Non-invasive assessment of severe liver fibrosis in patients with Fontan-associated liver disease: The VALDIG-EASL FONLIVER cohort.

BACKGROUND & AIMS: Fontan-type surgery is used as a palliation for congenital heart disease with univentricular physiology but may, in the long term, lead to advanced chronic liver disease. This study assessed the accuracy of conventional non-invasive models in assessing liver fibrosis and introduces a new risk score employing non-invasive tools. METHODS: A prospective, cross-sectional, observational study was conducted across five European centers and encompassing all consecutive adult patients with Fontan circulation, liver biopsy and non-invasive tests (elastography, APRI, FIB-4, Fibrosis score, Doha, GUCI, and AAR). The primary outcome was the identification of severe liver fibrosis on biopsy. Multivariable logistic regression identified non-invasive predictors of severe fibrosis, leading to the development and internal validation of a new scoring model named the FonLiver risk score. RESULTS: In total, 217 patients (mean [standard deviation] age, 27.9 [8.9] years; 50.7% males) were included. Severe liver fibrosis was present in 47.9% (95% CI 41.2%-54.5%) and correlated with a lower functional class, protein-losing enteropathy, and compromised cardiopulmonary and systemic hemodynamics. The final FonLiver risk score incorporated liver stiffness measurement using transient elastography and platelet count and demonstrated strong discrimination and calibration (area under the receiver operating curve [AUROC] of 0.81). The FonLiver risk score outperformed conventional prediction models (APRI, FIB-4, Fibrosis score, Doha, GUCI, and AAR), which all exhibited worse performance in our cohort (AUROC < 0.70 for all). CONCLUSION: Severe liver fibrosis is prevalent in adults following Fontan-type palliation and can be effectively estimated using with the novel FonLiver risk score. This scoring system can be easily incorporated into the routine assessment of patients with Fontan circulation.

Distinct regulations driving YAP1 expression loss in poroma, porocarcinoma and RB1-deficient skin carcinoma.

AIMS: Recently, YAP1 fusion genes have been demonstrated in eccrine poroma and porocarcinoma, and the diagnostic use of YAP1 immunohistochemistry has been highlighted in this setting. In other organs, loss of YAP1 expression can reflect YAP1 rearrangement or transcriptional repression, notably through RB1 inactivation. In this context, our objective was to re-evaluate the performance of YAP1 immunohistochemistry for the diagnosis of poroma and porocarcinoma. METHODS AND RESULTS: The expression of the C-terminal part of the YAP1 protein was evaluated by immunohistochemistry in 543 cutaneous epithelial tumours, including 27 poromas, 14 porocarcinomas and 502 other cutaneous tumours. Tumours that showed a lack of expression of YAP1 were further investigated for Rb by immunohistochemistry and for fusion transcripts by real-time PCR (YAP1::MAML2 and YAP1::NUTM1). The absence of YAP1 expression was observed in 24 cases of poroma (89%), 10 porocarcinoma (72%), 162 Merkel cell carcinoma (98%), 14 squamous cell carcinoma (SCC) (15%), one trichoblastoma and one sebaceoma. Fusions of YAP1 were detected in only 16 cases of poroma (n = 66%), 10 porocarcinoma (71%) all lacking YAP1 expression, and in one sebaceoma. The loss of Rb expression was detected in all cases except one of YAP1-deficient SCC (n = 14), such tumours showing significant morphological overlap with porocarcinoma. In-vitro experiments in HaCat cells showed that RB1 knockdown resulted in repression of YAP1 protein expression. CONCLUSION: In addition to gene fusion, we report that transcriptional repression of YAP1 can be observed in skin tumours with RB1 inactivation, including MCC and a subset of SCC.

Recurrent FOXK1::GRHL and GPS2::GRHL fusions in trichogerminoma.

We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in-frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well-delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests ('cell balls') was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20-positive Merkel cells were detected. RNA sequencing (RNA-seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT-qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA-seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland.

Recurrent YAP1::MAML2 fusions in "nodular necrotizing" variants of myxoinflammatory fibroblastic sarcoma: a comprehensive study of 7 cases.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare soft tissue tumor with a predilection for the distal extremities and a tendency for local recurrence. Morphologically, MIFS consists of spindle and bizarre epithelioid cells resembling virocytes embedded in a fibrous to myxoid stroma with an abundant inflammatory infiltrate. Importantly, the molecular landscape of MIFS is wide and includes: VGLL3 amplification, BRAF fusion/amplification and OGA/TGFBR3 rearrangements. In this study, we describe a variant of MIFS showing a frequent nodular configuration associated with necrosis and recurrent YAP1::MAML2 fusions. The cohort consisted of 7 patients (4 females and 3 males) ranging in age from 21 to 71 years (median: 47 years). Two tumors (28%) occurred in acral locations while the remaining cases were more widely distributed (thigh, n = 2; arm, n = 1; neck; n = 1; chest-wall, n = 1). Tumor size ranged from 10 to 38 mm (median: 20 mm). Histologically, lesions frequently presented as nodules with central areas of necrosis, and were predominantly composed of sheets of epithelioid cells with large vesicular nuclei and prominent nucleoli (Reed-Sternberg-like cells or virocytes). The stroma was mostly fibrous and showed a polymorphous inflammatory infiltrate. Myxoid stromal changes were focally seen in one case, and pseudolipoblasts were absent. The immunophenotype was nonspecific, with only pan-keratin (AE1-AE3) and cyclin D1 expression in a subset of cases. RNA-Sequencing detected YAP1::MAML2 fusions in 3/7 cases; aCGH showed no significant gene copy number variations in 4 tested cases, and FISH analysis showed no VGLL3 amplification in 1 tested case. Follow-up was available for 6 cases, ranging from 7 to 63 months (median: 42 months). Local recurrence and metastasis were not seen and one tumor showed spontaneous regression following initial biopsy. In conclusion, we describe a novel variant of MIFS with distinctive clinicopathological and molecular features for which we propose the term "nodular necrotizing" MIFS.

[Bilateral giant cell central granuloma of the jaws in a Noonan syndrome: About one case with emphasizing on bone giant cell lesions of the jaws]. / Granulome central à cellules géantes des maxillaires bilatéral dans le cadre d'un syndrome de Noonan : à propos d'un cas avec mise au point sur les lésions osseuses riches en cellules géantes des maxillaires.

We report the case of a 10-year-old child with bilateral mandibular localization of a central giant cell granuloma occurring in the setting of Noonan syndrome. The histological appearance was classic with two intermigled components, one fibrous with non-atypical mononuclear cells, the other consisting of numerous osteoclast-like giant cells. This aspect is similar to that observed in the brown tumor as well as that of cherubism, which can also give multiple bone lesions. We will discuss the other lesions to consider in case of benign giant cell bone lesions affecting the jawbones, sometimes multiple and part of which falls within the scope of RASopathies.

[From an optimal management of bone tissue samples to a quality patients' care in 2022 : A new paradigm]. / D'une gestion optimale des échantillons osseux à une prise en charge de qualité des malades en 2022 : un nouveau paradigme.

Bone tissue can be involved by primitive or metastatic tumors and requires a specific processing both at the department of pathology and during multidisciplinary meetings. The development of fine-needle percutaneous biopsies and of molecular techniques in bone tumor pathology requires a specific management. Moreover, decalcification of samples is crucial but can be deleterious if not controlled or not appropriate. The aim of this review is to provide recommendations for management and decalcification of bone tumor samples.

Effect of decalcification protocols on immunohistochemistry and molecular analyses of bone samples.

Diagnosis of osteocartilaginous pathologies depends on morphological examination and immunohistochemical and molecular biology analyses. Decalcification is required before tissue processing, but available protocols often lead to altered proteins and nucleic acids, and thus compromise the diagnosis. The objective of this study was to compare the effect of different methods of decalcification on histomolecular analyses required for diagnosis and to recommend an optimal protocol for processing these samples in routine practice. We prospectively submitted 35 tissue samples to different decalcification procedures with hydrochloric acid, formic acid, and EDTA, in short, overnight and long cycles for 1 to >10 cycles. Preservation of protein integrity was examined by immunohistochemistry, and quality of nucleic acids was estimated after extraction (DNA and RNA concentrations, 260/280 ratios, PCR cycle thresholds), analysis of DNA mutations (high-resolution melting) or amplifications (PCR, in situ hybridization), and detection of fusion transcripts (RT-PCR, in situ hybridization). Hydrochloric acid- and long-term formic acid-based decalcification induced false-negative results on immunohistochemistry and molecular analysis. EDTA and short-term formic acid-based decalcification (<5 cycles of 6 h each) did not alter antigenicity and allowed for detection of gene mutations, amplifications or even fusion transcripts. EDTA showed superiority for in situ hybridization techniques. According to these results and our institutional experience, we propose recommendations for decalcification of bone samples, from biopsies to surgical specimens.

A Rare Coexistence of Hybrid Tumor Low-grade Fibromyxoid Sarcoma/Sclerosing Epithelioid Fibrosarcoma and Hibernoma in the Same Thigh: A Case Report.

Introduction: We encountered a unique case of a patient with two distinct tumors coexisting in the same thigh. To the best of our knowledge, this combination of tumors in the same anatomical region has not been previously described in the literature. Case Report: This case report describes a 38-year-old Caucasian male with a painless mass in his right thigh, which was later diagnosed as a hybrid tumor composed of low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma, as well as a second tumor, which was diagnosed as a hibernoma. The patient underwent neoadjuvant chemotherapy and surgical excision, followed by adjuvant radiotherapy and treatment for metastatic recurrence. Conclusion: The rarity of this case highlights the need for interdisciplinary collaboration and further investigations into the behavior and management of hybrid tumors. This case also underscores the importance of an accurate histological diagnosis aided by immunohistochemistry and molecular analyses.

Retroperitoneal soft tissue sarcomas: Predictive factors for incomplete resection.

INTRODUCTION: Curative management of retroperitoneal sarcoma relies on surgery, and complete monoblock resection is one of the main prognostic factors. The goal of this study was to search predictive factors for incomplete resection. METHODS: All patients undergoing surgery for retroperitoneal sarcoma in two University hospitals between 2010 and 202 were included. The main endpoint was incomplete resection (R1 ad R2) after surgery. Secondary analysis was performed where marginal R0 resection was considered as complete. Univariate and multivariable analysis of demographics, radiological, surgical and pathologic criteria were performed. Overall survival, local and distant recurrence were evaluated. RESULTS: Fifty-eight patients were included in the study. Fifty patients had incomplete resection, of which seven had marginal R0 resection. In multivariable analysis, none of the factors analyzed were associated with incomplete resection. In secondary analysis, undifferentiated liposarcoma histology (OR 12.3, 95% CI [1.416-107.303], P=0.023) was statistically significantly associated with incomplete resection. Low grade (grade I) histology was predictive of complete resection (OR 0.24, 95% CI [0.060-0.959], P=0.043). Median follow-up duration was 27 months. Local and distant recurrence rates at three years were 37% and 22.4%, respectively. CONCLUSION: In this study, we highlighted several predictive factors for incomplete resection. These factors enable us to define target populations that could most benefit from complementary therapy along with surgery.

Intraosseous Hibernoma: A Rare Entity in Orthopedics With Peculiar Radiological Features.

Intraosseous hibernoma is a rare benign bone tumor derived from brown fat. It is typically found in the axial skeleton and is more commonly observed in women. It can manifest as a painful lesion or may be incidentally discovered. Intraosseous hibernoma often presents as a sclerotic lesion, although it can also manifest as a lytic lesion. Due to its varied radiographic appearance, it should be considered in the differential diagnosis of bone lesions as it can mimic metastatic lesions as well as other sclerotic and lytic bone lesions. Therefore, obtaining a biopsy of the lesion is crucial for an accurate diagnosis. In this report, we present the clinical, radiological, and histopathological findings of two cases of intraosseous hibernoma and provide a concise overview based on a review of the literature.

Novel KHDRBS1-NTRK3 rearrangement in a congenital pediatric CD34-positive skin tumor: a case report.

Cutaneous spindle-cell neoplasms in adults as well as children represent a frequent dilemma for pathologists. Along this neoplasm spectrum, the differential diagnosis with CD34-positive proliferations can be challenging, particularly concerning neoplasms of fibrohistiocytic and fibroblastic lineages. In children, cutaneous and superficial soft-tissue neoplasms with CD34-positive spindle cells are associated with benign to intermediate malignancy potential and include lipofibromatosis, plaque-like CD34-positive dermal fibroma, fibroblastic connective tissue nevus, and congenital dermatofibrosarcoma protuberans. Molecular biology has been valuable in showing dermatofibrosarcoma protuberans and infantile fibrosarcoma that are characterized by COL1A1-PDGFB and ETV6-NTRK3 rearrangements respectively. We report a case of congenital CD34-positive dermohypodermal spindle-cell neoplasm occurring in a female infant and harboring a novel KHDRBS1-NTRK3 fusion. This tumor could belong to a new subgroup of pediatric cutaneous spindle-cell neoplasms, be an atypical presentation of a plaque-like CD34-positive dermal fibroma, of a fibroblastic connective tissue nevus, or represent a dermatofibrosarcoma protuberans with an alternative gene rearrangement.

IDH mutation status in a series of 88 head and neck chondrosarcomas: different profile between tumors of the skull base and tumors involving the facial skeleton and the laryngotracheal tract.

Chondrosarcomas are rare primary malignant bone tumors that involve the head and neck region in 1% to 12% of cases. Central conventional chondrosarcoma is the most common subtype and is associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations in 50% to 60% of cases. We aimed to define the frequency of IDH1 and IDH2 gene mutations in a multicenter series of 88 cases of chondrosarcoma of the head and neck, including tumors involving the base of the skull (n = 30), the facial skeleton (n = 11), and the laryngeal and tracheal cartilages (n = 47). Petrous bone and cricoid cartilage were the most frequently involved sites for chondrosarcomas of the skull base and laryngotracheal tract (43.3% and 31.9%, respectively). Overall, 64.9% of craniofacial chondrosarcomas featured IDH mutations, with a high rate for skull base tumors (85.7%) but no IDH mutations in tumors of the facial skeleton. This different mutational profile could be related to the type of ossification, the bones of the base of the skull mainly resulting from endochondral ossification, and those of the face from intramembranous ossification. Conversely, mutation was infrequent in chondrosarcomas involving the laryngeal and tracheal cartilages (11.8% of 47 cases). Evaluation of IDH mutation status may be a useful diagnostic tool for bone tumors of the skull base, which are most often assessable with only small biopsy samples. The low rate of IDH mutations observed in laryngotracheal chondrosarcomas suggests a different mode of tumorigenesis needing further exploration.

Early detection of multiple bone and extra-skeletal metastases by body magnetic resonance imaging (BMRI) after treatment of Myxoid/Round-Cell Liposarcoma (MRCLS).

INTRODUCTION: Myxoid Round cell containing myxoid liposarcomas (MRCLS) have a high propensity to metastasize to soft tissue and bone. Whole Body Magnetic Resonance Imaging (BMRI) has been reported as a critical modality to early detect disease spreading in asymptomatic patients. The purpose of this study is to describe metastatic patterns and outcomes in patients through annual BMRI surveillance after diagnosis of MRCLS of the extremities and trunk. MATERIEL AND PATIENTS: This retrospective study included patients with histology confirmed MRCLS. Initial BMRI were done within 6 months following the first line treatment then once a year. RESULTS: Forty-five out of 51 consecutive MRCLS patients were included. At the last follow-up 10 patients (22.2%) had an extra-pulmonary soft-tissue or/and bone metastasis detected in a median delay of 22.7±16 months [0-49] from the diagnosis of the MRCLS. Nine patients were asymptomatic. Finally, 5-years metastatic free survival was 72±8%. All metastatic patients had multiple lesion within the year following the first lesion diagnosis. CONCLUSION: Systematic BMRI in MRCLS patients following treatment frequently identify extra-pulmonary metastasis in asymptomatic patients within the first 5 years of follow-up. Despite a long survival can be expected after diagnosis, extra-skeletal metastasis was a signal of disseminated disease.

Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression.

Chondrosarcomas are primary cancers of cartilaginous tissue with highly contrasting prognoses. These tumors are defined by recurrent mutations in the IDH genes and other genetic alterations including inactivation of CDKN2A and COL2A1; however, these have no clinical value. Here we use multi-omics molecular profiles from a series of cartilage tumors and find an mRNA classification that identifies two subtypes of chondrosarcomas defined by a balance in tumor differentiation and cell cycle activation. The microRNA classification reveals the importance of the loss of expression of the 14q32 locus in defining the level of malignancy. Finally, DNA methylation is associated with IDH mutations. We can use the multi-omics classifications to predict outcome. We propose an mRNA-only classifier to reproduce the integrated multi-omics classification, and its application to relapsed tumor samples shows the progressive nature of the classification. Thus, it may be possible to use mRNA-based signatures to detect patients with high-risk chondrosarcomas.