Comprehensive Genomic Profiling Alters Clinical Diagnoses in a Significant Fraction of Tumors Suspicious of Sarcoma.

PURPOSE: Tumor classification is a key component in personalized cancer care. For soft tissue and bone tumors, this classification is currently based primarily on morphology assessment and immunohistochemical staining. However, these standard-of-care methods can pose challenges for pathologists. We therefore assessed how whole-genome and whole-transcriptome sequencing (WGTS) impacted tumor classification and clinical management when interpreted together with histomorphology. EXPERIMENTAL DESIGN: We prospectively evaluated WGTS in routine diagnostics of 200 soft tissue and bone tumors suspicious for malignancy, including DNA and RNA isolation from the tumor, and DNA isolation from a peripheral blood sample or any non-tumor tissue. RESULTS: Based on specific genomic alterations or absence of presumed findings, WGTS resulted in reclassification of 7% (13/197) of the histopathological diagnoses. Four cases were downgraded from low-grade sarcomas to benign lesions, and two cases were reclassified as metastatic malignant melanomas. Fusion genes associated with specific tumor entities were found in 30 samples. For malignant soft tissue and bone tumors, we identified treatment relevant variants in 15% of cases. Germline pathogenic variants associated to a hereditary cancer syndrome were found in 22 participants (11%). CONCLUSION: We conclude that WGTS provides an important dimension of data which aids in the classification of soft tissue and bone tumors, correcting a significant fraction of clinical diagnoses, and identifies molecular targets relevant for precision medicine. However, genetic findings need to be evaluated in their morphopathological context, just as germline findings need to be evaluated in the context of patient phenotype and family history.

Real-world analysis of MET exon 14 mutations in non-small cell lung cancer: a retrospective study from two Swedish hospitals.

BACKGROUND: Real-World evidence on mesenchymal-epithelial transition exon 14 skipping mutations (METex14) in lung cancer remains limited. With an incidence of 3-4% across histological subtypes, METex14 is now an actionable target for MET inhibitors (METi) in advanced lung cancer, demonstrating response rates between 30-70%. Yet, its role in early stages and sensitivity to immune checkpoint inhibitors (ICIs) is still under exploration. MATERIAL AND METHODS: We conducted a retrospective analysis of the clinical data of lung cancer patients presenting with METex14 across all stages. These patients were treated at two Swedish University Hospitals: Karolinska and Skåne, between the years 2014 and 2022. RESULTS: We identified a total of 63 patients, of which 50 met the inclusion criteria. The median overall survival (OS) with corresponding 95% confidence intervals (95% CI) according to the stage was not reached (NR) for stage I, NR for stage II, 15 months (95% CI, 5.4-24.6) for stage III, and 17 months (95% CI, 9.2-NR) for stage IV. The median OS for stage IV patients who received a METi was 17 months (95% CI, 9.5-NR) vs. 10 months (95% CI, 6.2-NR) in patients without METi (p = 0.92; Hazard Ratio [HR] = 1.07). The median OS for stage IV patients who received ICIs was 18 months (95% CI, 16.5-NR) vs. 6 months (95% CI, 2.5-NR) in patients without ICIs (p = 0.15; HR = 0.47). The median OS for stage IV patients who received chemotherapy was 17 months (95% CI, 9.7-NR) vs. 10 months (95% CI, 4.5-NR) in patients without (p = 0.97; HR = 0.98). CONCLUSIONS: Our data suggest limited survival benefits from METi, ICIs, and chemotherapy for METex14 lung cancer patients. While not statistically significant, these findings underscore the need for larger trials for validation. Identifying effective treatments for this challenging lung cancer subtype remains a priority.

Long-term outcome after surgical resection of non-high-risk gastrointestinal stromal tumours without adjuvant therapy.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common intra-abdominal sarcoma. Risk classification systems, commonly the modified National Institutes of Health consensus criteria, identify tumour properties relating to patient outcomes. However, owing to limited long-term evidence, most guidelines recommend up to 10-year follow-up for all risk groups except very low-risk GIST. METHODS: This retrospective multicentre study included patients who had complete resection of primary, non-metastatic GIST from three Scandinavian sarcoma centres: Gothenburg (2004-2020), Stockholm (2000-2019), and Oslo (2000-2017). Medical records were reviewed for clinical details regarding diagnosis, treatment, and follow-up, and recurrence-free and disease-specific survival evaluated. RESULTS: The total cohort consisted of 1213 patients with GIST. High-risk patients and those treated with tyrosine kinase inhibitors were excluded. The remaining 649 patients were included in the present analysis: 118 with very low-, 381 with low-, and 150 with intermediate-risk GISTs. Five-year recurrence-free survival rates were 100, 98.5, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.246). Disease-specific survival rates 10 years after surgery were 100, 98.4, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.262). CONCLUSION: Patients with completely resected non-high-risk GISTs have an excellent long-term outcome, irrespective of risk group. Follow-up programmes to detect disease recurrences in these patients are probably not indicated.

Gastrointestinal stromal tumours (GISTs) originate from the muscle layer of the gastrointestinal tract. They are divided into risk groups according to size, location, and how quickly they grow. Patients with GIST, regardless of risk group, have been followed with imaging for several years after their tumour has been successfully removed with an operation. The aim of this study was to evaluate whether follow-up is necessary for patients in the lower-risk groups. Six hundred and forty-nine patients with GISTs from the lower-risk groups were followed for 5 years (median). Only 1.2 per cent of the patients experienced a recurrence of their cancer. It was concluded that patients with GIST in the lower-risk groups do not need follow-up with imaging after a successful operation.

Sarcoma care in the era of precision medicine.

Sarcoma subtype classification is currently mainly based upon histopathological morphology. Molecular analyses have emerged as an efficient addition to the diagnostic workup and sarcoma care. Knowledge about the sarcoma genome increases, and genetic events that can either support a histopathological diagnosis or suggest a differential diagnosis are identified, as well as novel therapeutic targets. In this review, we present diagnostic, therapeutic, and prognostic molecular markers that are, or might soon be, used clinically. For sarcoma diagnostics, there are specific fusions highly supportive or pathognomonic for a diagnostic entity-for instance, SYT::SSX in synovial sarcoma. Complex karyotypes also give diagnostic information-for example, supporting dedifferentiation rather than low-grade central osteosarcoma or well-differentiated liposarcoma when detected in combination with MDM2/CDK4 amplification. Molecular treatment predictive sarcoma markers are available for gastrointestinal stromal tumor (GIST) and locally aggressive benign mesenchymal tumors. The molecular prognostic markers for sarcomas in clinical practice are few. For solitary fibrous tumor, the type of NAB2::STAT6 fusion is associated with the outcome, and the KIT/PDGFRA pathogenic variant in GISTs can give prognostic information. With the exploding availability of sequencing technologies, it becomes increasingly important to understand the strengths and limitations of those methods and their context in sarcoma diagnostics. It is reasonable to believe that most sarcoma treatment centers will increase the use of massive-parallel sequencing soon. We conclude that the context in which the genetic findings are interpreted is of importance, and the interpretation of genomic findings requires considering tumor histomorphology.

Accumulation of tissue-resident natural killer cells, innate lymphoid cells, and CD8+ T cells towards the center of human lung tumors.

Lung cancer is a leading cause of cancer-related death worldwide. Despite recent advances in tissue immunology, little is known about the spatial distribution of tissue-resident lymphocyte subsets in lung tumors. Using high-parameter flow cytometry, we identified an accumulation of tissue-resident lymphocytes including tissue-resident NK (trNK) cells and CD8+ tissue-resident memory T (TRM) cells toward the center of human non-small cell lung carcinomas (NSCLC). Chemokine receptor expression patterns indicated different modes of tumor-infiltration and/or residency between trNK cells and CD8+ TRM cells. In contrast to CD8+ TRM cells, trNK cells and ILCs generally expressed low levels of immune checkpoint receptors independent of location in the tumor. Additionally, granzyme expression in trNK cells and CD8+ TRM cells was highest in the tumor center, and intratumoral CD49a+CD16- NK cells were functional and responded stronger to target cell stimulation than their CD49a- counterparts, indicating functional relevance of trNK cells in lung tumors. In summary, the present spatial mapping of lymphocyte subsets in human NSCLC provides novel insights into the composition and functionality of tissue-resident immune cells, suggesting a role for trNK cells and CD8+ TRM cells in lung tumors and their potential relevance for future therapeutic approaches.

An intraosseous myoepithelial carcinoma with a EWSR1::PBX3 fusion.

Herein we report a case of an intraosseous myoepithelial carcinoma harboring a EWSR1::PBX3 fusion gene. The patient was a 64-year-old male found to have a 7 cm destructive lesion in the distal ulna with an extraosseous soft tissue component. Microscopic examination of the resected tumor showed a spindle-cell lesion within a sclerotic stroma and intravascular tumor emboli. At higher power the tumor cells showed moderate nuclear atypia with a high mitotic count (20 per mm2 ). Immunohistochemistry revealed diffuse EMA positivity and focal pancytokeratin (AE1/AE3) and S100 expression, consistent with myoepithelial differentiation. NGS using the Oncomine Childhood Cancer Assay (Thermo Fisher Scientific, Inc.) revealed a EWSR1-PBX3 fusion and ABL amplification. The patient subsequently developed local recurrence as well as distant lymph node, lung and vertebral metastases; he is currently awaiting systemic treatment in the context of a clinical trial. In this report, we present a rare case of a skeletal myoepithelial tumor harboring a EWSR1::PBX3 fusion with demonstrated histological and clinical features of malignancy.

The role of neoadjuvant imatinib in gastrointestinal stromal tumor patients: 20 years of experience from a tertial referral center.

Surgery is the cornerstone of gastrointestinal stromal tumor (GIST) treatment, and adjuvant therapy with imatinib has improved survival for high-risk tumors. The use of imatinib preoperatively has been increasing, but efficacy and impact on patient outcomes have not been formally investigated. This is a retrospective study from a single-center cohort of patients diagnosed with GIST and treated with neoadjuvant imatinib at Karolinska University Hospital in Stockholm, Sweden over a 20-year period. Eighty-four patients diagnosed with GIST and treated with neoadjuvant imatinib were identified and included. Tumors were located throughout the whole gastrointestinal tract but most frequently in the stomach (n = 29; 35%) and the small intestine (n = 30; 36%), followed by the rectum (n = 12; 14%) and the gastroesophageal junction (n = 10; 12%). The tumors were large (mean 10.5 cm) and decreased after treatment (mean 7.6 cm). Main indications for neoadjuvant imatinib were tumor size or anatomical location. None of the patients with stomach tumors and four patients with tumors near the gastroesophageal junction underwent gastrectomy. Three patients with tumors in the small intestine underwent pancreaticoduodenectomy, whereas seven patients with rectal tumors underwent rectal amputation. After surgery, 94% (n = 79) of the tumors had R0-resection. About one-fourth experienced local relapse or distant metastasis. In conclusion, neoadjuvant imatinib can reduce tumor size and prevent high morbidity due to more extensive surgery, or at least reduce the extent of the surgery, especially for tumors in the stomach or small intestine.

Diagnosing gastrointestinal stromal tumors: The utility of fine-needle aspiration cytology versus biopsy.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are mesenchymal tumors in the intestinal tract originating from a precursor to the interstitial cells of Cajal, which plays a role in gastric motility. The preoperative diagnosis of GIST may be very important for the surgical approach or the need for neoadjuvant treatment and is often done in conjunction with molecular testing. DESIGN: GISTs diagnosed in Stockholm between 1999 and 2019 with biopsy and/or fine-needle aspiration (FNA) material were included. Clinical and tumor characteristics, as well as sample representability, ancillary techniques, diagnostic accuracy, and time to diagnosis, were categorized and compared. RESULTS: We identified 460 diagnostic samples from 347 patients, consisting of 212 biopsies and 248 FNAs. FNA cytology had a significantly (p < 0.05) better sample representability (92% vs. 77%), diagnostic accuracy (84% vs. 76%), and shorter time to diagnosis (4.5 vs. 12.3 days on average) in comparison with biopsies. In addition, ancillary techniques such as immunochemistry and molecular analysis for KIT and PDGFRA mutations could satisfactorily be performed on FNA materials. CONCLUSIONS: There are advantages to both biopsy and FNA cytology in diagnosing GISTs. While the significantly shorter time to diagnosis for FNA cytology can be due to institutional differences, its many strengths make it both an accurate and time-efficient method for preoperative diagnosis of GIST.