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BioRxiv : the Preprint Server For... Jun 2024Drosophila models for tumorigenesis and metastasis have revealed conserved mechanisms of signaling that are also involved in mammalian cancer. Many of these models use...
Drosophila 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 Drosophila development, when tissues are highly mitotically active, or stem cells are abundant. Fewer Drosophila tumorigenesis models use adult animals to initiate tumor formation when many tissues are largely terminally differentiated and postmitotic. The Drosophila 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 Drosophila 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 Drosophila 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 Drosophila 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 -
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 -
Pediatric and Developmental Pathology :... 2024Wilms tumor (WT) is the commonest cause of renal cancer in children. In Europe, a diagnosis is made for most cases on typical clinical and radiological findings, prior...
Wilms tumor (WT) is the commonest cause of renal cancer in children. In Europe, a diagnosis is made for most cases on typical clinical and radiological findings, prior to pre-operative chemotherapy. Here, we describe a case of a young boy presenting with a large abdominal tumor, associated with raised serum alpha-fetoprotein (AFP) levels at diagnosis. Given the atypical features present, a biopsy was taken, and histology was consistent with WT, showing triphasic WT, with epithelial, stromal, and blastemal elements present, and positive WT1 and CD56 immunohistochemical staining. During pre-operative chemotherapy, serial serum AFP measurements showed further increases, despite a radiological response, before a subsequent fall to normal following nephrectomy. The resection specimen was comprised of ~55% and ~45% stromal and epithelial elements, respectively, with no anaplasia, but immunohistochemistry using AFP staining revealed positive mucinous intestinal epithelium, consistent with the serum AFP observations. The lack of correlation between tumor response and serum AFP levels in this case highlights a more general clinical unmet need to identify WT-specific circulating tumor markers.
Topics: Humans; Wilms Tumor; alpha-Fetoproteins; Male; Biomarkers, Tumor; Kidney Neoplasms; Nephrectomy
PubMed: 38098239
DOI: 10.1177/10935266231213467 -
Modern Pathology : An Official Journal... Jan 2024Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due...
Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due to frequent resistance to chemotherapy. We hypothesized that DA WT cells might undergo changes, such as acquiring a persistent tolerance to DNA damage and copy number aberrations (CNAs), which could eventually lead to their resistance to chemotherapy treatment. Tissue sections from chemotherapy-treated DA WTs (n = 12) were compared with chemotherapy-treated nonanaplastic WTs (n = 15) in a tissue microarray system, enabling analysis of 769 tumor regions. All regions were scored for anaplastic features and immunohistochemistry was used to quantify p53 expression, proliferation index (Ki67), and DNA double-strand breaks (γH2AX). CNAs were assessed by array-based genotyping and TP53 mutations using targeted sequencing. Proliferation index and the frequency of DNA double-strand breaks (γH2AX dot expression) increased with higher anaplasia scores. Almost all (95.6%) areas with full-scale anaplasia had TP53 mutations or loss of heterozygosity, along with an increased amount of CNAs. Interestingly, areas with wild-type TP53 with loss of heterozygosity and only one feature of anaplasia (anaplasia score 1) also had significantly higher proliferation indices, more DNA double-strand breaks, and more CNAs than regions without any anaplastic features (score 0); such areas may be preanaplastic cell populations under selective pressure for TP53 mutations. In conclusion, we suggest that chemoresistance of DA WTs may be partly explained by a high proliferative capability of anaplastic cells, which also have a high burden of double-stranded DNA breaks and CNAs, and that there is a gradual emergence of anaplasia in WT.
Topics: Humans; Kidney Neoplasms; Anaplasia; Wilms Tumor; Mutation; Prognosis; DNA
PubMed: 37951357
DOI: 10.1016/j.modpat.2023.100382 -
American Journal of Translational... 2023Adult granulosa cell tumor (AGCT) is a rare ovarian sex-cord malignancy notorious for late recurrences and metastases. The cytologic features of AGCT at the metastatic...
INTRODUCTION
Adult granulosa cell tumor (AGCT) is a rare ovarian sex-cord malignancy notorious for late recurrences and metastases. The cytologic features of AGCT at the metastatic sites have been documented sporadically. Hence, knowledge of the characteristic cytomorphologic features is essential for an accurate diagnosis and distinguishing it from its pathologic mimics, especially at the metastatic sites.
MATERIALS AND METHODS
This was a retrospective study conducted over six years. The cytopathology electronic database was searched for the fine needle aspirates (FNA) reported as metastatic AGCT. A detailed cytomorphologic assessment was done for multiple cytologic features, including overall cellularity, cellular arrangement of the tumor cells, cell size, cell shape, nuclear pleomorphism, nuclear grooving, chromatin pattern, nucleolar prominence, mitotic figures, amount and character of cytoplasm, and the extracellular background.
RESULTS
There were 6 cases reported as metastatic AGCT on aspiration cytology. The smears in all the cases were cellular, with tumor cells arranged in loose aggregates, three-dimensional clusters, perivascular papillary fronds, and scattered singly. The most consistent cytologic features included microfollicular arrangement of monomorphic tumor cells with round-oval nuclei, fine chromatin, longitudinal nuclear grooving, and scant cytoplasm. Typical and metachromatically stained extracellular hyaline material were noted sporadically. None of the smears showed anaplasia, prominent macronucleoli, atypical mitoses, or necrosis.
CONCLUSIONS
The current study not only outlines the distinct cytologic attributes of AGCTs across various metastatic locations but also highlights its prevalent cytologic mimics. Additionally, it outlines key clinicopathologic traits that can aid in distinguishing and precisely diagnosing these tumors through cytological analysis.
PubMed: 37854236
DOI: No ID Found -
Radiologia 2023Meningiomas are tumors that originate in the arachnoid villi and are the most common non-glial neoplasm in the central nervous system. The clinical manifestations...
Meningiomas are tumors that originate in the arachnoid villi and are the most common non-glial neoplasm in the central nervous system. The clinical manifestations associated with meningioma depend, fundamentally, on its location. The location in the cerebral convexity is the most frequent, especially in the frontal lobes, manifesting with headache, motor disturbances, seizures and even neurocognitive disorders. There are 15 histologic subtypes of meningioma and three histologic grades. Within these, grades two and three have a worse prognosis and a higher rate of recurrence, as well as a radiological behavior that is generally more aggressive. Although there are some imaging features that can suggest a specific subtype, the definitive diagnosis will always require histological/molecular confirmation.
Topics: Humans; Meningioma; Diagnostic Imaging; Radiography; Prognosis; Meningeal Neoplasms
PubMed: 37758336
DOI: 10.1016/j.rxeng.2023.09.002 -
Cancers Sep 2023In meningiomas, TERT promotor mutations are rare but qualify the diagnosis of anaplasia, directly impacting adjuvant therapy. Effective screening for patients at risk...
PURPOSE
In meningiomas, TERT promotor mutations are rare but qualify the diagnosis of anaplasia, directly impacting adjuvant therapy. Effective screening for patients at risk for promotor mutations could enable more targeted molecular analyses and improve diagnosis and treatment.
METHODS
Semiautomatic segmentation of intracranial grade 2/3 meningiomas was performed on preoperative magnetic resonance imaging. Discriminatory power to predict TERT promoter mutations was analyzed using a random forest algorithm with an increasing number of radiomic features. Two final models with five and eight features with both fixed and differing radiomics features were developed and adjusted to eliminate random effects and to avoid overfitting.
RESULTS
A total of 117 image sets including training ( = 94) and test data ( = 23) were analyzed. To eliminate random effects and demonstrate the robustness of our approach, data partitioning and subsequent model development and testing were repeated a total of 100 times (each time with repartitioned training and independent test data). The established five- and eight-feature models with both fixed and different radiomics features enabled the prediction of TERT with similar but excellent performance. The five-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 91.8%/94.3%, mean accuracy of 85.5%/88.9%, mean sensitivity of 88.6%/91.4%, mean specificity of 83.2%/87.0%, and a mean Cohen's Kappa of 71.0%/77.7%. The eight-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 92.7%/94.6%, mean accuracy of 87.3%/88.9%, mean sensitivity of 89.6%/90.6%, mean specificity of 85.5%/87.5%, and a mean Cohen's Kappa of 74.4%/77.6%. Of note, the addition of further features of up to = 8 only slightly increased the performance.
CONCLUSIONS
Radiomics-based machine learning enables prediction of TERT promotor mutation status in meningiomas with excellent discriminatory performance. Future analyses in larger cohorts should include grade 1 lesions as well as additional molecular alterations.
PubMed: 37686690
DOI: 10.3390/cancers15174415