Diagnostic accuracy and safety of percutaneous core needle biopsy of retroperitoneal tumours.

BACKGROUND: Histologic subtype of cancer guides treatment sequencing and the extent of surgery for retroperitoneal tumours (RPTs) but concerns persist regarding percutaneous core needle biopsy (CNB). OBJECTIVE: Endpoints were the incidence of early complications, needle tract seeding (NTS) after CNB, diagnostic accuracy. METHODS: Between 2015 and 2022, data from patients with RPT who underwent a CNB and who operated on at Institut Curie were collected. We retrospectively reviewed the medical records and microscopic analysis of both CNB and surgical specimens to evaluate the diagnostic accuracy of CNB (quantified using positive and negative predictive values, PPV/NPV). RESULTS: 313 patients underwent CNB. In 10/326 (3 %) procedures, minor complications were observed. One of 212 (0.47 %) resected RPSs exhibited a local recurrence compatible with NTS. Microscopic analysis of CNB specimens allowed the classification of tumours between groups of cancers and benign/intermediate mesenchymal tumours in 307/313 (98 %) patients. Among the 204 patients with retroperitoneal sarcoma, the overall concordance between CNB and final pathology following resection was 178/204 (87.2 %). The respective PPVs of solitary fibrous tumour, dedifferentiated liposarcoma, leiomyosarcoma and well-differentiated liposarcoma were 100 %, 98 %, 97 % and 68 %, respectively. The diagnosis of a high-grade (G 2-3) sarcoma resulted in a high specificity (97 %) and PPV (98 %) but low sensitivity (76 %). CONCLUSIONS: CNB allowed the classification of RPT in the vast majority of patients with a low morbidity rate. Concordance with final diagnosis was high for sarcomas with the exception of well-differentiated liposarcoma. As a result, CNB results should be integrated with imaging/radiomics by multidisciplinary tumour boards.

Impact of guideline adherence and expert center referral on the early management and outcomes of uterine sarcoma patients: A retrospective analysis from the French NETSARC network.

OBJECTIVE: Uterine sarcomas are rare tumors with a poor prognosis. Their diagnosis is often incidental, following surgery. Our goal was to examine the early management strategies for uterine sarcomas, and to assess the impact of guideline adherence and expert center referral on both the management approaches and the clinical outcomes in patients with uterine sarcomas. METHODS: We retrospectively analyzed medical records from patients with uterine sarcoma referred to the Institut Curie and registered in the database of the French NETSARC network. RESULTS: In total, 100 patients, with a median age of 54 years, were included in the analyses. On MRI scans (n = 36), all patients had at least two signs suggestive of malignancy, and 77.8 % had four or more signs. No preoperative biopsy was performed in 65.6 % of cases. Only 14.1 % of patients underwent initial surgery at an expert center. Surgery performed outside the network was significantly associated with morcellation (32.9 % vs. 0 %; p = 0.036), fewer negative margins (R0 margins 52.4 % vs. 100 %; p = 0.006), and poor adherence to surgical guidelines (28.3 vs. 72.7 %; p = 0.013). Multivariate analysis showed that non-adherence to surgical recommendations was not significantly associated with relapse-free survival (HR = 0.54; 95 % CI [0.21-1.38]), but was an independent predictor of poor overall survival (HR = 0.12; 95 % CI [0.03-0.52]; p = 0.005). CONCLUSION: Despite a high frequency of suspicious clinical and radiological signs, a large proportion of women undergoing sarcoma surgery are treated outside of expert networks. We provide guidelines, integrating the clinical context and radiological signs to encourage early referral to reference centers for sarcoma.

Fusion-negative rhabdomyosarcoma 3D organoids to predict effective drug combinations: A proof-of-concept on cell death inducers.

Rhabdomyosarcoma (RMS) is the main form of pediatric soft-tissue sarcoma. Its cure rate has not notably improved in the last 20 years following relapse, and the lack of reliable preclinical models has hampered the design of new therapies. This is particularly true for highly heterogeneous fusion-negative RMS (FNRMS). Although methods have been proposed to establish FNRMS organoids, their efficiency remains limited to date, both in terms of derivation rate and ability to accurately mimic the original tumor. Here, we present the development of a next-generation 3D organoid model derived from relapsed adult and pediatric FNRMS. This model preserves the molecular features of the patients' tumors and is expandable for several months in 3D, reinforcing its interest to drug combination screening with longitudinal efficacy monitoring. As a proof-of-concept, we demonstrate its preclinical relevance by reevaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on transcriptomic data exploitation.

Expression, Prognostic Value and Correlation with HPV Status of Hypoxia-Induced Markers in Sinonasal Squamous Cell Carcinoma.

(1) Background: In head and neck squamous cell carcinoma, tumor hypoxia has been associated with radio/chemoresistance and poor prognosis, whereas human papillomavirus (HPV)-positive status has a positive impact on treatment response and survival outcomes. The aim of this study was to evaluate the expression and the potential prognostic value of hypoxia-induced endogenous markers in patients treated for squamous cell carcinoma of the nasal cavity and paranasal sinuses (SNSCC), and their correlation with HPV status. (2) Methods: In this monocentric study, patients treated in a curative intent for a SNSCC were screened retrospectively. Protein expression of CA-IX, GLUT-1, VEGF, VEGF-R1, and HIF-1α was determined by immunohistochemical staining, scored, and then correlated with overall survival (OS) and locoregional recurrence free survival (LRRFS). HPV status was assessed and correlated with hypoxic markers. (3) Results: 40 patients were included. A strong expression of CA-IX, GLUT-1, VEGF, and VEGF-R1 was detected in 30%, 32.5%, 50%, and 37.5% of cases, respectively. HIF-1α was detected in 27.5% of cases. High CA-IX expression was associated in univariate analysis with poor OS (p = 0.035), but there was no significant association between GLUT-1, VEGF, VEGF-R1, and HIF-1α expression, and OS/LRRFS. There was no correlation found between HPV status and hypoxia-induced endogenous markers (all p > 0.05). (4) Conclusions: This study provides data on the expression of hypoxia-induced endogenous markers in patients treated for SNSCC and underlines the potential role of CA-IX as a prognostic biomarker for SNSCC.

MDM4 amplification in atypical lipomatous tumors/well-differentiated liposarcoma: Private event or alternative oncogenic mechanism?

Adipocytic tumors are the most common mesenchymal tumors in soft tissues. Among them, a diagnostic challenge relies in the distinction between lipoma and atypical lipomatous tumor (ALT)/well differentiated liposarcoma (WDLPS), as both entities are often undistinguishable not only from a radiological point of view, but also at the microscopic level and particularly when dealing with small tumor specimen. Thus, detection of recurrent MDM2 amplifications may be the only criteria to discriminate malignant tumors from lipomas. In this study, we report the case of a patient diagnosed with a well differentiated, adipocytic tumor located in the inferior limb and lacking MDM2 amplification, whose diagnosis was reclassified for ALT/WDLPS after identification of an alternative MDM4 amplification by comparative genomic hybridization profiling, whole exome sequencing and fluorescence in situ hybridization (FISH). Screening of a cohort of 37 large, deep-seated, well-differentiated adipocytic tumors previously classified as lipomas using RT-qPCR and FISH failed to detect other cases of MDM4-amplified ALT/WDLPS. This report shows that MDM4 amplification is an exceptional molecular event alternative to MDM2 amplification in ALT/WDLPS. This alteration should be considered and looked for in suspicious adipocytic tumors to optimize their surgical management.

Percutaneous Uterine Needle Biopsy with Microscopic and Array-CGH Analyses for Preoperative Sarcoma Diagnosis in Patients with Suspicious Myometrial Tumors on MRI: A Prospective Pilot Study (SARCGYN).

BACKGROUND: Unlike for soft tissue sarcomas, percutaneous biopsy is not validated for uterine myometrial tumors, leading to leiomyosarcoma inadvertent morcellation and overtreatment in childbearing patients. This study aimed to evaluate preoperative percutaneous uterine needle biopsy (PUB) with microscopic examination (M-PUB) and array-comparative genomic hybridization (MCGH-PUB). METHODS: This was a prospective single-center cohort study including all consecutive patients who were candidates for hysterectomy because of suspected uterine leiomyosarcoma on magnetic resonance imaging (MRI) who received PUB. Microscopic and array-CGH analyses with genomic index (GI) counts were performed to guide the therapeutic strategy. Smooth-muscle tumors with suspect features with a GI above 15 were deemed malignant, as were tumors without microscopic malignant features with a complex genomic profile (GI above 30 or malignant profile). Preoperative diagnoses based on M-PUB and MCGH-PUB were compared with the postsurgical pathological specimen or follow-up. RESULTS: From November 2016 to February 2022, 34 patients were included. Based on the surgical specimen (N = 23) or follow-up (N = 11), final diagnoses were 11 sarcomas and 23 non-sarcomas. The median follow-up was 12 months (IQR 6-37). The diagnostic accuracies of M-PUB and MCGH-PUB were 94% and 100%, respectively. The sensitivity, specificity, and negative predictive value of MCGH-PUB were 100%, 100%, and 100%, respectively. A high GI was significantly associated with malignancy (P < 0.001). Genomic analyses allowed malignancy upgrades for four tumors. There were no complications and no dissemination along the biopsy track. CONCLUSION: MCGH-PUB is safe and accurate for preoperatively diagnosing uterine sarcomas and should be used routinely after suspicious MRI to tailor surgery.

Desmoid Tumors Arising on the Mesenteric Surgical Scar of Abdominal Sarcomas.

A sporadic desmoid tumor (DT) is a rare type of tumor of the mesenchymal connective tissues is now considered an intermediate disease or locally aggressive. They may develop on scars or after traumatism, favored by growth factors released during the initial phase of wound healing. Most of the abdominal DT arising on a scar is described on the wall incision. In this report, we describe two cases of DT arising on the intraperitoneal surgical scar, shortly after the resection of a low-grade retroperitoneal liposarcoma and a low-risk gastric gastrointestinal stromal tumor (GIST). Inconsistency between low risk according to the classification of the primary sarcoma and early local recurrence (LR) should raise the possibility of DT. Core needle biopsy (CNB) should be performed when it is feasible, including on local recurrences (LR). Surveillance has become the first-line treatment for DT. In case of progression between two imaging during the surveillance phase, surgery, when it's not mutilating, is indicated for selected cases as second-line treatment.

Novel EWSR1::UBP1 fusion expands the spectrum of spindle cell rhabdomyosarcomas.

Over the last decade, the development of next-generation sequencing techniques has led to the molecular dismantlement of adult and pediatric sarcoma, with the identification of multiple gene fusions associated with specific subtypes and currently integrated into diagnostic classifications. In this report, we describe and discuss the identification of a novel EWSR1-UBP1 gene fusion in an adult patient presenting with multi-metastatic sarcoma. Extensive pathological, transcriptomic, and genomic characterization of this tumor in comparison with a cohort of different subtypes of pediatric and adult sarcoma revealed that this fusion represents a novel variant of spindle cell rhabdomyosarcoma with features of TFCP2-rearranged subfamily.

Verrucous Venous Malformation-Subcutaneous Variant.

BACKGROUND: Verrucous venous malformation (VVM), previously called "verrucous hemangioma," typically involves the dermis and the subcutaneous fat. We have encountered patients with VVM confined to the hypodermis. MATERIALS AND METHODS: During a nearly 20-year period, 13 patients, aged 2-17 years, presented with a subcutaneous mass in the limb without clinically obvious epidermal alterations. Consequently, operative excisions did not include the skin. RESULTS: Histopathologically, the specimens were composed of blood-filled channels with morphologic characteristics of capillaries and veins that infiltrated adipose tissue. Aggregates often formed nodules with variable fibrosis and a component of large and radially oriented vessels. A diagnosis of VVM was supported by endothelial immunopositivity for GLUT-1 (25%-75% immunopositive channels in 16/16 specimens); D2-40 (1%-25% channels in 14/15 specimens); and Prox-1 (1%-50% of channels in 14/16 specimens). A MAP3K3 mutation was identified by droplet digital PCR in 3 of the 6 specimens. CONCLUSIONS: Diagnosis of VVM in this uncommon location is challenging because of absence of epidermal changes and lack of dermal involvement. Imaging is not pathognomonic, and mimickers are many. Appropriate immunohistochemical stains and molecular analysis contribute to the correct diagnosis.

Neoadjuvant Everolimus for Adult Giant Mesenteric Cystic Lymphangioma with mTOR Pathway Activation.

Cystic lymphangioma are rare benign vascular or lymphatic tumors, diagnosed mostly in newborns or children, that may become life-threatening because of local invasiveness. Surgical "en-bloc" resection with negative margins is the only curative treatment, but some patients are diagnosed with unresectable tumors. We describe the case of a young adult with giant unresectable mesenteric lymphangioma. Extensive pathological characterization as well as whole exome and transcriptome sequencing enabled us to identify mTOR pathway activation within endothelial tumor cells. The patient was treated with everolimus and experienced major partial response, leading to the surgical resection of the residual lesions. This case highlights the importance of molecular characterization of adult cystic lymphangioma for mTOR pathway activation because multidisciplinary therapeutic approaches, including neoadjuvant everolimus and secondary surgery, can lead to complete cure of this rare condition. KEY POINTS: The case of an adult patient diagnosed with giant unresectable mesenteric cystic lymphangioma, in which activation of the mTOR pathway was documented at both the pathological and transcriptomic levels, is reported. This patient showed major partial response to the mTOR inhibitor everolimus, which led to the successful resection of residual tumor lesions after 9 months of treatment. This report shows that mTOR targeting should be considered as neoadjuvant treatment in adult large cystic lymphangioma, as it can lead to complete surgery and cure of this rare condition.

The histopathology of congenital haemangioma and its clinical correlations: a long-term follow-up study of 55 cases.

AIMS: Congenital haemangiomas (CHs) can be subdivided into different subtypes [rapidly involuting CHs (RICHs), non-involuting CHs (NICHs), and partially involuting CHs (PICHs)]. During the first few days of life, RICHs may be associated with transient but sometimes marked thrombocytopenia. We sought to assess the histological aspects and clinicopathological correlations of the three subtypes. METHODS AND RESULTS: We assessed the histopathological features of 10 RICHs, 25 NICHs, and 20 PICHs, described the patients' long-term clinical outcomes, and assessed clinicopathological correlations. All CHs were located in the dermis and hypodermis, and comprised both capillary lobules (with three distinct histopathological patterns) and extralobular large vessels. Most of the extralobular vessels were abnormal veins and abnormal lymphatic vessels. We did not observe significant correlations between the CH subtype, the histopathological pattern, and the time of the histopathological assessment. Interestingly, unexpected intralobular expression of podoplanin was found in neonatal biopsies of five RICHs and PICHs. Four of these five patients had concomitant thrombocytopenia. The podoplanin staining intensity decreased over time as the thrombocytopenia resolved and the tumour shrank. CONCLUSION: The histopathological features were similar in all three subtypes of CH, and were related to the time since disease onset; we consider that RICH, PICH and NICH form a single entity and differ only in their involuting potential. Along with the transient expression of intralobular podoplanin observed in some specimens from the newborn, the lobular architecture might lead to misdiagnosis of tufted haemangioma or kaposiform haemangioendothelioma.

Evaluating the prognostic potential of the Ki67 proliferation index and tumour-infiltrating lymphocytes in olfactory neuroblastoma.

AIMS: Olfactory neuroblastomas (ONBs) are rare malignant tumours that arise in the nasal vault. To date, the Hyams grade remains the only widely used histological grading system. However, it is based only on morphological criteria, and has not been updated since 1988. The objective of this study was to explore the prognostic potential of the Ki67 proliferation index (PI) and tumour-infiltrating lymphocytes (TILs) in ONB. METHODS AND RESULTS: A retrospective study was conducted on a bicentric series of 45 cases. The Ki67 PI was determined by counting at least 1000 nuclei on whole slides. TILs were evaluated with CD20, CD4 and CD8 immunohistochemical markers on whole slides. In this series, Hyams grades I, II, III and IV accounted for 13.4%, 44.4%, 20% and 22.2% of all cases, respectively. The Ki67 PI ranged from 1 to 93; the Ki67 PI was significantly higher in Hyams grade III-IV ONBs than in Hyams grade I-II ONBs (P < 0.0001). A Ki67 PI of ≥25 was associated with poorer survival (P = 0.02). TILs were present in both stromal and intratumoral compartments, but were located predominantly in the stromal component of the tumour. The numbers of intratumoral CD8+ cells/mm2 and CD4+ cells/mm2 were greater in high-grade ONBs than in low-grade ONBs (P = 0.0015 and P = 0.043, respectively). The numbers of T cells/mm2 and B cells/mm2 were not associated with survival, but a CD4/CD8 ratio of >2 was significantly associated with shorter survival (P = 0.04). CONCLUSION: Our findings suggest that the Ki67 PI and TILs could be used as prognostic markers, as a potential alternative to the Hyams grade.

Surgery and protontherapy in Grade I and II skull base chondrosarcoma: A comparative retrospective study.

OBJECTIVE: Skull base chondrosarcoma is a rare tumour usually treated by surgery and proton therapy. However, as mortality rate is very low and treatment complications are frequent, a less aggressive therapeutic strategy could be considered. The objective of this study was to compare the results of surgery only vs surgery and adjuvant proton therapy, in terms of survival and treatment adverse effects, based on a retrospective series. METHODS: Monocentric retrospective study at a tertiary care centre. All patients treated for a skull base grade I and II chondrosarcoma were included. We collected data concerning surgical and proton therapy treatment and up-to-date follow-up, including Common Terminology Criteria for Adverse Events (CTCAE) scores. RESULTS: 47 patients (23M/24F) were operated on between 2002 and 2015; mean age at diagnosis was 47 years-old (10-85). Petroclival and anterior skull base locations were found in 34 and 13 patients, respectively. Gross total resection was achieved in 17 cases (36%) and partial in 30 (64%). Adjuvant proton therapy (mean total dose 70 GyRBE,1.8 GyRBE/day) was administered in 23 cases. Overall mean follow-up was 91 months (7-182). Of the patients treated by surgery only, 8 (34%) experienced residual tumour progression (mean delay 51 months) and 5 received second-line proton therapy. Adjuvant proton therapy was associated with a significantly lower rate of relapse (11%; p = 0.01). There was no significant difference in 10-year disease specific survival between patients initially treated with or without adjuvant proton therapy (100% vs 89.8%, p = 0.14). Difference in high-grade toxicity was not statistically significant between patients in both groups (25% (7) vs 11% (5), p = 0.10). The most frequent adverse effect of proton therapy was sensorineural hearing loss (39%). CONCLUSION: Long-term disease specific survival was not significantly lower in patients without adjuvant proton therapy, but they experienced less adverse effects. We believe a surgery only strategy could be discussed, delaying as much as possible proton therapy in cases of relapse. Further prospective studies are needed to validate this more conservative strategy in skull base chondrosarcoma.

Olfactory Epithelial Hamartoma: A New Subtype of Sinonasal Hamartoma.

Sinonasal epithelial hamartomas occurring in adults are classified as seromucinous hamartoma (SMH) or respiratory epithelial adenomatoid hamartoma (REAH). We describe herein a novel subtype of adult sinonasal hamartoma that contains olfactory epithelium, a histologic feature not previously reported in the literature. Our pathology department database was retrospectively searched for sinonasal hamartomas containing areas of olfactory epithelium. Six relevant cases (3 male and 3 female patients; age, 30 to 77 y) were retrieved, and available pathology slides and clinical and imaging data from patient charts were reviewed. Five of the lesions were unilateral solitary, polypoid, pedunculated masses, 38 to 80 mm in length, lodged in the nasal olfactory cleft. The sixth lesion was associated with bilateral nasal polyposis, and its precise localization was not known. All patients were treated by transnasal endoscopic surgery. None of the 3 patients who had received adequate follow-up evaluation exhibited recurrence. Histologically, all lesions resembled SMH or REAH, with areas of olfactory epithelium comprising olfactory receptors and sustentacular and basal cells. Olfactory epithelium was observed at the lesion surface or in invaginated gland-like structures, and it contained focal aggregates of filamentous cell processes. Some olfactory receptor cells or cell processes were also present in the seromucinous gland component of lesions. Olfactory receptor cells expressed CD56 (neural cell adhesion molecule), and the filamentous aggregates contained CD56, neurofilaments, and synaptophysin. Aside from SMH and REAH, we have described a third subtype of adult sinonasal hamartoma-olfactory epithelial hamartoma-which shares the benign character of the other 2.