High-grade Malignancy Research Articles

A single-center experience of central nervous system tumors in children under three years old

PurposeThis study aims to summarize the characteristics of children under three years old (≤3 years) with central nervous system (CNS) tumors and to investigate the factors that influence their overall survival (OS) time.MethodsWe treated 171 pediatric patients (≤3 years) with CNS tumors at Yuquan Hospital of Tsinghua University from January 2016 to June 2023. Of these, 162 cases were successfully followed up. Kaplan–Meier survival analysis and Cox regression were utilized to evaluate factors potentially influencing OS of malignancies.ResultsThere was a male predominance among the patients. The three most common tumors were embryonal tumors, gliomas, and craniopharyngiomas. Gross total resection (GTR) was achieved in select cases. Patients with high-grade malignancies were advised to undergo chemotherapy and/or radiotherapy after surgery. Optic gliomas and diffuse midline gliomas were partially resected and treated with adjuvant treatments. The median survival time of low-grade malignant tumors was 41.5 months, while that of high-grade malignant tumors was 15 months. Kaplan–Meier survival analysis identified the factors potentially influencing OS of malignancies: extent of resection, CNS WHO grade, grade of malignancies, and Ki-67 labeling index (Ki-67 LI). Subsequent multivariate analysis highlighted the interactive factor (extent of resection × CNS WHO grade) along with Ki-67 LI, as the most significant variables. Factors such as sex, age, tumor location, and onset-to-treatment time appeared not to affect OS.ConclusionsGTR remains the cornerstone of treatment for children (≤3 years) with CNS tumors, except for optic glioma, diffuse midline glioma, and germinoma. The interactive factor (extent of resection × CNS WHO grade) and Ki-67 LI are the most significant factors affecting OS. The implementation of preoperative neoadjuvant chemotherapy and early postoperative chemotherapy may enhance prognosis.

Clinicopathological study of a rare neuroectodermal neoplasm of the cranium.

Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, rapidly growing pigmented neoplasm originating from the neural crest. Predominantly affecting infants, it commonly occurs in the head and neck region. MNTI is often locally aggressive with a high recurrence rate. It can be clinically and histologically confused with high-grade malignancies despite being considered benign. We present four cases diagnosed as MNTI through histopathological examination alongside a literature review and would like to study the clinico-radiological findings and histopathological spectrum of this rare entity. This retrospective study (January 2018-March 2024) included cases diagnosed histologically as MNTI. Clinical data, including age, gender, and presentation, were collected. Histological and immunohistochemical analyses were performed using various markers. Four cases (age range, 4-17months; mean, 5.2months) were analyzed. Males were more affected than females (3:1). All presented with scalp swelling. MRI revealed large extra-axial masses with varying contrast enhancement. Histopathology showed biphasic cellular morphology with primitive small round cells and epithelioid cells containing melanin. All cases exhibited brisk mitotic activity and extensive desmoplasia. Immunohistochemically, primitive cells were strongly positive for synaptophysin, while epithelioid cells were positive for cytokeratin and HMB45. Ki-67 indices ranged from 30 to 80%. Follow-up revealed one patient succumbed to sepsis and one had a recurrence. Understanding the clinical and pathological spectrum of MNTI is essential for accurate diagnosis and effective treatment. This study contributes to the existing knowledge by expanding the cohort and enhancing the understanding of this rare tumor.

Differential expression of the SLC34A2 gene in different histological subtypes of ovarian carcinomas

BACKGROUND: Patients with ovarian carcinoma demonstrate different sensitivity to chemotherapy; therefore, to increase the effectiveness of treatment, it is necessary to take into account the characteristics of each patient's tumor, including the histological subtype. AIM: To search for new molecular markers of ovarian cancer by analyzing the expression of candidate genes, including BAX, SLC34A2, MUC16, CD300A, and XKR8, in ovarian carcinomas of different histological subtypes. MATERIAL AND METHODS: Analysis of the expression of the BAX, SLC34A2, MUC16, CD300A, and XKR8 genes in 33 carcinomas taking into account their histological subtypes was performed using real-time polymerase chain reaction. Tumor samples from patients with ovarian carcinoma were obtained from the Blokhin National Medical Research Center of Oncology (Moscow) and the Republican Clinical Oncology Dispensary (Kazan) and divided into groups by histological subtypes: serous of high (n=16) and low (n=6) grade malignancy, endometrioid (n=8) and mucinous (n=3). Additional analysis was performed using microarray data from the Gene Expression Omnibus open database to determine the expression of selected candidate genes in ovarian carcinomas of different histological subtypes. The dataset included 4 normal ovary samples and 95 ovarian carcinoma samples of different histological subtypes: serous (n=41), endometrioid (n=37), and mucinous (n=13). Statistical analysis of the data was performed using Prism software. Nonparametric Dunn's test was used to compare gene expression in several patient groups. RESULTS: The expression level of the SLC34A2 gene was increased in low-grade serous carcinomas (p=0.0257) compared to mucinous carcinomas. Using bioinformatics analysis, we found increased expression of the SLC34A2 gene in serous (p=0.0023) and endometrioid ovarian carcinomas (p=0.0355) compared to normal ovarian tissues. CONCLUSION: The SLC34A2 gene can be considered as a potential molecular marker for differential diagnosis of ovarian cancer histological subtypes and a target for therapy of patients with low-grade serous ovarian carcinoma.

Fine-needle aspiration and effusion cytology of thoracic SMARCA4-deficient undifferentiated tumor and SMARCA4-deficient non-small cell lung carcinoma: A multi-institutional experience with 27 patients.

Thoracic switch/sucrose nonfermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4)-deficient (SD) malignancies, including SD undifferentiated tumor (SD-UT) and SD non-small cell lung carcinoma (SD-NSCLC), have been recently described. The cytologic features of these neoplasms in fine-needle aspiration (FNA) and effusion specimens have rarely been reported in the literature. This study aimed to describe and compare the spectrum of cytologic, immunohistochemical, and clinical features ofthese high-grade malignancies recently encountered at the participating institutions. This study documented clinical and imaging characteristics of tumors from 27 patients. Sixteen cytomorphologic features and immunohistochemical findings were compared between SD-UT and SD-NSCLC samples. Twenty three FNAs, two bronchial brushings, and two pleural fluids were evaluated, including 17 SD-UT cases (mean patient age, 70 years) and 10 SD-NSCLC cases (mean patient age, 62 years). Both malignancies presented with large thoracic masses and/or hilar/mediastinal lymphadenopathy. All SD-UT cytologic samples had a discohesive or mixed cohesive-discohesive architecture, and most (13 of 17) showed predominant rhabdoid or mixed rhabdoid-epithelioid features. Most SD-NSCLC cytologic samples (nine of 10) were either cohesive or mixed cohesive-discohesive and had a predominantly epithelioid morphology (eight of 10). Keratins and claudin-4 were negative or focally positive in SD-UT samples, whereas they were diffusely positive in SD-NSCLC samples. Both malignancies were negative for TTF-1 and p40/p63 and showed loss of expression of SMARCA4. Although there is considerable clinical and cytopathologic overlap between SD-UT and SD-NSCLC, some key features allow for their distinction. SD-UT is mostly discohesive with rhabdoid or mixed rhabdoid-epithelioid features, whereas SD-NSCLC often has cohesive epithelioid morphology. The combination of clinical presentation, cytomorphology, and immunohistochemistry is essential for a definitive diagnosis.

Initial feasibility cohort of temporally modulated pulsed proton re-irradiation (TMPPR) for recurrent high-grade intracranial malignancies

Recurrent high-grade intracranial malignancies have a grim prognosis and uniform management guidelines are lacking. Re-irradiation is underused due to concerns about irreversible side effects. Pulsed-reduced dose rate radiotherapy (PRDR) aims to reduce toxicity while improving tumor control by exploiting dose-rate effects. We share our initial experience with temporally modulated pulsed proton re-irradiation (TMPPR), focusing on workflow, safety, feasibility, and outcomes for the first patient cohort. TMPPR was administered to patients with recurrent or progressive central nervous system malignancies using intensity modulated proton therapy with three fields. Patient and treatment data were collected, responses categorized using RANO assessment, and toxicities graded using CTCAE v5.0. Five patients received TMPPR between October 2022 and May 2023, with a median age of 54 years (Range: 32–72), and a median time from initial radiotherapy to re-RT of 23 months (Range 14–40). Treatment was completed without delay, with a median dose of 60 GyRBE in 30 fractions. Initial treatment response assessment showed complete (n = 1) or partial (n = 3) responses. Limited toxicity was observed, primarily grade 2 alopecia and one case of radiation necrosis graded at 2. This early experience demonstrates the feasibility of TMPPR delivery, highlighting the importance of prospective evaluations in the re-irradiation setting.

Undifferentiated embryonal sarcoma of the liver masquerading as a cystadenoma in a young adult: a case report

BackgroundUndifferentiated embryonal sarcoma of the liver is an infrequent hepatic malignancy, primarily observed in the pediatric population. This neoplasm is exceedingly rare among adults. Despite its scarcity in adult cases, it remains imperative to accurately discern undifferentiated embryonal sarcoma of the liver utilizing diverse imaging modalities to prevent misdiagnosis with more prevalent benign and malignant hepatic masses. In this case, a comprehensive imaging examination was conducted, encompassing ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography–computed tomography scans. Notably, the positron emission tomography–computed tomography scan revealed 18F-fluorodeoxyglucose uptake characteristics indicative of malignancy, providing a pivotal clue for prompt diagnosis of undifferentiated embryonal sarcoma of the liver.Case presentationThis report presents the diagnostic procedure employed for a 37-year-old female patient of Han ethnicity in China diagnosed with undifferentiated embryonal sarcoma of the liver. The patient was admitted with a 2-day history of mid-upper quadrant abdominal pain. The patient’s temperature and inflammatory markers, such as white blood cell count and hypersensitive reactive protein, were slightly elevated. Ultrasound showed a cystic–solid nodule in the liver. The computed tomography revealed a cystic mass in the right lobe of the liver, characterized by a low-density shadow and a lack of significant enhancement during contrast-enhanced scanning, initially suggesting cystadenoma. Enhanced magnetic resonance imaging revealed a block-like abnormal signal shadow in the right hepatic lobe, suggestive of various etiologies, including benign lesions, cystadenoma with hemorrhage, or hemangioma with hemorrhage. However, the positron emission tomography–computed tomography showed increased 18F-fluorodeoxyglucose consumption within both the cystic wall and lesion, raising suspicion of malignancy. Surgical resection of the posterior hepatic lobe was performed under general anesthesia after comprehensive preoperative preparations. During the procedure, a space-occupying lesion was identified in the right posterior hepatic lobe, adhering to the diaphragm. Surface liver parenchyma overlying the tumor exhibited rupture, with several blood clots visible. The tumor was successfully and completely excised. Pathological examination revealed a fusiform cell tumor, necrosis, hemorrhage, cystic changes, cellular atypia, mitotic images, and eosinophilic globules suggestive of undifferentiated embryonal sarcoma of the liver. Immunohistochemical staining indicated CK (+), vimentin (Vim; +), Desmin (+), actin (−), α1-AT (+), GPC-3 (+), PDGFRa (+), MDM2 (+), P16 (+), Ki-67 (+) 30–35%, and PAS (+). The patient underwent five cycles of combination chemotherapy with ifosfamide and epirubicin, administered at 21-day intervals at our hospital. Following 3 years of postoperative surveillance, the patient remained stable, with no evidence of hepatic tumor recurrence.ConclusionOn the basis of this case and a comprehensive literature review, we recommend that clinicians consider the possibility of undifferentiated embryonal sarcoma of the liver in patients presenting with non-specific clinical and serological markers, particularly when there is inconsistency between ultrasound and computed tomography imaging findings, along with elevated 18F-fluorodeoxyglucose uptake observed in both the cystic wall and lesion on positron emission tomography–computed tomography examination. Given the rarity and high-grade malignancy of undifferentiated embryonal sarcoma of the liver, heightened clinical awareness and recognition are crucial for early diagnosis and successful therapy.

YAP1 Status Defines Two Intrinsic Subtypes of LCNEC with Distinct Molecular Features and Therapeutic Vulnerabilities.

Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non-small cell lung cancer approaches. To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models. In this study, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and is characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK- and AXL-targeting strategies, including a novel preclinical AXL chimeric antigen receptor-expressing T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by the expression of SCLC subtype-defining transcription factors, especially ASCL1 and NEUROD1, and as expected, given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including delta-like ligand 3 and CD56 targeting, as is with novel preclinical delta-like ligand 3 and CD56 chimeric antigen receptor-expressing T cells, and DNA damage repair inhibition. YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.

Malignant Rhabdoid Tumor masquerading as Neuroblastoma: A rare Case-report

Abstract Introduction/Objective Malignant rhabdoid tumors (MRT) predominantly impact infants and young children, typically occurring around the age of 15 months. While they can emerge from soft tissues throughout the body, but commonly initiate in the kidneys. Neuroblastoma-like characteristics are seldom observed within the varied phenotypes of malignant rhabdoid tumors. Here, we present an exceptionally rare and distinctive subtype of malignant rhabdoid tumor exhibiting features akin to neuroblastoma localized within the unusal parapharyngeal space. Methods/Case Report A 2-month-old female presented to the ED with an enlarging right cervical neck mass. The mother reported a one-week history of upper respiratory tract symptoms and noticed an enlarging mass of her right neck. CT reported a “parapharyngeal abscess with airway compression”. The patient was started on Augmentin with no significant improvement. Repeat CT with contrast demonstrated an enlarging rim-enhancing 3 cm mass involving the right parapharyngeal space, trachea, and right carotid arteries. Laryngoscopy and incisional biopsy of right neck lymph nodes demonstrated a high-grade malignancy with prominent nucleoli, high N/C ratio and scant cytoplasm. The tumor tested positive for CD 99, synaptophysin, and neurofilament, leading to the initial diagnosis of neuroblastoma. However, molecular analysis uncovered the loss of INI-1 on 22q11.2, prompting a reevaluation and a final diagnosis of MRT with neuroblastoma-like characteristics was made. Results (if a Case Study enter NA) NA Conclusion A range of tumors displaying distinct “rhabdoid” cytological features are collectively termed as malignant rhabdoid tumors (MRTs). Conventional immunohistochemistry (IHC) staining for CD99, synaptophysin, neurofilament, and myogenin might suggest neuroblastoma, Ewing sarcoma, or rhabdomyosarcoma. However, the absence of INI-1 expression provides a definitive diagnosis. INI-1 loss, a purported tumor suppressor gene located on chromosome 22q11.2, solidifies the tumor’s classification as malignant rhabdoid tumor (MRT). Additionally, a positive neurofilament stain in MRT is crucial for diagnostic and therapeutic assessments. This differentiation is vital, given the dismal prognosis of MRT with a 5-year survival rate of less than 10%.

Efficacy of surgery in the management of multiple recurrences of retroperitoneal dedifferentiated liposarcoma.

Retroperitoneal dedifferentiated liposarcoma is associated with a high risk of recurrence; however, treatment strategies that are more effective than surgery remain to be established. This study aimed to determine the optimal number of surgeries that would be effective for patients with recurrent disease. Furthermore, the improvement in prognosis was evaluated according to the malignancy level. The effect of each type of surgery on the prognosis of 118 patients with retroperitoneal dedifferentiated liposarcoma treated at the Osaka International Cancer Institute between 1997 and 2022 was investigated. Among the 118 patients, 103 underwent initial surgery, while 54 and 30 patients underwent second and third surgeries, respectively. The overall and disease-free survival rates of each group were compared using the Kaplan-Meier method, and the log-rank test was used to determine statistical significance in univariate analysis. 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) was used to assess malignancy. Maximum standardized uptake values (SUVmax) of ≥ 4 and < 4 were classified as high and low malignancy, respectively. The first and second surgeries resulted in a significant improvement in the overall survival rate, regardless of the malignancy level (p < 0.001); however, no significant improvement in prognosis was observed after the third surgery (p = 0.077). Low-grade malignancies are associated with a better postoperative prognosis, even in cases of recurrence. In contrast, high-grade malignancies exhibit a reduction in surgical efficacy. This study highlights the importance of considering the tumor malignancy level and the patient's overall condition when deciding whether to perform repeated surgical interventions. Surgical treatment can prolong overall survival, even in patients with recurrence; however, it is advisable to assess malignancy levels when determining the suitability of surgery beyond the second recurrence.

Carcinomes neuroendocrines à grandes cellules (CNEGC) : actualités 2024

Large cell neuroendocrine carcinomas (LCNECs) are rare tumors with high grade malignancy and poor prognosis. The management of LCNECs remains complex and several clinical situations (induction, metastatic stages, etc.) are still debating. While the impact of molecular profiling of these tumors on optimal systemic treatment choice has yet to be demonstrated, the prospective evaluation of immunotherapy in metastatic stages is ongoing and could open up new therapeutic options.1877-1203/© 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Angiogenesis in endometrial cancer: clinical and biological significance

Objective: to summarize the available data on the features of vascularization of endometrioid adenocarcinoma (EAC). Material and Methods. The search for relevant sources was performed in the “PubMed” database using the keywords “endometrium + cancer + angiogenesis”, “endometrium + cancer + angiogenesis + lymph”. Of the selected sources, 78 were included in this review. Results. Angiogenesis is an important and necessary stage in the pathogenesis of the appearance, progression and metastasis of EAC and, thus, the study of tumor vascularization provides an opportunity to improve diagnosis and personalized approach to treatment. Vascular density correlates with advanced stage of EAC, high grade of malignancy, myometrial invasion, cervical and adnexal lesions, vascular invasion, metastases to lymph nodes (LN), the presence of cancer cells in the peritoneal fluid, low overall survival and survival without tumor progression. There are publications that deny the connection of vascularization with the histological type of tumor, its grade, lymphovascular invasion, lymph node metastases, the depth of myometrial invasion, and these publications even prove that microvessel density is not an independent prognostic factor. So, there is still no consensus and final opinion, as evidenced by low or high vascularization of EAC. Recently, there are many drugs that affect both the processes of angiogenesis directly and the inducers and factors that control vascular growth. Unfortunately, all such drugs have a fairly high toxicity, and resistance to them very quickly develops. Conclusion. Despite numerous results of studies devoted to the study of the formation of blood vessels and isolated data on lymphangiogenesis in EAC, there is no data in the literature on studying changes in the vascularization of LN in gynecological cancer. However, proangiogenic and antiangiogenic factors are disseminated throughout the body and must exert their effects in distant organs and tissues. Based on changes in the vascularization of LN, it will apparently become possible to predict the activity of angiogenesis in the primary tumor, assess the prognosis of the disease, and the effectiveness of the treatment. In addition, significant expression of the vascular network in an enlarged lymph node biopsied for diagnosis may be a symptom of the development of a malignant tumor in the lymph collection region, even in the absence of metastases.

Ovarian stimulation response and fertility outcomes in patients with breast cancer across different stages, grades, and hormone receptor status for fertility preservation

BackgroundThis study aimed to explore the potential impact of stage, grade, and hormone receptor profile on ovarian stimulation response and fertility preservation outcomes. MethodsThis retrospective cohort study evaluated data from breast cancer patients who underwent fertility preservation at a tertiary medical center between 2014 and 2022. The outcomes of women with low-stage cancer (stages I and II) were compared with those of women with high-stage disease (stages III and IV or lymph node metastasis). Similarly, we compared those with low-grade (grades 1 and 2) and high-grade (grade 3) malignancies. In addition, we compared different hormone statuses of breast cancer (1) estrogen receptor (ER) positive vs. ER-negative and (2) triple-negative breast cancer (TNBC) vs. non-TNBC. The primary outcome measured was the number of mature oocytes, while the secondary outcomes included the numbers of total oocytes retrieved, peak estradiol levels, and subsequent fertility preservation outcomes. ResultsA total of 47 patients were included. Patients with high-grade tumors had a comparable number of mature oocytes (8 vs. 10, p = 0.08) compared to patients with low grade cancers. The stage-based analysis revealed a similar number of mature oocytes (8 vs. 10, p = 0.33) between high/low stage patients. In the hormone receptor-based analysis, no differences were seen in mature oocytes collected between the ER-positive/ER-negative group (9 vs. 9, p = 0.87) and the TNBC/non-TNBC group (11 vs. 9, p = 0.13). The utilization rate was 27.6% (13/47). ConclusionOur study showed similar ovarian stimulation response and fertility preservation outcomes among breast cancer patients with different prognostic factors.

Quality of life and survivorship in patients with low-grade ovarian cancer

ObjectiveHigh-grade (HGOC) and low-grade ovarian carcinoma (LGOC) are distinct malignancies with different biological features, treatment paradigms, and life expectancies. However, differences in quality of life (QOL), sleep, and depressive symptoms have not been examined by grade, and neither have inflammatory profiles associated with these symptoms. We aim to characterize QOL and biomarkers by OC grade. MethodsParticipants included patients with HGOC (N = 578) or LGOC (N = 85). Participants completed baseline assessments of psychosocial factors prior to primary surgery or neoadjuvant chemotherapy and contributed saliva for cortisol and blood for interleukin-6 (IL-6) quantification. Samples were collected intraoperatively to quantify tumor cortisol. General linear models were used to examine differences in biological and psychological variables by grade. ResultsAt baseline, patients with LGOC reported less depression (p = 0.018) and sleep disturbances (p = 0.014), but no significant difference in depressive mood (p = 0.11) or QOL (p = 0.51) compared to patients with HGOC, adjusting for age and disease stage. There were trends towards lower tumor cortisol levels (p = 0.078) in LGOC compared to HGOC. One-year post-diagnosis, we found a significant improvement in QOL and fatigue, and a decrease in vegetative depression and IL-6 levels irrespective of grade. ConclusionsWe present the first characterization of psychosocial experiences of patients with LGOC. Despite having a better disease prognosis, patients with LGOC were just as likely to have mood disturbances as those with HGOC. There was a trend towards differences in tumor cortisol by grade. Our findings highlight the need to address well-being in patients with both low- and high-grade ovarian malignancies.

TGFβ in malignant canine mammary tumors: relation with angiogenesis, immunologic markers and prognostic role

Transforming growth factor-β (TGFβ) and FoxP3 regulatory T cells (Treg) are involved in human breast carcinogenesis. This topic is not well documented in canine mammary tumors (CMT). In this work, the tumoral TGFβ expression was assessed by immunohistochemistry in 67 malignant CMT and its correlation to previously determined FoxP3, VEGF, and CD31 markers and other clinicopathologic parameters was evaluated. The high levels of TGFβ were statistically significantly associated with skin ulceration, tumor necrosis, high histological grade of malignancy (HGM), presence of neoplastic intravascular emboli and presence of lymph node metastases. The observed levels of TGFβ were positively correlated with intratumoral FoxP3 (strong correlation), VEGF (weak correlation) and CD31 (moderate correlation). Tumors that presented a concurrent high expression of TGFβ/FoxP3, TGFβ/VEGF, and TGFβ/CD31 markers were statistically significantly associated with parameters of tumor malignancy (high HGM, presence of vascular emboli and nodal metastasis). Additionally, shorter overall survival (OS) time was statistically significantly associated with tumors with an abundant TGFβ expression and with concurrent high expression of TGFβ/FoxP3, TGFβ/VEGF, and TGFβ/CD31. The presence of lymph node metastasis increased 11 times the risk of disease-related death, arising as an independent predictor of poor prognosis in the multivariable analysis. In conclusion, TGFβ and Treg cells seem involved in tumor progression emerging as potential therapeutic targets for future immunotherapy studies.

Different Prostatic Tissue Microbiomes between High- and Low-Grade Prostate Cancer Pathogenesis.

Numerous human pathologies, such as neoplasia, are related to particular bacteria and changes in microbiome constituents. To investigate the association between an imbalance of bacteria and prostate carcinoma, the microbiome and gene functionality from tissues of patients with high-grade prostate tumor (HGT) and low-grade prostate tumor (LGT) were compared utilizing next-generation sequencing (NGS) technology. The results showed abnormalities in the bacterial profiles between the HGT and LGT specimens, indicating alterations in the make-up of bacterial populations and gene functionalities. The HGT specimens showed higher frequencies of Cutibacterium, Pelomonas, and Corynebacterium genera than the LGT specimens. Cell proliferation and cytokine assays also showed a significant proliferation of prostate cancer cells and elevated cytokine levels in the cells treated with Cutibacterium, respectively, supporting earlier findings. In summary, the HGT and LGT specimens showed differences in bacterial populations, suggesting that different bacterial populations might characterize high-grade and low-grade prostate malignancies.

FGFR Alterations in Thyroid Carcinoma: A Novel Class of Primary Drivers with Significant Therapeutic Implications and Secondary Molecular Events Potentially Mediating Resistance in Thyroid Malignancy.

Background: Diagnostic classification of thyroid malignancy is primarily accomplished through examination of histomorphological features and may be substantiated and clarified by molecular data. Individual molecular drivers show relatively robust and specific associations with histological subtypes of thyroid malignancy, including BRAF sequence variants and kinase gene fusions in papillary thyroid carcinoma, predominantly RAS variants in follicular-patterned neoplasia, and additional "late" mutations affecting TERT promoter, TP53, and the PI3K/AKT/PTEN pathway in high-grade malignancies. Given the oncogenic role of FGFR, particularly FGFR1-3, the goal of this study was to explore the role of FGFR in thyroid carcinoma biology. Methods: We completed a multicenter retrospective observational study for thyroid carcinomas with pathogenic alterations in the FGFR gene family. We performed this study by querying the molecular data accumulated for thyroid carcinomas from each center. Results: Overall, 5030 sequenced thyroid malignancies were reviewed, yielding 17 tumors with FGFR alterations, including 11 where FGFR was the primary molecular driver and 6 where FGFR was a secondary pathogenic alteration, with a subset for which there was available clinical follow-up data. Of the 11 carcinomas with an FGFR driver, 9 were gene fusions involving FGFR2:VCL (4 tumors), TG::FGFR1 (3 tumors), FGFR2::CIT, and FGFR2::SHTN1, and the remaining 2 were driven by FGFR1 amplification. In the 6 tumors where a canonical driver of thyroid neoplasia was present (5 cases) or no clear primary driver was detected (1 case), sequencing detected secondary FGFR2 p.W290C, p.Y375C, and p.N549K, as well as FGFR1 p.N546K in the respective tyrosine kinase domains, some at subclonal variant allele frequencies. Conclusions: This study presents the first description of a collection of thyroid carcinomas grouped by primary driver alterations in FGFR, as well as a cohort of thyroid tumors with secondary alterations that potentially lead to tumor progression or resistance to targeted therapy. Given the availability of small molecular inhibitors targeting oncogenic FGFR, this study emphasizes the significant implications for patients from identification of FGFR alterations as they are currently under-recognized in the literature and, most importantly, have potential novel treatment options.

ACTH-producing adrenocortical carcinoma: an exceedingly rare diagnosis

BackgroundAdrenocortical carcinoma is a very rare endocrinopathy that has a poor prognosis and is frequently associated with ACTH-independent Cushing’s syndrome. Despite having an adrenocortical carcinoma, our patient surprisingly had an ACTH-dependent Cushing’s syndrome.Case report.A 26-year-old female presented with Cushing’s syndrome and an abdominal mass. Imaging studies revealed an adrenal mass consistent with a high-grade malignancy. Laboratory workup showed hypercortisolism, hyperandrogenism, and hypokalemia with normal levels of metanephrines. Unexpectedly, her ACTH levels were remarkably elevated. The pathological analysis of a tumor sample was conclusive for adrenocortical carcinoma with immunopositivity for ACTH.ConclusionsOur patient suffered from an adrenocortical carcinoma that was ectopically producing ACTH. This case emphasizes that physicians should have a broad-minded approach when evaluating cases of rare endocrine malignancies.

Expanding the Spectrum of NUTM1 -Rearranged Sarcoma : A Clinicopathologic and Molecular Genetic Study of 8 Cases.

Apart from the lethal midline carcinoma (NUT carcinoma), NUTM1 translocation has also been reported in mesenchymal tumors, but is exceedingly rare. Here, we describe a series of 8 NUTM1 -rearranged sarcomas to further characterize the clinicopathologic features of this emerging entity. This cohort included 2 males and 6 females with age ranging from 24 to 64 years (mean: 51y; median: 56y). Tumors occurred in the colon (2), abdomen (2), jejunum (1), esophagus (1), lung (1) and infraorbital region (1). At diagnosis, 6 patients presented with metastatic disease. Tumor size ranged from 1 to 10.5cm (mean: 6cm; median: 5.5 cm). Histologically, 4 tumors were composed of primitive small round cells to epithelioid cells intermixed with variable spindle cells, while 3 tumors consisted exclusively of small round cells to epithelioid cells and 1 tumor consisted predominantly of high-grade spindle cells. The neoplastic cells were arranged in solid sheets, nests, or intersecting fascicles. Mitotic activity ranged from 1 to 15/10 HPF (median: 5/10 HPF). Other features included rhabdoid phenotype (4/8), pronounced nuclear convolutions (2/8), prominent stromal hyalinization (2/8), focally myxoid stroma (1/8), foci of osteoclasts (1/8), and necrosis (1/8). By immunohistochemistry, all tumors showed diffuse and strong nuclear staining of NUT protein, with variable expression of pancytokeratin (AE1/AE3) (2/8), CK18 (1/8), CD99 (3/8), NKX2.2 (2/8), cyclin D1 (2/8), desmin (2/8), BCOR (2/8), S100 (1/8), TLE1 (1/8), and synaptophysin (1/8). Seven of 8 tumors demonstrated NUTM1 rearrangement by fluorescence in situ hybridization analysis. RNA-sequencing analysis identified MXD4::NUTM1 (3/7), MXI1::NUTM1 (3/7), and MGA::NUTM1 (1/7) fusions, respectively. DNA-based methylation profiling performed in 2 cases revealed distinct methylation cluster differing from those of NUT carcinoma and undifferentiated small round cell and spindle cell sarcomas. At follow-up (range: 4 to 24mo), 1 patient experienced recurrence at 8.5 months, 4 patients were alive with metastatic disease (5, 10, 11, and 24mo after diagnosis), 3 patients remained well with no signs of recurrence or metastasis (4, 6, and 12mo after diagnosis). Our study further demonstrated that NUTM1 -rearranged sarcoma had a broad range of clinicopathologic spectrum. NUT immunohistochemistry should be included in the diagnostic approach of monotonous undifferentiated small round, epithelioid to high-grade spindle cell malignancies that difficult to classify by conventional means. DNA-based methylation profiling might provide a promising tool in the epigenetic classification of undifferentiated sarcomas.

A Review and Case Series of Uterine Lipoleiomyomata

Purpose: The purpose of this case series is to understand the prevalence, clinical significance, pathophysiology, pathology findings, and workup of uterine lipoleiomyomas. Methods: This case series, with cases in February and March of 2023, includes the presentation, clinical management, and pathologic diagnosis of two separate uterine lipoleiomyomas. Separate chart reviews were performed on each patient, including frozen and permanent section pathologic findings. Micropictographs were obtained from hematoxylin and eosin-stained slides. This project was acknowledged as “IRB-exempt” by the MU Institutional Review board. Results: Case 1: A 51-year-old G3P2 woman presented with six months of severe postmenopausal bleeding, severe left-lower quadrant pelvic pain, and lightheadedness. A transvaginal ultrasound revealed a heterogeneous, thickened endometrial echo of 3.9 centimeters and a probable left ovarian dermoid cyst. CT showed distension of endometrial cavity due to polyps and/or submucosal masses, as well as a fat-containing mass in the uterine corpus. Hysteroscopy with dilation and curettage was performed with pathology of high-grade malignancy. Differential diagnosis at this time included high-grade stromal sarcoma, undifferentiated carcinoma, adenosarcoma, or malignant mixed Mullerian tumor. Patient underwent MRI due to concern for malignancy, which showed FDG-avid endometrial thickening with no other FDG-avid areas of concern. Histopathologic diagnosis found carcinosarcoma of the uterus, two positive lymph nodes, and an incidental finding of lipoleiomyoma. Plan for medical management with gynecologic oncology will include chemotherapy and vaginal cuff brachytherapy for uterine carcinosarcoma. Case 2: A 50-year-old G5P5 woman presented with increasing vaginal spotting and worsening urge incontinence. CT showed increased size of heterogeneous mass in right lateral uterine wall, consistent with previously identified fibroid/leiomyoma. An adjacent fat-containing lesion was identified within the uterine wall. Patient underwent MRI which revealed large uterine mass at the fundus, with an associated fatty component. Due to the abnormal rate of fibroid growth, and the fat component, there was concern for uterine sarcoma and/or malignant transformation of leiomyoma. Histopathologic diagnosis found lipoleiomyoma with benign atrophic endometrium, paratubal cysts of bilateral fallopian tubes, and follicular cyst of the right ovary. Follow-up in one year was recommended. Conclusion: Lipoleiomyomas are uncommon benign entities, occurring most commonly in postmenopausal women, similarly to uterine fibroids. While asymptomatic patients can be managed conservatively, these tumors can cause vaginal bleeding, pain, and urinary or fecal incontinence and can be definitively treated with hysterectomy. While imaging is necessary to initially characterize the lesion and determine concern for malignancy, histopathologic diagnosis remains the gold standard for diagnosis. Lipoleiomyomas are associated with other gynecologic malignancies, metabolic disorders, and rarely tumor-to-tumor metastasis. For this reason, careful clinical evaluation and surgical management are required for complete evaluation of the patient.

Impact of implementing the first edition of the Paris system for reporting: A systematic review and meta-analysis.

Urine cytology is a noninvasive, widely used diagnostic tool for screening and surveillance of genitourinary tract neoplasms. However, the absence of unified terminology and clear objective morphological criteria limits the clinical benefit of urine cytology. The Paris System for Reporting Urine Cytology (TPS) was developed with the goal of standardizing reporting and improving urine cytology performance in detecting high-grade malignancy (HGM). We aimed to evaluate potential effects of TPS on improving urine cytology diagnostic performance and clinical utility by conducting a systematic review and meta-analysis. We searched six electronic databases to identify cross-sectional and cohort studies written in English assessing the accuracy of urine cytology in detecting genitourinary tract malignancies of patients under surveillance or with clinical suspicion of malignancy from January 2004 to December 2022. We extracted relevant data from eligible studies to calculate relative distribution of cytology diagnostic categories; ratio of atypical to HGM cytology diagnosis; and risk of HGM (ROHGM) and HGM likelihood ratio (HGM-LR) associated with cytology diagnostic categories. We used a generalized linear mixed model with logit transformation to combine proportions and multilevel mixed-effect logistic regression to pool diagnostic accuracy measurements. We performed meta-regression to evaluate any significant difference between TPS and non-TPS cohorts. We included 64 studies for 99,796 combined total cytology samples, across 31 TPS and 49 non-TPS cohorts. Pooled relative distribution [95% confidence interval (CI)] of negative for high-grade urothelial carcinoma (NHGUC)/negative for malignancy (NM); atypical urothelial cells (AUC); suspicious for high-grade urothelial carcinoma (SHGUC)/suspicious for malignancy (SM); low-grade urothelial neoplasm (LGUN); and HGM categories among satisfactory cytology cases were 83.8% (80.3%-86.9%), 8.0% (6.0%-10.6%), 2.2% (1.4%-3.3%), 0.01% (0.0%-0.1%), and 4.2% (3.2%-5.5%) in TPS versus 80.8% (76.8-2.7%), 11.3% (8.6%-14.7%), 1.8% (1.2%-2.7%), 0.01% (0.0%-0.1%), and 3.3% (2.5%-4.3%) in non-TPS cohorts. Adopting TPS classification resulted in a significant increase in the frequency of NHGUC and a reduction in AUC cytology diagnoses, respectively. The AUC/HGM ratio in TPS cohort was 2.0, which showed a statistically significant difference from the atypical/HGM ratio of 4.1 in non-TPS cohort (p-value: 0.01). Moreover, the summary rate (95% CI) of LGUN called AUC on cytology significantly decreased to 20.8% (14.9%-28.3%) in the TPS compared with 34.1% (26.4%-42.8%) in non-TPS cohorts. The pooled ROHGM (95% CI) was 20.4% (6.2%-50.0%) in nondiagnostic (NDX), 15.5% (9.6%-24.2%) in NHGUC, 40.2% (30.9%-50.2%) in AUC, 80.8% (72.9%-86.8%) in SHGUC, 15.1% (5.7%-34.3%) in LGUN, and 91.4% (87.3%-94.3%) in HGM categories in TPS studies. NHGUC, AUC, SHGUC, and HGM categories were associated with HGM-LR (95% CI) of 0.2 (0.1-0.3), 0.9 (0.6-1.3), 6.9 (2.4-19.9), and 16.8 (8.3-33.8). Our results suggest that TPS 1.0 has reduced the relative frequency of AUC diagnosis, AUC/HGM ratio, and the frequency of LGUNs diagnosed as AUC on cytology. Adopting this classification has improved the clinical utility of SHGUC and HGM cytology diagnoses in ruling in high-grade lesions. However, an NHGUC diagnosis does not reliably rule out the presence of a high-grade lesion.