Dual immunotherapy alternating with anti-PD-1 antibody plus liposomal doxorubicin show good efficacy in prostate epithelioid hemangioendothelioma: a case report.

Epithelioid hemangioendothelioma is a rare vascular malignancy, and currently, there is no standard treatment regimen for this disease and existing treatment options have limited efficacy. In this case report, we present a patient with lung and lymph node metastases from prostate epithelioid hemangioendothelioma who achieved a significant partial response. This was accomplished through alternating nivolumab therapy with ipilimumab and liposomal doxorubicin, resulting in a progression-free-survival more than 6 months to date. The treatment was well-tolerated throughout. Our report suggests that dual immunotherapy alternating with anti-PD-1antibody plus doxorubicin may be a potential treatment modality for epithelioid hemangioendothelioma. However, larger sample studies are necessary to ascertain the effectiveness of this treatment strategy and it is essential to continue monitoring this patient to sustain progression-free survival and overall survival.

Successful treatment of pediatric patients with high-grade gliomas featuring leptomeningeal metastases by targeting BRAF V600E mutations with dabrafenib plus trametinib: two illustrative cases.

A combination of BRAF and MEK inhibitors is reported to be effective for gliomas with the BRAF V600E mutation; however, its efficacy in gliomas with leptomeningeal metastases (LMM) is still unknown. In this report, we describe two pediatric patients with high-grade glioma featuring the BRAF V600E mutation who were treated with dabrafenib and trametinib for LMM. Both 2 cases underwent craniotomy for primary intracranial lesions and were diagnosed as a high-grade glioma with BRAF V600E mutation; one case was consistent with anaplastic pleomorphic xanthoastorocytoma, the other was epithelioid glioblastoma. They received standard treatment for the lesions but subsequently were found to have new lesions including multiple spinal dissemination. We started administering dabrafenib and trametinib. Within a few days of starting treatment, the symptoms improved dramatically and MRI performed one month after the prescription of the two drugs demonstrated remission of both brain and spinal lesions. This report shows that dabrafenib and trametinib are effective not only for recurrent lesions but also for LMM in pediatric patients.

CT, MRI, and PET/CT imaging features of thoracic spine epithelioid hemangioma: a retrospective observational study.

Introduction: Epithelioid hemangioma (EH) is an intermediate locally aggressive tumor that consists of epithelioid cells and endothelial cell differentiation, which can occur at any age, but is most common between the ages of 30 and 40 years. EH in the thoracic spine is rare, and accurate diagnosis is critical to treatment planning. Our aim was to explore the imaging and clinical data of thoracic spine EH to improve the understanding of this rare disease. Methods: From January 1, 2018 to June 30, 2023, a database of thoracic spine masses was retrospectively reviewed. Five patients with histologically proven thoracic spine EH and complete imaging available were identified and analyzed. Computed tomography (CT) and magnetic resonance imaging (MRI) findings were evaluated separately by two radiologists with more than 10 years of experience. Positron emission tomography (PET)/CT was conducted by two nuclear medicine diagnostic technologists with at least 5 years of experience. Results: The patients included three male and two female patients aged 23 to 56 years (mean age was 38.4 ± 14.3 years). All patients underwent CT, MRI, and 18F-FDG PET/CT examination before treatment. Four patients were limited to one vertebral involvement, only one patient had multiple vertebral involvement, and all tumors involved the accessories, including one involving the posterior ribs. The maximum diameter of the tumor ranged from 2.7 to 4.3. Conclusions: CT, MRI, and 18F-FDG PET/CT findings of thoracic spine EH have certain characteristics, and understanding these imaging findings will help to obtain accurate diagnosis before surgery.

[MRI manifestations of 40 cases with the hepatic epithelioid hemangioendothelioma classification based on the morphology and size].

Objective: To explore the MRI characteristics of the hepatic epithelioid hemangioendothelioma (HEHE) classification according to morphology and size. Methods: The clinical, pathological, and MRI imaging data of 40 cases with HEHE confirmed pathologically from December 2009 to September 2021 were retrospectively analyzed. A paired sample t-test was used for comparison between the two groups. Results: There were 40 cases (5 solitary, 24 multifocal, 9 local fusion, and 2 diffuse fusion) and 214 lesions (163 nodules, 31 masses, and 20 fusion foci). The most common features of lesions were subcapsular growth and capsular depression. The signal intensity of lesions ≤1cm was usually uniform with whole or ring enhancement. Nodules and mass-like lesions ≥1cm on a T1-weighted image had slightly reduced signal intensity or manifested as a halo sign. Target signs on a T2-weighted image were characterized by: target or centripetal enhancement; fusion-type lesions; irregular growth and hepatic capsular retraction, with ring or target-like enhancement in the early stage of fusion and patchy irregular enhancement in the late stage; blood vessels traversing or accompanied by malformed blood vessels; focal bleeding; an increasing proportion of extrahepatic metastases and abnormal liver function with the type of classified manifestation; primarily portal vein branches traversing; and reduced overall intralesional bleeding rate (17%). Lollipop signs were presented in 19 cases, with a high expression rate in mass-type lesions (42%). The fusion lesions were expressed, but the morphological manifestation was atypical. The diffusion-weighted imaging mostly showed high signal or target-like high signal. An average apparent diffusion coefficient of lesions was (1.56±0.36) ×10(-3)mm(2)/s, which was statistically significantly different compared with that of adjacent normal liver parenchyma (t=8.28, P<0.001). Conclusion: The MRI manifestations for the HEHE classification are closely related to the morphology and size of the lesions and have certain differences and characteristics that are helpful for the diagnosis of the disease when combined with clinical and laboratory examinations.

Inflammatory myofibroblastic tumor from molecular diagnostics to current treatment.

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic rate. Diagnostic challenges arise from the diverse pathological presentation, variable symptomatology, and lack of different imaging features. However, IMT is identified by the fusion of the anaplastic lymphoma kinase (ALK) gene, which is present in approximately 70% of cases, with various fusion partners, including ran-binding protein 2 (RANBP2), which allows confirmation of the diagnosis. While surgery is the preferred approach for localized tumors, the optimal long-term treatment for advanced or metastatic disease is difficult to define. Targeted therapies are crucial for achieving sustained response to treatment within the context of genetic alteration in IMT. Crizotinib, an ALK tyrosine kinase inhibitor (TKI), was officially approved by the US Food and Drug Administration (FDA) in 2020 to treat IMT with ALK rearrangement. However, most patients face resistance and disease progression, requiring consideration of sequential treatments. Combining radiotherapy with targeted therapy appears to be beneficial in this indication. Early promising results have also been achieved with immunotherapy, indicating potential for combined therapy approaches. However, defined recommendations are still lacking. This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy.

Epithelioid Hemangioendothelioma of Spleen and Bone: A Case Report.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor that can originate in various parenchymatous organs, soft tissue, and bone. Extrahepatic involvement is exceedingly rare. In this case, multifocal disease in the spleen and bone was present. Bone lesions showed a target appearance. Splenic lesions showed delayed enhancement of solid components with persistent rim enhancement. A bone biopsy with CAMTA1 staining confirmed the diagnosis. Teaching point: The presence of multifocal bone and splenic lesions can raise suspicion of EHE when other multifocal diseases are excluded.

Renal epithelioid angiomyolipomas overexpress TFE3 and the TFE3-regulated gene TRIM63 in the absence of TFE3 rearrangement.

Angiomyolipoma (AML) is a neoplasm within the perivascular epithelioid cell tumor family that occurs somewhat frequently in the kidney. Most are indolent and discovered incidentally, with rare tumors demonstrating malignant clinical behavior. A small subset of renal AMLs with epithelioid features are associated with aggressive behavior, and may demonstrate morphologic overlap with renal cell carcinomas (e.g., clear cell renal cell carcinoma (RCC), TFE3-rearranged RCC). Prior studies of spindle cell and epithelioid AMLs have identified rare examples with underlying TFE3 gene fusions. TFE3 protein expression (demonstrated by immunohistochemistry) with no evidence of concurrent TFE3 rearrangements has been reported previously in 4/24 AMLs (17%) (Argani et al. Am J Surg Pathol 34:1395-1406, 2010). Currently, the relationship between TFE3 protein expression, TFE3 fusions, and expression of TFE3-mediated genes remains incompletely understood in renal epithelioid AMLs. We sought to explore these relationships using TFE3 break-apart fluorescence in situ hybridization (FISH) and TRIM63 RNA in situ hybridization (ISH) on epithelioid AMLs with moderate to strong TFE3 expression by immunohistochemistry. RNA sequencing (fusion panel) was performed on two cases with negative FISH results to assess for FISH-cryptic gene fusions. The series comprised five epithelioid AMLs from four patients (three women, one man) aged 13 to 76 years. All were considered positive for TFE3 by immunohistochemistry (2 + /3 + expression). TRIM63 ISH was performed on four specimens from three patients, yielding positive results in 3/3 tumors (100%) that were successfully analyzed. TFE3 break-apart FISH was performed on all samples, demonstrating a TFE3 rearrangement in only 1/4 tumors (25%). RNA sequencing demonstrated the absence of productive TFE3 gene fusions in three tumors with negative break-apart TFE3 FISH results. This study demonstrates that renal epithelioid AMLs overexpress TFE3 and TFE3-mediated genes (TRIM63) even in the absence of TFE3 rearrangements. This finding could be explained by functional upregulation of TFE3 secondary to activation of the mammalian target of rapamycin complex 1 (mTORC1). Expression of TFE3 and TRIM63 in this tumor type represents a potential pitfall, given the morphologic and immunophenotypic overlap between epithelioid AML and TFE3-altered renal cell carcinoma.

A Young Female with a Hepatic Epithelioid Hemangioendothelioma.

Background: Primary hepatic epithelioid hemangioendothelioma (HEHE) is an extremely rare tumour of vascular origin with an incidence of <0.1 cases per 100,000 people worldwide. Case description: A 29-year-old female with the history of epigastric pain and unintentional weight loss (3 kg over six months) was referred for upper endoscopy. The examination was without visual pathological findings, but a rapid urease test was positive. First-line treatment with clarithromycin-containing triple therapy for Helicobacter pylori infection was given. After completion of eradication therapy, diffuse abdominal pain developed. An abdominal computed tomography (CT) showed multiple liver nodules. Three consecutive core liver biopsies were performed and were inconclusive. A subsequent surgical liver nodule resection was performed. Histopathology of the specimen revealed grade 2 hepatocellular carcinoma; bone scintigraphy was negative for metastasis. A multidisciplinary team (MDT) recommended giving the patient sorafenib, which was poorly tolerated. The histology was reviewed using immunohistochemistry staining at the request of the oncologist, which showed expression of CD31 and CD34. Based on clinical, morphological and immunohistochemistry findings, a diagnosis of hepatic epithelioid hemangioendothelioma was made. Based on the multidisciplinary team's findings, liver transplantation was indicated as the only curative treatment. Conclusion: Because of the rarity of this disease, combining clinical, radiological and histopathological methods as well as an MDT approach can help to reach the correct final diagnosis. As demonstrated in this clinical case, it is crucial to perform immunohistochemistry of a liver biopsy to confirm a HEHE diagnosis. LEARNING POINTS: Hepatic epithelioid hemangioendothelioma is a rare vascular tumour that is often misdiagnosed and mismanaged.This case emphasises the critical importance of interdisciplinary teamwork and the use of non-invasive and invasive techniques to achieve a definitive diagnosis.

Epigenetic age acceleration is a distinctive trait of epithelioid sarcoma with potential therapeutic implications.

Recently, DNA methylation clocks have been proven to be precise age predictors, and the application of these clocks in cancer tissue has revealed a global age acceleration in a majority of cancer subtypes when compared to normal tissue from the same individual. The polycomb repressor complex 2 plays a pivotal role in the aging process, and its targets have been shown to be enriched in CpG sites that gain methylation with age. This complex is further regulated by the chromatin remodeling complex SWItch/Sucrose Non-Fermentable and its core subunit, notably the tumor suppressor gene SMARCB1, which under physiological conditions inhibits the activity of the polycomb repressor complex 2. Hence, the loss of function of core members of the SWItch/sucrose non-fermentable complex, such as the tumor suppressor gene SMARCB1, results in increased activity of polycomb repressor complex 2 and interferes with the aging process. SMARCB1-deficient neoplasms represent a family of rare tumors, including amongst others malignant rhabdoid tumors, atypical teratoid and rhabdoid tumors, and epithelioid sarcomas. As aging pathways have recently been proposed as therapeutic targets for various cancer types, these tumors represent candidates for testing such treatments. Here, by deriving epigenetic age scores from more than 1000 tumor samples, we identified epigenetic age acceleration as a hallmark feature of epithelioid sarcoma. This observation highlights the potential of targeting aging pathways as an innovative treatment approach for patients with epithelioid sarcoma.

Germ Cell Tumor of the Testis: Lethal Subtypes of a Curable Cancer.

Germ cell tumor of the testis (GCT) is a curable cancer even when it is widely metastatic; however, outcomes can differ based on tumor histology. Chemo-resistance in certain phenotypes, such as teratoma and yolk sac tumor, contributes to poor clinical outcomes in some patients with GCT. Despite this resistance to S-YSTemic therapy, many of these tumor subtypes remain amenable to surgical resection and possible cure. In this study, we report on a series of seven patients highlighting two chemo-resistant subtypes of nonseminomatous germ cell tumor (NSGCT), sarcomatoid yolk sac tumor (S-YST), and epithelioid trophoblastic tumor (ETT) for which early resection rather than additional salvage chemotherapy or high-dose intense chemotherapy might provide a superior clinical outcome and enhance cure rate.

Case of stage 0 pulmonary sarcoidosis pathologically diagnosed via transbronchial lung cryobiopsy.

A 45-year-old male was diagnosed with arrhythmia during a routine health examination. Findings from different modalities, such as echocardiography and radiography, were consistent with cardiac involvement in sarcoidosis. There was no ocular involvement or superficial lymph node enlargement. A chest computed tomography scan did not reveal any pulmonary lesions or bilateral hilar lymphadenopathy. To pathologically diagnose systemic sarcoidosis, transbronchial lung cryobiopsy was performed. Results showed pathological evidence of noncaseating epithelioid granulomas. Herein, we present a case in which sarcoidosis diagnosis was confirmed via transbronchial lung cryobiopsy despite the absence of respiratory lesions on computed tomography scan.

Spontaneous remission of a pulmonary sclerosing epithelioid fibrosarcoma: a case report of a possible abscopal effect.

Background: Spontaneous remission (SR) is defined as the complete or partial disappearance of a diagnosed malignant disease in the absence of known active medical treatment. The role of the immune system is thought to be important, but has not yet been elucidated. On this matter, there are studies that suggest that the abscopal effect (AE), which is defined as the remission of untreated lesions beyond the irradiated area, may be explained by the activation of a systemic immune response against the tumor. Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of soft tissue sarcoma that is characterized by a slow evolution, with local recurrences and late metastases. The treatment is based on surgery, leaving a minimal role to chemotherapy (ChT) and radiotherapy (RT) for metastatic unresectable disease, and no cases of SR have been reported in the literature so far. Case Description: We present the case of a patient with a lung metastatic recurrence of SEF, diagnosed and treated with surgery 8 years before. After progression to pazopanib and other ChT drugs, because of the chest pain associated with a pleural mass invading the second costal arch, the patient received antalgic local RT treatment. Months later, and without any further treatment, a partial remission of all the tumoral lesions was presented, and she is alive 25 years after the first diagnosis. Conclusions: As far as reported in the literature, this is the first case of SR in SEF. Among the possible causes of this SR, we think that the most plausible is that palliative treatment with RT of the pleural mass induced an AE, leading to a reduction of all tumoral lesions, even those outside the irradiated region.

TRIM24 Cooperates with Ras Mutation to Drive Glioma Progression through snoRNA Recruitment of PHAX and DNA-PKcs.

The factors driving glioma progression remain poorly understood. Here, the epigenetic regulator TRIM24 is identified as a driver of glioma progression, where TRIM24 overexpression promotes HRasV12 anaplastic astrocytoma (AA) progression into epithelioid GBM (Ep-GBM)-like tumors. Co-transfection of TRIM24 with HRasV12 also induces Ep-GBM-like transformation of human neural stem cells (hNSCs) with tumor protein p53 gene (TP53) knockdown. Furthermore, TRIM24 is highly expressed in clinical Ep-GBM specimens. Using single-cell RNA-sequencing (scRNA-Seq), the authors show that TRIM24 overexpression impacts both intratumoral heterogeneity and the tumor microenvironment. Mechanically, HRasV12 activates phosphorylated adaptor for RNA export (PHAX) and upregulates U3 small nucleolar RNAs (U3 snoRNAs) to recruit Ku-dependent DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Overexpressed TRIM24 is also recruited by PHAX to U3 snoRNAs, thereby facilitating DNA-PKcs phosphorylation of TRIM24 at S767/768 residues. Phosphorylated TRIM24 induces epigenome and transcription factor network reprogramming and promotes Ep-GBM-like transformation. Targeting DNA-PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep-GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep-GBM-like transformation and suggest a potential therapeutic strategy for patients with Ep-GBM.

Uterine epithelioid trophoblastic tumor with the main manifestation of increased human chorionic gonadotropin: A case report.

BACKGROUND: Epithelioid trophoblastic tumor (ETT) is an extremely rare malignant gestational trophoblastic neoplasm commonly presenting with abnormal vaginal bleeding, abdominal pain, and increased human chorionic gonadotropin (hCG). This study reported a case of uterine ETT with the main manifestation being increased hCG. CASE SUMMARY: A 39-year-old female was referred to the Ningbo Maternal and Child Hospital of China in December 2022, complaining of increased hCG levels for 1 month. Magnetic resonance imaging revealed gestational trophoblastic tumor, and hysteroscopic electrotomy and curettage of intrauterine hyperplasia were performed. The patient was diagnosed with uterine ETT through postoperative pathological examination and immunohistochemical results. Total laparoscopic hysterectomy and bilateral salpingectomy were performed, and hCG levels returned to normal. The patient was without recurrence during the postoperative 3-month follow-up. CONCLUSION: This study reported a case of uterine ETT with the main manifestation being increased hCG, highlighting that ETT should be considered in the presence of abnormal hCG. A total laparoscopic hysterectomy is recommended.

Uterine perivascular epithelioid cell tumors (PEComa) and the accuracy of proposed classification systems in predicting the malignant versus non-malignant behavior.

OBJECTIVE: To compare the accuracy of available classification systems (Folpe, modified Folpe, Bennet, and Schoolmester) in predicting the behavior of uterine Perivascular Epithelioid Cell tumors (PEComas). METHODS: We reviewed the pathology registry to identify all uterine PEComas treated at our center. We conducted a systematic literature review searching electronic databases from inception to November 2023. We included all references reporting at least one case of uterine PEComa; cases associated with tuberous sclerosis complex were excluded. Patient-level data were extracted by identified records. Survival analysis was used to assess the accuracy of all proposed classification systems to classify uterine PEComas as malignant versus non-malignant. RESULTS: Six uterine PEComas were treated at our center. The literature search identified 101 uterine PEComas from 32 studies. Eighty-five out of 107 PEComas (28 studies and our series) reported enough follow-up data and details to apply all four classifications. The modified Folpe classification demonstrated the highest hazard ratio (HR) for relapse (HR:8.63; 95% confidence interval [CI] 2.06-36.1) and death due to PEComa (HR:6.8, 95%CI:0.89-51.6) for malignant versus non-malignant PEComas. Changing the cut-off of PEComa size to ≥8 cm and mitotic figures per 50 high power fields to ≥5, the HR for recurrence lowered (HR:6.26; 95% CI 2.20-17.80), but HR for death increased (HR:10.3; 95% CI 1.35-77.80). CONCLUSIONS: The modified Folpe classification was the most accurate in predicting the PEComa behavior. Changing the cut-off of PEComa size and number of mitotic figures may improve the accuracy in predicting death due to disease.

Dual Malignancies Discovered: A Rare Case of Malignant Peritoneal Epithelioid Mesothelioma and Lung Adenocarcinoma.

Clinicians diagnosing malignant peritoneal epithelioid mesothelioma (MPM or MPeM) have historically had challenges due to the low incidence of the disease, as well as the often vague symptomatology that patients present with. Newer advances in technology, specifically in immunocytochemistry, have provided a clearer path to diagnosis. Additionally, malignant mesotheliomas must be differentiated from carcinomas. This is done via histology, immunocytochemistry, as well as a careful incorporation of the patient's clinical history. In this case, we present an asymptomatic 73-year-old non-smoker female with no past medical history of asbestos exposure. She was diagnosed with MPM following a routine abdominal hernia repair. Subsequent workup revealed a lung infiltrate that was successfully biopsied and resected, evidently found to be adenocarcinoma. A careful review of the resulting pathology, as well as the interpretation of immunocytochemistry, supported the notion that the patient had two independent malignant processes occurring at once. This case underscores the rarity of two similar, yet distinct cancers, as well as epidemiology, symptomatology, histology, immunocytochemistry, and prognosis.

PLAG1-Rearranged Uterine Sarcomas: A Study of 11 Cases Showing a Wide Phenotypical Spectrum Not Limited to Myxoid Leiomyosarcoma-like Morphology.

PLAG1 gene fusions were recently identified in a subset of uterine myxoid leiomyosarcomas (M-LMS). However, we have encountered cases of PLAG1-rearranged uterine sarcomas (PLAG1-US) lacking M-LMS-like morphology and/or any expression of smooth muscle markers. To better characterize their clinicopathological features, we performed a multi-institutional search which yielded 11 cases. The patients ranged in age from 34-72 years (mean: 57). All tumors arose in the uterine corpus, ranging in size from 6.5-32 cm (mean: 15). The most common stage at presentation was pT1b (n=6), three cases had stage pT1 (unspecified) and one case each presented in stage pT2a and pT3b. Most were treated only by hysterectomy with adnexectomy. The follow-up (range: 7-71 months; median: 39 months) was available for 7 patients. Three cases (7-21 months of follow-up) had no evidence of disease. Three out of 4 remaining patients died of disease within 55-71 months, while the last developed peritoneal spread and was transferred for palliative care at 39 months. Morphologically, the tumors showed a high inter- and intratumoral heterogeneity. M-LMS-like and epithelioid LMS-like morphology was present in 3 and 5 primary tumors, respectively, the rest mostly presented as non-descript ovoid/spindle cell sarcomas. Unusual morphological findings included prominently hyalinized stroma (n=3), adipocytic differentiation with areas mimicking myxoid liposarcoma (n=2), osteosarcomatous differentiation (n=1) and undifferentiated pleomorphic sarcoma-like areas (n=1). The mitotic activity ranged from 3-24 mitoses/10 high-power fields (mean: 9), 3/10 cases showed necrosis. In 3/11 cases, no expression of SMA, h-caldesmon or desmin was noted, whereas 5/5 cases expressed PLAG1. By RNA-sequencing, the following fusion partners were identified: PUM1, CHCHD7 (each n=2), C15orf29, CD44, MYOCD, FRMD6, PTK2 and TRPS1 (each n=1). One case only showed PLAG1 gene break by FISH. Our study documents a much broader morphological spectrum of PLAG1-US than previously reported, encompassing but not limited to M-LMS-like morphology with occasional heterologous (particularly adipocytic) differentiation. Since it is currently difficult to precisely define their line of differentiation, for the time being, we suggest using a descriptive name PLAG1-rearranged uterine sarcoma.

Primary pulmonary epithelioid hemangioendothelioma metastatic to the pleura and mediastinal lymph node with a prominent rhabdoid cytomorphology showing CAMTA1::WWTR1 fusion and novel PRDM1 and TNFRSF14 mutations.

Cases of epithelioid hemangioendothelioma with WWTR1::CAMTA1 fusion can show rhabdoid cytomorphology. Lack of intracytoplasmic luminal spaces, marked rhabdoid cytomorphology, and variability in the expression of vascular markers makes the diagnosis of EHE challenging. Therefore, a high level of suspicion and ancillary studies (immunohistochemistry and next generation sequencing) help reach a definitive diagnosis in these cases.