Objective
Synovial sarcomas (SS) are rare soft tissue tumours defined by the SYT‐SSX fusion gene. The tumours are composed of mesenchymal cells with varying degrees of epithelial differentiation. ...Cytomorphological descriptive studies are limited to small series and single cases. In this study we systematically examined the cytological features of SS diagnosed at our institution.
Methods
SS diagnosed by fine‐needle aspiration (FNA) cytology at our institution between 2006 and 2018 were reviewed by a panel of senior cytopathologists. Clinical and cytopathological characteristics were categorised and described.
Results
A total of 38 SS FNAs were identified from 35 patients. The cytomorphology was uniform, presenting as highly cellular smears of clusters and individual cells with mixed round, oval and spindle cells. We frequently observed pericapillary arrangement and occasionally pink background stroma was seen. Glandular formation or epithelial components were identified in the majority of cases which on histology were subtyped as biphasic SS. Pleomorphism and mitoses were rare. Immunocytochemical analysis was frequently positive for vimentin, epithelial membrane antigen, Bcl2 and, in recent cases, TLE1. Pan‐cytokeratins and CK7 could occasionally be positive in biphasic cases. The diagnostic SYT‐SSX fusion gene was detected in all FNA specimens using polymerase chain reaction or fluorescence in situ hybridisation.
Conclusions
SS have distinct and uniform cytopathological features. Molecular genetic analysis for SYT‐SSX are invaluable for diagnosing SS with FNA and should be implemented in cytopathological laboratories that routinely perform soft tissue diagnostics.
Synovial sarcomas are rare soft tissue tumors defined by the SYT‐SSX fusion gene. In this study, we demonstrate that synovial sarcomas have distinct and homogenous cytopathologic features. Molecular genetic analysis for SYT‐SSX are invaluable for diagnosing SS with FNA and should be implemented in cytopathological laboratories which routinely perform soft tissue diagnostics.
Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets. Methods: All of the ...consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel. Results: Patients with high-grade ovarian epithelial cancer were consented to prospective molecular characterization. Clinical information was extracted from their medical record. Tumour DNA was subjected to sequencing, and selected patients received PARP inhibitor therapy. Conclusions: Tumours from 274 women were sequenced, including high-grade serous carcinoma (n = 252), clear cell carcinoma (n = 4), carcinosarcoma (n = 9), endometrioid carcinoma (n = 3), undifferentiated carcinoma (n = 1), and mixed tumours (n = 5). Genomic profiling did not influence histologic diagnosis. Mutations were identified in TP53, BRCA1, BRCA2, as well as additional homologous recombination repair pathway genes BARD1, ATR, CHEK2, PALB2, RAD51D, RAD50, SLX4, FANCA, RAD51C, and RAD54L. In addition, mutations in PTEN and CDKN2A were identified. Several somatic mutations with implications for germline testing were identified, including RMI1, STK11, and CDH1. Germline testing identified 16 previously unknown BRCA1/2 carriers. Finally, 20 patients were treated with the PARP inhibitor olaparib based on the sequencing results.
A preterm infant with central hypoventilation was diagnosed with multifocal neuroblastoma. Congenital anomalies of the autonomic nervous system in association with neuroblastoma are commonly ...associated with germline mutations in PHOX2B. Further, the ALK gene is frequently mutated in both familial and sporadic neuroblastoma. Sanger sequencing of ALK and PHOX2B, SNP microarray of three tumor samples and whole genome sequencing of tumor and blood were performed. Genetic testing revealed a germline ALK F1174I mutation that was present in all tumor samples as well as in normal tissue samples from the patient. Neither of the patient’s parents presented the ALK variant. Array profiling of the three tumor samples showed that two of them had only numerical aberrations, whereas one sample displayed segmental alterations, including a gain at chromosome 2p, resulting in two copies of the ALK-mutated allele. Whole genome sequencing confirmed the presence of the ALK variant and did not detect any aberrations in the coding or promotor region of PHOX2B. This study is to our knowledge the first to report a de novoALK F1174I germline mutation. This may not only predispose to congenital multifocal neuroblastoma but may also contribute to the respiratory dysfunction seen in this patient.
Tumors with anaplastic lymphoma kinase (ALK) fusion rearrangements, including non-small-cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors ...(TKIs), underscoring the notion that such cancers are addicted to ALK activity. Although mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, because of lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germline
mutations as well as a novel
variant.
generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 mo treatment, the residual primary tumor shrunk, was surgically removed, and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 mo treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.
Background
Half the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor.
131
...I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of
177
Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent
177
Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. “A phase II trial of
177
Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N” (EudraCT No: 2020-004445-36,
ClinicalTrials.gov
Identifier: NCT04903899) evaluates this new dosing schedule.
Methods
The LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (
https://www.siopen.net
). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022.
Results
The pediatric use of the Investigational Medicinal Product (IMP)
177
Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (
68
Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3–5 years.
Discussion
In this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors.
Ovarian cancer was 2018 ranked as the eighth most common cancer diagnosis and cause of death in women. Of these, the most common histological type is high-grade serous carcinoma. There is a ...diagnostic challenge in the early detection of ovarian tumors leading to more advanced stages at diagnosis and poor prognosis which especially concerns the high-grade subtypes. This increases the need for continuous development of treatment strategies and there is an ongoing focus on personalized medicine. For example, BRCA1/2 pathogenic variant carriers respond well to platinumbased chemotherapies as well as PARP inhibitors. Not only high-grade ovarian cancer but also other subtypes may be associated with hereditary variants representing different cancer predisposition syndromes (CPS) pointing to the need for genetic counseling and testing.Paper I of this doctoral thesis regards high-grade epithelial ovarian tumors and their association with the most common CPS associated with ovarian tumors, namely the Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Molecular characterization was performed to evaluate potential diagnostic and actionable variants. 274 high-grade tumors were DNA sequenced using a targeted panel. In addition to mutations in TP53, BRCA1, and BRCA2 there were also findings in other homologous recombination repair pathway genes as well as other genes such as PTEN and CDKN2A. Sixteen previously unknown BRCA1/2carriers were identified. Twenty patients received PARP inhibitor treatment based on the sequencing results.The development of molecular methods during recent years has entailed findings of diagnostic and prognostic markers as well as potential treatment targets. These have shown the value of molecular characterization in parallel to morphology and immunohistochemical analyses. One of the discovered molecular markers is a specific somatic FOXL2 mutation in certain types of sex cord-stromal tumors (SCSTs). Germline and somatic DICER1 mutations in Sertoli Leydig cell tumors and SMARCA4 mutations in Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) are two other examples. The role of the FOXL2 C134W mutation in SCSTs is further investigated in paper II of this doctoral thesis in which morphologic features were evaluated in relation to FOXL2 mutation status in 44 cases of SCSTs. The dominating growth pattern (72.7%) was diffuse/solid with several tumors showing marked heterogenous architecture. In the initial histopathological review, 12 cases were given an altered diagnosis based on morphology alone. The study concluded that one cannot reliably identify FOXL2mutation-positive tumors solely by morphologic features.In the pediatric population, ovarian tumors are rare. Also, the type of ovarian tumor differs from the adult population. Another difference is that the care for pediatric patients demands special consideration regarding the choice of treatment due to the constant growth and development of the affected child. These are important factors to support research into pediatric ovarian tumors. Paper IIIof this doctoral thesis has gathered a population-based cohort of 345 ovarian tumors in children aged 0-19 registered in the Swedish Cancer Registry between 1970-2014. Descriptive statistics are reported and when the material was available (n=260), morphologic review was performed.
Ovarian tumors in the pediatric population are rare. The incidence and frequency of subtypes differ between children and adults. Although not all tumors are aggressive, they may still lead to ...morbidity. The goal of this study was a comprehensive review of malignant ovarian tumors in children and adolescents diagnosed and registered in Sweden.
Individuals were identified through a search in the National Cancer Register, limited for ages 0–19, years 1970–2014. Stored tumor diagnostic material from regional biobanks was retrieved and reviewed.
The study includes 345 individuals with ovarian tumors and 70.7% of them were between 15 and 19 years at time of diagnosis. No differences in incidence over time or geographic location were identified. The average follow-up time was 21.2 years and 5-year survival was 88.4%. Survival was similar in the different time periods, except for 1970–1979.
Review was possible for 260 cases, resulting in 85 epithelial tumors, 121 GCTs, 47 SCSTs and 7 others. For age 0–4 years SCSTs dominated (85.7%), for 5–9- and 10–14-years GCTs dominated (70,8% and 75.0% respectively), and for age 15–19 years epithelial tumors dominated (43.8%). There was a strong agreement between review diagnosis and original diagnosis (Cohen's κ 0.944). Differentiating between entities within the sex cord-stromal group posed the biggest diagnostic challenge.
Ovarian tumors in children and adolescents are rare and distinct from their adult counterparts regarding incidence and frequency. There was a strong concurrence between original and review diagnoses. The greatest diagnostic difficulty was subtyping of epithelial tumors and differentiating between tumors within the SCST group.
Display omitted
•Registry-based case review demonstrated 33.0% epithelial, 46.2% germ cell, 18.1% sex cord stromal, and 2.7% other tumors.•There is a strong agreement between the review diagnosis and the original diagnosis.•Total 5-year survival was 88.4%, with a worse survival in the cohort 1970–79.•Malignant epithelial tumors contributed 24% of tumor-related mortality events in this cohort.•The greatest diagnostic difficulty was subtyping within the epithelial and sex cord stromal group.
BackgroundGermline pathogenic variants in DICER1 cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for ...specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (Global developmental delay, Lung cysts, Overgrowth, Wilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.MethodsWhole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with DICER1 RNase III domain mutations were performed.ResultsA de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of DICER1 was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome.ConclusionThe phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to DICER1 hotspot mutations in the RNase IIIb domain. We show that an individual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome (‘DICER1 syndrome plus’), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.
Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The histopathologic diagnosis of these tumors can be challenging. A recurrent somatic ...mutation of the forkhead box L2 (FOXL2) gene has been identified in adult GCT. In this retrospective single-center study of 44 SCST, a morphologic review together with analysis of FOXL2 C134W was evaluated in relation to tumor morphology. In addition, TERT promoter mutation testing was performed. Twelve of 36 cases got an altered diagnosis based on morphology alone. The overarching architectural growth pattern in 32/44 (72.7%) tumors was diffuse/solid with several tumors showing markedly heterogeneous architecture. In correlation to FOXL2 C134W mutation status, cytoplasmic color, and nuclear shape, differed between the FOXL2 C134W positive and FOXL2 C134 W negative groups, but these differences were not significant when comparing them separately. Nineteen of 44 cases underwent TERT promoter sequencing with a positive result in 3 cases; 2 adult GCTs and 1 cellular fibroma. Three patients developed a recurrence of which 2 were FOXL2 C134W positive adult GCTs and the third was an unclassified SCST. In conclusion, the morphologic and immunohistochemical diagnosis of different SCSTs is challenging and one cannot reliably identify FOXL2 mutation-positive tumors solely by morphologic features. Therefore, broad use of molecular analysis of the FOXL2 C134W mutation is suggested for SCSTs, and further studies are needed to evaluate the clinical outcome of these tumors as well as the diagnostic and prognostic implications of TERT promoter mutations.
Hydatidiform moles are rare and thus most pathologists and geneticists have little experience with their diagnosis. It is important to promptly and correctly identify hydatidiform moles given that ...they are premalignant disorders associated with a risk of persistent gestational trophoblastic disease and gestational trophoblastic neoplasia. Improvement in diagnosis can be achieved with uniformization of diagnostic criteria and establishment of algorithms. To this aim, the Pathology and Genetics Working Party of the European Organisation for Treatment of Trophoblastic Diseases has developed guidelines that describe the pathological criteria and ancillary techniques that can be used in the differential diagnosis of hydatidiform moles. These guidelines are based on the best available evidence in the literature, professional experience and consensus of the experts’ group involved in its development.
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