The Role of Methylation Analysis in Distinguishing Cellular Myxoma from Low-Grade Myxofibrosarcoma.

Cellular myxoma is a benign soft tissue tumor frequently associated with GNAS mutation that may morphologically resemble low-grade myxofibrosarcoma. This study aimed to identify the undescribed methylation profile of cellular myxoma and compare it to myxofibrosarcoma. We performed molecular analysis on twenty cellular myxomas and nine myxofibrosarcomas and analyzed the results using the methylation-based DKFZ sarcoma classifier. A total of 90% of the cellular myxomas had GNAS mutations (four loci had not been previously described). Copy number variations were found in all myxofibrosarcomas but in none of the cellular myxomas. In the classifier, none of the cellular myxomas reached the 0.9 threshold. Unsupervised t-SNE analysis demonstrated that cellular myxomas form their own clusters, distinct from myxofibrosarcomas. Our study shows the diagnostic potential and the limitations of molecular analysis in cases where morphology and immunohistochemistry are not sufficient to distinguish cellular myxoma from myxofibrosarcoma, particularly regarding GNAS wild-type tumors. The DKFZ sarcoma classifier only provided a valid prediction for one myxofibrosarcoma case; this limitation could be improved by training the tool with a more considerable number of cases. Additionally, the classifier should be introduced to a broader spectrum of mesenchymal neoplasms, including benign tumors like cellular myxoma, whose distinct methylation pattern we demonstrated.

Tumor Microenvironment in Male Breast Carcinoma with Emphasis on Tumor Infiltrating Lymphocytes and PD-L1 Expression.

Male breast cancer (MBC) is rare and usually presents as a locally advanced disease. Stromal tumor-infiltrating lymphocytes (sTILs) are associated with a better response to neoadjuvant chemotherapy and improved prognosis in all molecular subtypes of female breast cancer, but their role in MBC is less clear. We studied sTILs and the expression of programmed cell death ligand 1 (PD-L1) and pan-TRK in MBC. We retrospectively studied 113 cases of MBC surgically treated between 1988 and 2015. The tumors were evaluated for histological type and grade, stage, intrinsic subtype and sTILs. We performed immunohistochemistry for PD-L1 (clone SP142) and pan-TRK (clone EPR17341) on tissue microarrays. Pan-TRK positive cases were further analyzed by next-generation sequencing. The median age was 69 years (range 60−77). Invasive carcinoma of no special type was found in 94.7% of cases, of which 53.1% were grade 2. Estrogen receptor was positive in 92% of the tumors, progesterone receptor in 85.8%, androgen receptor in 70.8%; 4.4% were human epidermal growth factor receptor 2 (HER2)-positive, and 55.8% HER2-low. 40.7% of tumors were luminal A and 51.3% luminal B, 4.4% HER2-enriched and 3.5% triple negative carcinoma. sTILs density was <50% in 96.4% of the tumors, >50% in 3.6% of the tumors. PD-L1 immune cell score >1% was found in 7.1% of the tumors (all of luminal subtype). A weak focal cytoplasmic pan-TRK staining was present in 8.8% but without NTRK fusion. Neither sTILs nor PD-L1 had statistically significant outcomes. Our findings suggest that a subset of MBC patients harbors an immunological environment characterized by increased sTILs with PD-L1 expression. These patients may potentially benefit from immune checkpoint inhibitor therapy. Frequent HER2-low may offer novel anti-HER2 treatment options.

Broadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions.

Fusions involving NTRK1, NTRK2, and NTRK3 are oncogenic drivers occurring in a spectrum of mesenchymal neoplasms ranging from benign to highly malignant tumors. To gain further insights into the staining profile with the pan-TRK assay, we analyzed a large number of soft tissue sarcomas and correlated our findings with molecular testing. Additionally, we expand the spectrum of NTRK-fusion tumors by reporting a mesenchymal lesion in the lung as well as a mesenchymal skin lesion in the spectrum of benign fibrous histiocytoma with NTRK-fusion. We retrospectively reviewed soft tissue sarcomas diagnosed at the Diagnostic and Research Institute of Pathology, Medical University of Graz, between 1999 and 2019, and cases from the consultation files of one of the authors (BLA). In total, 494 cases were analyzed immunohistochemically with pan-TRK antibody (clone EPR17341, RTU, Roche/Ventana) and positive cases (defined as any cytoplasmic/nuclear staining in more than 1% of tumor cells) underwent next-generation sequencing (NGS). Immunohistochemical staining was observed in 16 (3.2%) cases. Eleven cases with focal weak and moderate cytoplasmic/membranous or focal moderate to strong nuclear staining did not harbor an NTRK-fusion (three synovial sarcomas, three leiomyosarcomas, two extraskeletal myxoid chondrosarcomas, and one each: dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxofibrosarcoma). Four cases showed strong diffuse nuclear and/or cytoplasmatic staining, and one case showed diffuse, but weak cytoplasmic staining. All these cases demonstrated an NTRK-fusion (LMNA-NTRK1, IRF2BP2-NTRK1, TMB3-NTRK1, ETV6-NTRK3, RBPMS-NTRK3). Pan-TRK assay (clone EPR17341, RTU, Roche, Ventana) immunohistochemistry serves as a reliable diagnostic marker that can also be expressed in non-NTRK-rearranged mesenchymal neoplasms. It can be used as a surrogate marker for identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement, if patients are undergoing targeted therapy. Additionally, we identified NTRK-fusion-positive, primary mesenchymal tumors of the lung and the skin.

[The wide range of drug related changes seen in gastrointestinal biopsies]. / Die grosse Bandbreite von Medikamenten-induzierten Veränderungen in gastrointestinalen Biopsien.

The wide range of drug related changes seen in gastrointestinal biopsies Abstract. Interpretation of biopsies from the gastrointestinal tract has becoming more challenging as the number of new medications, especially in cancer patients, is constantly increasing. Distinctive drug-associated mechanisms can cause different types of mucosal injury. These features are frequently overlapping since number of histological patterns is limited. This review focuses on range of drug-induced changes seen in GI biopsies and their key diagnostic features that can help the pathologist to differentiate between different drugs and other possible differential diagnosis. Furthermore, a good clinical correlation in these cases is of an outermost importance for the correct diagnosis and treatment.

A comparative study assessing the efficacy and safety of radiofrequency ablation versus surgical treatment for osteoid osteoma: retrospective analysis in a single institution.

OBJECTIVE: We aim to evaluate the efficacy of CT-guided percutaneous radiofrequency ablation (RFA) and surgical treatment in osteoid osteoma (OO) treated at the Medical University of Graz. MATERIALS AND METHODS: In a single-institution study, we analysed data from January 2005 to January 2021 of patients with histological/radiological diagnosis of OO. CT and MRI scans were reviewed for typical findings. Means (with SD) and medians (with IQR) were reported for normally and non-normally distributed variables. Differences between groups were assessed using chi-squared tests and t-tests. RESULTS: One hundred nineteen patients (mean age: 21.6 ± 10.9 years; 63.9% males) with confirmed OO were retrospectively evaluated. 73 and 43 patients underwent RFA and surgery, respectively. In three cases, RFA combined with surgery was performed. Pre-intervention, 103 patients (88.8%) had undergone CT, and 101 had an MRI (87.1%). The nidus was confirmed in 82.5% of cases with CTs (85/103) and 63.4% with MRIs (64/101). The majority of nidi were located cortically (n = 96; 82.8%), most frequently in the femur (38 patients, 33.3%) with a median size of 8.0 mm (IQR: 5.0-12.0 mm). Median symptom duration before treatment was 6.0 (IQR: 4.0-13.0) months. The complication rate was 12.1% (14/116; 15.1% RFA vs. 7.0% surgery; p = 0.196). In total, 11.2% of patients had persistent symptoms after one week with clinical success rates of RFA and surgery, 86.3% and 90.7% (p = 0.647), respectively. CONCLUSION: Compared to surgical treatment, CT-guided percutaneous RFA is a safe, minimally invasive, reliable, and efficient treatment option for OO. CRITICAL RELEVANCE STATEMENT: This article critically assesses the diagnosis and treatment of osteoid osteoma, emphasising accurate imaging, and detailing a non-invasive option for effective management. KEY POINTS: • This study analyses 116 cases of OO at one institution, focusing on symptom persistence, recurrence in short-term follow-up, and complications in two study groups. • Surgery showed higher, though not statistically significant, success despite comparable symptom persistence; CT displayed typical OO features more than MRI, regardless of the intramedullary, cortical and subperiosteal location as well as the site of the affected bone. • CT-guided RFA is an effective therapeutic alternative for OO compared to surgical intervention. In case of atypical OO appearance, RFA is not the first-line treatment.

Comparison of Nuclear Grade, Necrosis, and Histologic Subtype Between Biopsy and Resection in Pleural Malignant Mesothelioma: An International Multi-Institutional Analysis.

OBJECTIVES: Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM. METHODS: Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions. RESULTS: Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens. CONCLUSIONS: Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.