasia in Wilms tumor is difficult sometimes creating diagnostic errors and is worsened by the use of neoadjuvant...
PURPOSE
The determination of the presence or absence of anaplasia in Wilms tumor is difficult sometimes creating diagnostic errors and is worsened by the use of neoadjuvant chemotherapy, which causes cellular alterations that may mimic anaplasia. This study described the histological features of Wilms tumor and their association with WT1 and p53 expression in archived specimens in South Western Uganda.
PATIENTS AND METHODS
A series of 308 formalin-fixed paraffin-embedded tissue blocks belonging to 85 children were retrospectively recruited in the only public Histopathology laboratory in South Western Uganda. Rabbit monoclonal Anti-Wilms tumor protein antibody [(CAN-R9) IHC-56-2] ab89901 and rabbit monoclonal Anti-p53 antibody [E26] ab32389 were used to assess the expression of WT1 and p53, respectively. The expression of WT1 and p53 were reported as proportions, Chi-square was also performed to assess for associations and statistical significance was considered when the p-value was less than 0.05.
RESULTS
The median age was 3.5 with an interquartile range of (2-6) years. Mixed histology was the most common at 35.29% (95% CI:25.77-46.14). Anaplasia was present in 5.88% (95% CI:2.44-13.52) of the specimens. p53 and WT1 expressions were 13.0% (95% CI:7.25-22.04), and 41.0% (95% CI: 31.11-52.04), respectively.
CONCLUSION
Mixed-type histology is the most common histologic feature of Wilms tumor with high expression of WT1 and a low expression of p53 implying that these can be used routinely to confirm the diagnosis as well as anaplasia in South Western Uganda.
PubMed: 38476972
DOI: 10.2147/CMAR.S449982 -
Urology Annals 2024Emphasis on grossing to reporting for the assessment of histopathological parameters predicting outcomes in Wilms tumor.
Grossing to reporting of Wilms tumor with emphasis on proper sampling in treatment-naive and postchemotherapy specimens and their clinicopathological correlation with outcome.
CONTEXT
Emphasis on grossing to reporting for the assessment of histopathological parameters predicting outcomes in Wilms tumor.
AIMS
To analyze various clinicopathological parameters that effect outcomes in treatment naïve and post chemotherapy Wilms tumor specimens.
SETTINGS AND DESIGN
This was a retrospective observational study.
SUBJECTS AND METHODS
All patients diagnosed with Wilms tumor between 2012 and 2018 at our institute will be included with their clinical findings, laboratory reports, and radiological findings. The patients will be categorized into two groups based on treatment protocol (Society of Pediatric Oncology (SIOP) or the National Wilms Tumor Study Group/Children's Oncology Group (COG) guidelines) used. Details of Grossing and reporting protocols used for the in pre treatment and post treatment specimens will be analyzed. Follow-up till December 2020 will be analyzed.
STATISTICAL ANALYSIS USED
Chi-square and Fisher's exact tests were used for statistical analysis.
RESULTS
A total of 36 patients with the diagnosis of Wilms tumor were included in the present study. The mean age of presentation was 3.9 ± 0.7 years, and males were more common than females. Most of them presented as abdominal mass and few with isolated hematuria. Twenty-six (72%) patients were treated under SIOP protocol with preoperative neoadjuvant chemotherapy. Ten patients underwent upfront surgery as per COG protocol. In SIOP group patients, the mean tumor size was 9.3cm. Forty percent ( = 10) we mixed histological type followed by blastemal type constituting (32%, = 8). Regressive and epithelial histological types constituted 16% ( = 4) and 12% ( = 3), respectively. In the SIOP group 72% ( = 19) had no anaplasia and 28% ( = 7) had anaplasia. Fifty seven percent ( = 15) cases were Stage I, followed by 26.9% = 7) and 11.5% ( = 3) being Stage II and Stage III, respectively. Ten patients underwent upfront surgery as per COG protocol. The mean tumor size among this group was 8 cm ranging from 7 cm to 11 cm. Eight (80%) cases had favorable histology and two cases showed focal anaplasia. Heterologous differentiation is seen in 3 (70%). Out of the 10 cases, one case was Stage I, six were Stage 2, one was Stage III, and two were clinical Stage IV. None of the cases showed either vessel or lymph node metastasis. All the patients received adjuvant chemotherapy postsurgery and were followed up till December 2020 for (at least 3 years). Of 25 patients in the SIOP group, 18 (72%) had complete remission with no radiological evidence of residual disease. Of the 10 patients in the COG group, 6 (70%) had complete remission.
CONCLUSIONS
Histopathological evaluation of Wilms tumor is a critical aspect in the management of Wilms tumor, as tumor characteristics are different in the tumors treated under SIOP and COG protocols, which will ultimately affect the prognostic risk stratification. This necessitates the knowledge of the important grossing and reporting of these tumors under the two protocols.
PubMed: 38415234
DOI: 10.4103/ua.ua_60_23 -
Cureus Jan 2024Acinic cell carcinoma (ACC) is an exceedingly rare type of triple-negative breast cancer (TNBC). We are reporting a case of a 46-year-old female patient who presented...
Acinic cell carcinoma (ACC) is an exceedingly rare type of triple-negative breast cancer (TNBC). We are reporting a case of a 46-year-old female patient who presented with a palpable lump in her left breast not associated with pain, pruritis, or change of skin color. An open biopsy revealed a mass of about 20 x 25 mm of fleshy, white tan with a lobular configuration and necrosis. The histopathological examination revealed cells with cytoplasmic granularity arranged in a microglandular pattern and a solid pattern, and the case was initially reported as ACC. The most remarkable feature was the presence of small and large, brightly eosinophilic cytoplasmic granules, and some cells are clear or multivacuolated, resembling lipoblasts. Cellular pleomorphism and anaplasia are very mild, and the mitotic activity was very low. The tumor showed a scant and vascularized stroma in the area of hyalinization. Small clusters of lymphoid infiltration in the stroma were seen. Histochemical stains revealed that the acinar cells in ACC contain abundant diastase-resistant, periodic acid Schiff (PAS)-positive cytoplasmic granules. Mucicarmine and Alcian blue were negative. The immunohistochemistry workup revealed that the case was positive for discovered on gastrointestinal stromal tumors-1 (DOG-1) and the positivity pattern ranged from apical membranous, cytoplasmic, and complete membranous. In addition, the tumor cells were positive for low-molecular-weight cytokeratin, carcinoembryonic antigen (CEA), and epithelial membrane antigen (EMA). The FISH workup for the ETV6-NTRK3 fusion was negative, arguing against secretory carcinoma (SC). A diagnosis of acinar cell carcinoma of the breast is very rare, and the presence of cytoplasmic granules is helpful for its diagnosis. In the absence of these granules, the diagnosis is very difficult, and other diagnoses will be put in the differential diagnosis, particularly SC, lactating adenosis, and microglandular adenosis. Immunohistochemical and histochemical stains and genetic workups will support the diagnosis of ACC.
PubMed: 38298310
DOI: 10.7759/cureus.51427