In the last two decades, various therapies have been introduced for lung carcinoma patients, including tyrosine-kinase inhibitors for different mutations. While some of them are specific to specific ...tumor types, others, like NTRK1-3 fusions, are found in various solid tumors. The occurrence of an NTRK1,2 or 3 fusion acts as a biomarker for efficient treatment with NTRK inhibitors, irrespectively of the tumor type. However, the occurrence of the NTRK1-3 fusions in lung carcinomas is extremely rare. We performed a retrospective analysis to evaluate the applicability of immunohistochemistry with the pan-TRK antibody in the detection of NTRK fusions in lung carcinomas. The study cohort included 176 adenocarcinomas (AC), 161 squamous cell carcinomas (SCC), 31 large-cell neuroendocrine carcinomas (LCNEC), and 19 small cell lung carcinomas (SCLC). Immunohistochemistry (IHC) was performed using the pan-TRK antibody (clone EPR17341, Ventana) on tissue microarrays, while confirmation for all positive cases was done using RNA-based Archer FusionPlex MUG Lung Panel. On IHC staining, 12/387 samples (3.1%) demonstrated a positive reaction. Ten SCC cases (10/161, 6.2%), and two LCNEC cases (2/31, 6.5%) were positive. Positive cases demonstrated heterogeneous staining of tumor cells, mostly membranous with some cytoplasmic and in one case nuclear pattern. RNA-based sequencing did not demonstrate any NTRK1-3 fusion in our patients' collective. Our study demonstrates that pan-TRK expression in lung carcinoma is very low across different histologic types. NTRK1-3 fusions using an RNA-based sequencing approached could not be detected. This stresses the importance of confirmation of immunohistochemistry results by molecular methods.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Primary malignant bone tumors are uncommon and their accurate classification requires careful correlation of clinical, radiological, and pathologic findings. It is a heterogeneous group of tumors ...with a wide spectrum of morphology and their biological potential can be of low- or high-grade, depending on their risk for developing metastases. Over the past several decades, the classification of bone sarcomas has remained largely constant. However, some of the tumors have been reclassified and several new entities have emerged. In this review, we will focus on pleomorphic fibrosarcoma/UPS and dedifferentiated bone tumors, discuss their key diagnostic features, differential diagnosis, and their relation to prognosis.
In the ongoing development of bioresorbable implants, there has been a particular focus on magnesium (Mg)-based alloys. Several Mg alloys have shown promising properties, including a lean, ...bioresorbable magnesium-zinc-calcium (Mg-Zn-Ca) alloy designated as ZX00. To our knowledge, this is the first clinically tested Mg-based alloy free from rare-earth elements or other elements. Its use in medial malleolar fractures has allowed for bone healing without requiring surgical removal. It is thus of interest to assess the resorption behavior of this novel bioresorbable implant.
(1) What is the behavior of implanted Mg-alloy (ZX00) screws in terms of resorption (implant volume, implant surface, and gas volume) and bone response (histologic evaluation) in a sheep model after 13 months and 25 months? (2) What are the radiographic changes and clinical outcomes, including patient-reported outcome measures, at a mean of 2.5 years after Mg-alloy (ZX00) screw fixation in patients with medial malleolar fractures?
A sheep model was used to assess 18 Mg-alloy (ZX00) different-length screws (29 mm, 24 mm, and 16 mm) implanted in the tibiae and compared with six titanium-alloy screws. Micro-CT was performed at 13 and 25 months to quantify the implant volume, implant surface, and gas volume at the implant sites, as well as histology at both timepoints. Between July 2018 and October 2019, we treated 20 patients with ZX00 screws for medial malleolar fractures in a first-in-humans study. We considered isolated, bimalleolar, or trimalleolar fractures potentially eligible. Thus, 20 patients were eligible for follow-up. However, 5% (one patient) of patients were excluded from the analysis because of an unplanned surgery for a pre-existing osteochondral lesion of the talus performed 17 months after ZX00 implantation. Additionally, another 5% (one patient) of patients were lost before reaching the minimum study follow-up period. Our required minimum follow-up period was 18 months to ensure sufficient time to observe the outcomes of interest. At this timepoint, 10% (two patients) of patients were either missing or lost to follow-up. The follow-up time was a mean of 2.5 ± 0.6 years and a median of 2.4 years (range 18 to 43 months).
In this sheep model, after 13 months, the 29-mm screws (initial volume: 198 ± 1 mm3) degraded by 41% (116 ± 6 mm3, mean difference 82 95% CI 71 to 92; p < 0.001), and after 25 months by 65% (69 ± 7 mm3, mean difference 130 95% CI 117 to 142; p < 0.001). After 13 months, the 24-mm screws (initial volume: 174 ± 0.2 mm3) degraded by 51% (86 ± 21 mm3, mean difference 88 95% CI 52 to 123; p = 0.004), and after 25 months by 72% (49 ± 25 mm3, mean difference 125 95% CI 83 to 167; p = 0.003). After 13 months, the 16-mm screws (initial volume: 112 ± 5 mm3) degraded by 57% (49 ± 8 mm3, mean difference 63 95% CI 50 to 76; p < 0.001), and after 25 months by 61% (45 ± 10 mm3, mean difference 67 95% CI 52 to 82; p < 0.001). Histologic evaluation qualitatively showed ongoing resorption with new bone formation closely connected to the resorbing screw without an inflammatory reaction. In patients treated with Mg-alloy screws after a mean of 2.5 years, the implants were radiographically not visible in 17 of 18 patients and the bone had homogenous texture in 15 of 18 patients. No clinical or patient-reported complications were observed.
In this sheep model, Mg-alloy (ZX00) screws showed a resorption to one-third of the original volume after 25 months, without eliciting adverse immunologic reactions, supporting biocompatibility during this period. Mg-alloy (ZX00) implants were not detectable on radiographs after a mean of 2.5 years, suggesting full resorption, but further studies are needed to assess environmental changes regarding bone quality at the implantation site after implant resorption.
The study demonstrated successful healing of medial malleolar fractures using bioresorbable Mg-alloy screws without clinical complications or revision surgery, resulting in pain-free ankle function after 2.5 years. Future prospective studies with larger samples and extended follow-up periods are necessary to comprehensively assess the long-term effectiveness and safety of ZX00 screws, including an exploration of limitations when there is altered bone integrity, such as in those with osteoporosis. Additional use of advanced imaging techniques, such as high-resolution CT, can enhance evaluation accuracy.
Pre-analytical factors, such as fixation time, influence morphology of diagnostic and predictive immunohistochemical staining, which are increasingly used in the evaluation of lung cancer. Our aim ...was to investigate if variations in fixation time influence the outcome of immunohistochemical staining in lung cancer. From lung resections, specimen with tumor size bigger than 4 cm, 10 samples were obtained: 2 were put through the standard fixation protocol, 5 through the delayed, and 3 through the prolonged fixation protocol. After paraffin embedding, tissue microarrays (TMAs) were made. They were stained with 20 antibodies and scored for quality and intensity of staining. Samples with delay in fixation showed loss of TMA cores on glass slides and deterioration of tissue quality leading to reduction in the expression of CK 7, Keratin MNF116, CAM 5.2, CK 5/6, TTF-1, C-MET, Napsin A, D2-40, and PD-L1. Prolonged fixation had no influence on the performance of immunohistochemical stains. Delay of fixation negatively affects the expression of different immunohistochemical markers, influencing diagnostic (cytokeratins) and predictive (PD-L1) testing. These results emphasize the need for adequate fixation of resection specimen.
Cellular myxoma is a benign soft tissue tumor frequently associated with
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
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
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Trichoblastic carcinosarcoma is a seldom biphasic adnexal tumor with malignant epithelial and mesenchymal components. The authors report the first tumor on the neck developed from preexistent ...trichoblastoma showing aggressive, recurrent behavior. An 82‐year‐old man presented with a solitary 3‐cm exophytic lesion. Histology verified the diagnosis of trichoblastic carcinosarcoma. Four years earlier, a trichoblastic carcinoma arising in a preexisting trichoblastoma was excised at the same location. Despite successful surgical treatments, three local recurrences within 4 years were diagnosed. After the second relapse, the patient agreed on adjuvant radiation. Twelve months later, another relapse was excised in toto. In the last surgical specimen, only the mesenchymal component was found. Copy number variation analysis of the preexisting tumor and two recurrences revealed the same entity and additional chromosomal aberrations in the recurrences. Adnexal carcinosarcomas are seldom, yet presumably underdiagnosed biphasic tumors with aggressive growth potential. They should have adequate preoperative clarification with wide tumor excision, as radiosensitivity seems to be of limited effect.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Up to 85% of gastrointestinal stromal tumors (GIST) harbor mutually exclusive mutations in the KIT or the PDGFRA gene. Among others, known as wild type GIST, succinate dehydrogenase (SDH)‐deficient ...tumors develop due to genetic or epigenetic alterations in any of four SDH genes. Herein, we present a unique case of SDH‐deficient GIST with an unusual heterogeneous SDHA and SDHB staining pattern and mutations detected in the SDHA and KIT gene. A 50‐year‐old patient presented with a 5 cm large gastric tumor with a multinodular/plexiform growth pattern, mixed epithelioid and spindle cell morphology, and focal pronounced nuclear atypia with hyperchromasia and high mitotic activity. Immunohistochemically, CD117 and DOG‐1 were positive. SDHB and SDHA stains showed loss of expression in some of the nodules, whereas others presented with an unusually weak patchy positivity. Molecular analysis revealed a point mutation in exon 5 of the SDHA gene and a mutation in exon 11 of the KIT gene. We hypothesize that based on the allele frequency of SDHA and KIT mutations the tumor is best regarded as SDH‐deficient GIST in which the SDHA mutation represents the most likely driver mutation. The identified KIT mutation raises the distinct possibility that the KIT mutation is a secondary event reflecting clonal evolution. This is the first case of a treatment naïve GIST harboring a somatic SDHA and a KIT mutation, challenging the dogma that oncogenic mutations in treatment naïve GIST are mutually exclusive.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and purpose - Cat scratch disease (CSD) is a self-limiting disease caused by Bartonella (B.) henselae. It is characterized by granulomatous infection, most frequently involving lymph ...nodes. However, it can present with atypical symptoms including musculoskeletal manifestations, posing a diagnostic challenge. We describe the prevalence and demographics of CSD cases referred to a sarcoma center, and describe the radiological, histological, and molecular findings.
Patients and methods - Our cohort comprised 10 patients, median age 27 years (12-74) with clinical and radiological findings suspicious of sarcoma.
Results - 7 cases involved the upper extremities, and 1 case each involved the axilla, groin, and knee. B. henselae was found in 6 cases tested using polymerase chain reaction and serology in 5 cases. 9 cases were soft tissue lesions and 1 lesion involved the bone. 1 patient had concomitant CSD with melanoma metastasis in enlarged axillary lymph nodes. On MRI, 5 soft tissue lesions were categorized as probably inflammatory. In 3 cases, with still detectable lymph node structure and absent or initial liquefaction, the differential diagnosis included lymph node metastasis. A sarcoma diagnosis was suggested in 4 cases. The MRI imaging features of the bone lesion were suspicious of a bone tumor or osteomyelitis.
Interpretation - Atypical imaging findings cause a diagnostic challenge and the differential diagnosis includes malignant neoplasms (such as sarcoma or carcinoma metastasis) and other infections. The distinction between these possibilities is crucial for treatment and prognosis.
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DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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