PEC-PRO: A new prognostic score from a series of 87 patients with localized perivascular epithelioid cell neoplasms (PEComas) treated with curative intent.

BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. Previously described clinicopathologic features aimed at distinguishing benign from malignant variants but lacked prognostic value. METHODS: This retrospective analysis examined clinicopathologic data from patients who had localized PEComa across French Sarcoma Network centers. The authors analyzed 12 clinicopathologic features in a Cox proportional hazard framework to derive a multivariate prognostic risk model for event-free survival (EFS). They built the PEComa prognostic score (PEC-PRO), in which scores ranged from 0 to 5, based on the coefficients of the multivariate model. Three groups were identified: low risk (score = 0), intermediate risk (score = 1), and high risk (score ≥ 2). RESULTS: Analyzing 87 patients who had a median 46-month follow-up (interquartile range, 20-74 months), the median EFS was 96.5 months (95% confidence interval [CI], 47.1 months to not applicable), with 2-year and 5-year EFS rates of 64.7% and 58%, respectively. The median overall survival was unreached, with 2-year and 5-year overall survival rates of 82.3% and 69.3%, respectively. The simplified Folpe classification did not correlate with EFS. Multivariate analysis identified three factors affecting EFS: positive surgical margins (hazard ratio [HR], 5.17; 95% CI, 1.65-16.24; p = .008), necrosis (HR, 3.94; 95% CI, 1.16-13.43; p = .030), and male sex (HR, 3.13; 95% CI, 1.19-8.27; p = 0.023). Four variables were retained in the prognostic model. Patients with low-risk PEC-PRO scores had a 2-year EFS rate of 93.7% (95% CI, 83.8%-100.0%), those with intermediate-risk PEC-PRO scores had a 2-year EFS rate of 67.4% (95% CI, 53.9%-80.9%), and those with high-risk PEC-PRO scores had a 2-year EFS rate of 2.3% (95% CI, 0.0%-18.3%). CONCLUSIONS: The PEC-PRO score reliably predicts the risk of postoperative recurrence in patients with localized PEComa. It has the potential to improve follow-up strategies but requires validation in a prospective trial.

Immune-Desert Tumor Microenvironment in Thoracic SMARCA4-Deficient Undifferentiated Tumors with Limited Efficacy of Immune Checkpoint Inhibitors.

BACKGROUND: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. MATERIALS AND METHODS: Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non-small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. RESULTS: Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. CONCLUSION: SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.

SMARCA4-deficient rhabdoid tumours show intermediate molecular features between SMARCB1-deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type.

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1 ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4 ) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1 , ECRTSMARCA4 , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1 ; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1 , potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Superficial CD34-positive fibroblastic tumor and PRDM10-rearranged soft tissue tumor are overlapping entities: a comprehensive study of 20 cases.

AIMS: Superficial CD34-positive fibroblastic tumor (SCD34FT) and PRDM10-rearranged soft tissue tumor (PRDM10-STT) are rare mesenchymal tumors. These lesions have clinicopathological similarities, but their relationship remains controversial. This study aimed to characterise a series of cases of SCD34FT and PRDM10-STT. METHODS AND RESULTS: Ten lesions each of SCD34FT and PRDM10-STT were studied using immunohistochemistry, array-comparative genomic hybridisation (aCGH), RNA sequencing and exome sequencing. Tumors mainly occurred in young adults, were generally small (< 5 cm) and arose predominantly in the superficial soft tissues of the lower extremities. Follow-up data were available in 15 cases (SCD34FT, n = 7, median 16 months; PRDM10-STT, n = 8, median 14 months), local recurrences occurred in four cases (SCD34FT, two of 10; PRDM10-STT, two of 10), while no distant spread was documented. Morphologically, tumors were relatively well-circumscribed and composed of sheets and fascicles of spindle and pleomorphic cells showing low mitotic activity (< 1/mm²) without necrosis. Other findings included: granular cell change, lipoblast-like cells, ectatic blood vessels with fibrinous material, myxoid stromal changes, metaplastic bone and increased mitotic activity (> 1/mm²). All tumors diffusely expressed CD34, while pan-keratin and desmin were commonly seen focally. SynCAM3 was diffusely expressed in 12 cases (SCD34FT, n = 5; PRDM10-STT, n = 7), independently of fusion status. aCGH profiles were 'flat' (PRDM10-STT, n = 4; SCD34FT, n = 2) and exome sequencing showed no recurrent pathogenic mutations (PRDM10-STT, n = 2; SCD34FT, n = 4). Overall, the only morphological features seen exclusively in PRDM10-STT were myxoid stromal changes (three of 10) and metaplastic bone (two of 10). CONCLUSION: We expand the current knowledge on PRDM10-STT and SCD34FT and provide additional evidence for considering them as overlapping entities.

NFATc2-rearranged sarcomas: clinicopathologic, molecular, and cytogenetic study of 7 cases with evidence of AGGRECAN as a novel diagnostic marker.

NFATc2-rearranged sarcomas (NFATc2-Sarcomas) are infrequent round cell tumors characterized by EWSR1-NFATc2 fusions and FUS-NFATc2 fusions. Although our knowledge on these neoplasms has increased recently, novel diagnostic tools and more comprehensive series are still needed. Here, we describe the features of a series of seven molecularly confirmed NFATc2-Sarcomas (EWSR1-NFATc2, n = 4; FUS-NFATc2, n = 3) and demonstrate the utility of AGGRECAN immunohistochemistry for their identification. Patients were four males and three females, ranging in age from 19 to 66 years (median: 33). All were primary bone tumors (femur, n = 4; tibia, n = 2; ilium, n = 1), frequently infiltrating the surrounding soft tissues. Treatment often consisted of neoadjuvant chemotherapy and surgery. Follow-up was available for six patients (median 18 months, range 5-102 months), three patients died of disease and four patients are currently alive. Histologically, tumors consisted of monotonous round cells growing in lobules and sheets in variable amounts of fibrous to myxoid stroma. Other findings included spindle cells, corded and trabecular architecture, nuclear pleomorphism, cartilaginous differentiation, and osteoid-like matrix. Histological response to neoadjuvant chemotherapy was poor in all resection specimens available for review (n = 4). Tumors were diffusely positive for AGGRECAN and CD99 (7/7), and a subset expressed Pan-Keratin (AE1-AE3; 3/6), S100 (2/6), BCOR (2/6), ETV-4 (2/5), WT1 (2/6), and ERG (2/5). Desmin, NKX3-1, and SATB2 were negative (0/6). Diffuse AGGRECAN staining was also seen in 8/129 round cell sarcomas used for comparison, including mesenchymal chondrosarcoma (7/26) and CIC-sarcoma (1/26). Array-CGH showed complex karyotypes with recurrent deletions of tumor suppressor genes (CDKN2A/B, TUSC7, and DMD) in three FUS-NFATC2 cases and a simpler profile without homozygous losses in one EWSR1-NFATc2 case. Segmental chromosomal gains covering the loci of the fusion genes were detected in both variants. Overall, our study confirms and expands previous observations on NFATc2-sarcomas and supports that AGGRECAN is a useful biomarker of these tumors.

Correction: NFATc2-rearranged sarcomas: clinicopathologic, molecular, and cytogenetic study of 7 cases with evidence of AGGRECAN as a novel diagnostic marker.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Conformity to Clinical Practice Guidelines at Initial Management in Adult Soft Tissue and Visceral Tumors since the Implementation of the NetSarc Network in Eastern France.

BACKGROUND: Soft tissue sarcomas are rare and heterogenous tumors that are hard to diagnose. The aim of this study was to evaluate local practices and conformity to clinical practice guidelines (CPGs) for their initial diagnostic management. MATERIALS AND METHODS: Patients were carriers of a soft tissue or visceral tumor, presented at a sarcoma tumor board (STB) between 2010 and 2016. Conformity to CPGs was evaluated using ten criteria designed for this purpose. Associations between different factors and conformity to composite criteria, reflecting the three main diagnostic steps (imaging, biopsy and histological report) were analyzed. RESULTS: A total of 643 patients were included. A preoperative tumor imaging assessment and a biopsy were performed according to CPGs in 80.8% and 36.8% of the cases, respectively. When done, the first surgical resection was R0 in 30.3% of cases, R1 in 28.6%, and R2 in 10.9%. The rest of the operated patients with sarcoma had a second surgical excision (11.4%), an intraoperative fragmentation (4.3%), or margins were unknown (14.4%). Six of the ten quality criteria presented a conformity rate higher than 70%. Two criteria with a conformity rate lower than 20% were the most controversial: presentation at a STB before biopsy and freezing of a tumor fragment. A multivariate analysis revealed that the common predictor of nonconformity to composite criteria was the initial management in a nonexpert center. CONCLUSION: Initial diagnostic management requires improvement, especially outside of specialized centers. IMPLICATIONS FOR PRACTICE: This article supports the essential need to refer patients with soft tissue tumors to specialized centers to improve the management of sarcomas beginning at the diagnostic phase. Indeed, the reported data were very similar to those already described at the national level of the NetSarc network and indicate the necessity to keep raising awareness about this simple issue: early referral to reference centers will save lives.

Aggressive digital papillary adenocarcinoma: A clinicopathological study of 19 cases.

BACKGROUND: Aggressive digital papillary adenocarcinomas (ADPA) are malignant tumors of sweat glands having recurrence/metastatic potential. OBJECTIVE: We sought to describe the clinical/histopathological characteristics of a series of ADPA. METHODS: This is a retrospective case series of 19 ADPA. RESULTS: The tumors occurred in 17 men and 2 women (mean age: 47 years). They involved digits (15), big toe (3), and palm (1), and measured from 3 to 30 mm. They were mostly solid and cystic, with papillary projections and tubular structures. Atypia was mostly mild to moderate. Tumors tested positive for p63, keratin 7, keratin 77 (eccrine duct-specific), PHLDA1, and epithelial membrane antigen in most cases, and for carcinoembryonic antigen, smooth muscle actin, S100 protein, estrogen, progesterone, and androgen receptors in 50%. Mean Ki67 proliferation index was 15%. Local recurrence was observed in 4 cases. One patient had axillary lymph node metastasis. Histopathologic parameters were not predictive of evolution. Conservative surgical treatment, performed in 7 of 19 cases, did not result in more recurrences than amputation. LIMITATIONS: The study was retrospective and the number of cases is small. CONCLUSION: ADPA are histologically variable, but papillary projections are always present. Keratin 77 expression suggests an eccrine origin. P63 is helpful to exclude metastasis. Conservative surgery may be sufficient in some cases.

Intralymphatic CD30+ T-cell proliferation during DRESS: a mimic of intravascular lymphoma.

INTRODUCTION: We describe the case of a patient presenting with drug rash with eosinophilia and systemic symptoms (DRESS), where cutaneous biopsy revealed intravascular atypical lymphocytes suggestive of lymphoma. CASE REPORT: A 77-year-old man was treated with antibiotics for a hip prosthesis infection. Eight weeks later, he developed a maculo-papulous eruption, edema of the extremities, fever and blood eosinophilia. Cutaneous biopsy revealed an atypical T-cell proliferation into the dermal lymphatic vessels. The lymphocytes were mid-sized, with mitoses and apoptotic figures. They were CD3+, CD4+, CD5+ and some were CD30+. There was no T-cell receptor (TcR) clonal rearrangement. Complete regression of cutaneous eruption and eosinophilia was observed after ceasing treatment with antibiotics. The diagnosis was that of a benign atypical intralymphatic T-cell proliferation associated with DRESS. DISCUSSION: The occurrence of atypical dermal CD30+ T-cells in cutaneous biopsy during benign reactive conditions such as arthropod bites or scabies is well-known. The intralymphatic localization of such atypical reactive lymphocytes is much less common and represents a diagnostic pitfall because it can suggest aggressive intravascular lymphoma. CONCLUSION: We report the first case of benign atypical intralymphatic CD30+ T-cell proliferation associated with DRESS. Diagnostic clues include immunohistochemistry, absence of TcR clonal rearrangement, and anatomo-clinical correlation.

Superficial acral fibromyxoma: a case of missed diagnosis.

Superficial acral fibromyxoma (SAFM) is a rare, benign, slow-growing fibroblastic tumour of the soft tissue that is part of the group of myxoid soft-tissue neoplasms. It is a rare entity and usually occurs in the acral regions. We report the case of a 64-year-old man who presented to the emergency room for a lesion expected to have occurred as a result of an ingrown toenail. Because this patient had a history of repeated recurrences despite multiple surgical wedge excisions, we performed a complete surgical excision, and the pathological analysis confirmed the suspected diagnosis of SAFM. There was no recurrence at the 6-month follow-up. This case highlights the fact that this tumour is still misunderstood and underrecognized by surgeons and this often leads to delayed diagnosis. Although it is a rare entity, clinicians should be aware of this tumour in cases of recurring ingrown toenails.

Management of a rare mandibular giant cell tumor of bone by neoadjuvant denosumab therapy and surgery: A 4-year follow-up case report.

INTRODUCTION: Giant cell tumor of bone (GCTB) is a very rare tumor encountered in the jaws and its histology is quite similar to the more common giant cell granuloma of the jaws (GCGJ). These two entities can be easily confused in maxillofacial region. They are classically managed surgically, but in some localizations and in specific medical-surgical contexts, neoadjuvant therapy with denosumab may be indicated. This report tends to reinforce existing evidence in favor of the use of a neoadjuvant approach, particularly for localization of GCTB in the orofacial region. PRESENTATION OF CASE: This is a 57-year-old female patient, an alcoholic smoker, in whom a voluminous mandibular radiolucent lesion was discovered during a routine X-ray by her dentist. After medical imaging assessment and incisional biopsy, diagnosis of GCTB was established. A neoadjuvant denosumab therapy was proposed first followed by a secondary surgical curettage. After 4 years' follow-up, complete healing was observed with no recurrence of the lesion. DISCUSSION: Surgical management of aggressive GCTB is risky particularly in localizations involving the sacrum, spine or craniofacial skeleton with a high residual recurrence rate. The use of denosumab to stop tumor progression and facilitate secondary excision surgery is a recent approach that is now well documented in the literature showing promising results with a low rate of side effects. CONCLUSION: This case of mandibular GCTB is to our knowledge the unique case described in this localization and treated by denosumab neoadjuvant therapy followed by surgery with a 4-year follow-up showing a complete healing.

All pineal tumors expressing germ cell tumor markers are not necessarily germ cell tumors: histopathological and molecular study of a midline primary intracranial sarcoma DICER1-mutant.

Primary intracranial sarcoma DICER1-mutant is a rare and newly recognized tumor type introduced in the 2021 WHO Classification of Central Nervous System Tumors. It is defined as a spindle cell sarcoma dysplaying eosinophilic intracytoplasmic globules, myogenic differentiation, and DICER1 gene mutation, either somatic or germline. Most reported cases were hemispheric except one, recently described in the pineal region. Here, we report the case of a 12 year-old boy with a pineally located tumor. Despite midline location, poorly differenciated morphology and germ cell marker expression, the association of DICER1 and NF1 hotspot mutations and a specific DNA methylation signature finally lead to the diagnosis of primary intracranial sarcoma DICER1-mutant instead of germ cell tumor. Furthermore, our molecular exploratory results involved a pathway, which was not previously evidenced in those DICER1 mutated cerebral sarcoma that is the canonical Wnt signaling driving likely a part of oncogenesis in this newly described pineal entity.

Innovative approach to lymphadenectomy in breast sarcoma.

Lymphatic dissemination is thought to be a rare event in breast sarcomas. The decision to perform axillary clearance is challenging. In our prospective cohort, we aimed to evaluate the frequency and factors determining lymph node (LN) involvement in breast sarcomas, with the aim of proposing a decision tree/algorithm for the realization of LN clearance in breast sarcomas. PATIENTS AND METHODS: Fourty-five women were surgically treated for breast sarcomas from 1982 to 2020. Angiosarcomas and other sarcomas were compared in terms of LN involvement, recurrence, and mortality. RESULTS: Twenty-three patients underwent axillary lymphadenectomy. Initial LN involvement was diagnosed in one case of D2-40 positive, primary angiosarcoma for which preoperative imaging detected a suspicious LN confirmed by preoperative histology. Among the 22 patients who had no initial axillary lymphadenectomy, two patients with D2-40 positive angiosarcoma had recurrent cancer in LN (internal mammary group in 1 and homolateral axilla in 1). The average follow-up in the overall population was 6.2 years (±8.3). The cohort's overall recurrence rate was 33% (15/45) and the time of recurrence after initial surgery was on average 2.4 years (±3.1). For the three patients with LN metastases, time to recurrence after surgery was 3.7 years (±4.5). There was no significant difference in the overall recurrence rate depending on whether or not lymphadenectomy was initially performed (respectively 26% vs 41% OR=1.11, P=0.29). DISCUSSION/CONCLUSION: Systematic axillary clearance leads to overtreatment in breast sarcomas. A decision tree, including radiological examination of the axilla, histological type of sarcoma, and D2-40 positivity, could be a decision aid in the choice of axillary clearance.

An integrative ultrasound-pathology approach to improve preoperative phyllodes tumor classification: A pilot study.

OBJECTIVE: Preoperative diagnosis of phyllodes tumor (PT) is challenging, core-needle biopsy (CNB) has a significant rate of understaging, resulting in suboptimal surgical planification. We hypothesized that the association of imaging data to CNB would improve preoperative diagnostic accuracy compared to biopsy alone. METHODS: In this retrospective pilot study, we included 59 phyllodes tumor with available preoperative imaging, CNB and surgical specimen pathology. RESULTS: Two ultrasound features: tumor heterogeneity and tumor shape were associated with tumor grade, independently of CNB results. Using a machine learning classifier, the association of ultrasound features with CNB results improved accuracy of preoperative tumor classification up to 84%. CONCLUSION: An integrative approach of preoperative diagnosis, associating ultrasound features and CNB, improves preoperative diagnosis and could thus optimize surgical planification.

Together Intra-Tumor Hypoxia and Macrophagic Immunity Are Driven Worst Outcome in Pediatric High-Grade Osteosarcomas.

BACKGROUND: Osteosarcomas (OTS) represent the most common primary bone cancer diagnosed in adolescents and young adults. Despite remarkable advances, there are no objective molecular or imaging markers able to predict an OTS outcome at diagnosis. Focusing on biomarkers contributing broadly to treatment resistance, we examine the interplay between the tumor-associated macrophages and intra-tumor hypoxia. METHODS: Radiological and immunohistochemical (IHC) data were correlated with the outcome in a retrospective and monocentric cohort of 30 pediatric OTS. We studied hypoxic (pS6, phospho-mTor, HIF-1α and carbonic anhydrase IX (CAIX)) and macrophagic (CD68 and CD163) biomarkers. RESULTS: The imaging analyses were based on MRI manual volumetric measures on axial post-contrast T1 weighted images, where, for each tumor, we determined the necrotic volume and its ratio to the entire tumor volume. When they were above 50 cm3 and 20%, respectively, they correlated with a worse overall survival (p = 0.0072 and p = 0.0136, respectively) and event-free survival (p = 0.0059 and p = 0.0143, respectively). IHC assessments enable a significant statistical link between HIF-1α/CAIX hyper-expressions, CD68+ cells and a worse outcome, whereas activation of mTor pathway was linked to a better survival rate and CD163+ cells. CONCLUSIONS: This study evidenced the links between hypoxia and immunity in OTS, as their poor outcome may be related to a larger necrotic volume on diagnostic MRI and, in biopsies, to a specific IHC profile.