Canadian Multicentric Pan-TRK (CANTRK) Immunohistochemistry Harmonization Study.

Tumor-agnostic testing for NTRK1-3 gene rearrangements is required to identify patients who may benefit from TRK inhibitor therapies. The overarching objective of this study was to establish a high-quality pan-TRK immunohistochemistry (IHC) screening assay among 18 large regional pathology laboratories across Canada using pan-TRK monoclonal antibody clone EPR17341 in a ring study design. TRK-fusion positive and negative tumor samples were collected from participating sites, with fusion status confirmed by panel next-generation sequencing assays. Each laboratory received: (1) unstained sections from 30 cases of TRK-fusion-positive or -negative tumors, (2) 2 types of reference standards: TRK calibrator slides and IHC critical assay performance controls (iCAPCs), (3) EPR17341 antibody, and (4) suggestions for developing IHC protocols. Participants were asked to optimize the IHC protocol for their instruments and detection systems by using iCAPCs, to stain the 30 study cases, and to report the percentage scores for membranous, cytoplasmic, and nuclear staining. TRK calibrators were used to assess the analytical sensitivity of IHC protocols developed by using the 2 reference standards. Fifteen of 18 laboratories achieved diagnostic sensitivity of 100% against next-generation sequencing. The diagnostic specificity ranged from 40% to 90%. The results did not differ significantly between positive scores based on the presence of any type of staining vs the presence of overall staining in ≥1% of cells. The median limit of detection measured by TRK calibrators was 76,000 molecules/cell (range 38,000 to >200,000 molecules/cell). Three different patterns of staining were observed in 19 TRK-positive cases, cytoplasmic-only in 7 samples, nuclear and cytoplasmic in 9 samples, and cytoplasmic and membranous in 3 samples. The Canadian multicentric pan-TRK study illustrates a successful strategy to accelerate the multicenter harmonization and implementation of pan-TRK immunohistochemical screening that achieves high diagnostic sensitivity by using laboratory-developed tests where laboratories used centrally developed reference materials. The measurement of analytical sensitivity by using TRK calibrators provided additional insights into IHC protocol performance.

Clinical impact of whole-body MRI in staging and surveillance of patients with myxoid liposarcoma: a 14-year single-centre retrospective study.

OBJECTIVE: To assess the clinical impact of regular whole-body magnetic resonance imaging (WBMRI) surveillance in myxoid liposarcoma patients. METHODS: This was a retrospective cohort study of myxoid liposarcoma patients who underwent at least one WBMRI at our institution between October 2006 and December 2020. The effect of WBMRI on clinical management, namely treatment modification or additional diagnostic investigations was studied. A standardised WBMRI surveillance protocol was instituted in 2015. We compared patient outcomes for the metastatic patients who had and had not received regular WBMRI surveillance and performed survival analysis for both subgroups. RESULTS: Of the 56 patients (60.7% male, median age: 48.1 years) who underwent 345 WBMRI, 17 (30.3%) had metastases, and 168 WBMRI were performed in this group. The median imaging follow-up for the entire cohort was 35 months; the metastatic group had a median follow-up of 42 months. WBMRI changed the clinical management in 13 (76.5%) metastatic patients, with 33 instances of treatment modification. Thirty-five lesions were labelled 'indeterminate,' 16 (45.7%) had additional investigations/interventions, and 4 (11.4%) were confirmed to be metastatic. Twenty-one metastatic lesions were missed initially on WBMRI and confirmed on subsequent WBMRI, of which 5 (23.8%) were clinically significant. The 5-year survival since the detection of metastasis was better in the regular surveillance subgroup (85.7% vs. 45%), but this was not statistically significant (p = 0.068). Five patients (8.9%) developed their first metastasis more than 5 years after diagnosing the primary lesion. CONCLUSION: Regular WBMRI surveillance of myxoid liposarcoma patients considerably impacts clinical management by frequently influencing treatment decisions. CLINICAL RELEVANCE STATEMENT: WBMRI has been recently recommended as an imaging option for the staging and surveillance of myxoid liposarcoma patients. Our study highlights the impact of regular WBMRI surveillance on the clinical management of these patients and how it affects their survival.

Aggressive Behavior Predictors in Solitary Fibrous Tumor: Demographic, Clinical, and Histopathologic Characteristics of 81 Cases.

BACKGROUND: Solitary fibrous tumor (SFT) is a rare mesenchymal tumor with an intermediate tendency to metastasize. Meningeal hemangiopericytoma (HPC), arising in the meningeal membranes, also is considered an SFT. Although SFT is assumed to show an unpredictable behavior, the authors defined some factors associated with its aggressive behavior. METHODS: This retrospective study was based on the medical records of 81 SFT patients treated surgically, with the median follow-up period of 59 months. The patients were assigned to three histopathologic groups based on the 2016 WHO classification: group 1 (SFT, 29 patients), group 2 (cellular SFT/hemangiopericytoma [HPC], 27 patients), and group 3 (malignant SFT/anaplastic HPC, 25 patients). RESULTS: The SFT histopathologic classification was associated with distant metastasis (DM) (p = 0.007). The multivariate analysis showed that cellular SFT had an independent impact on DM (odds ratio [OR] = 25.42; p = 0.006). Tumor diameter larger than 7.25 cm was correlated with DM (p = 0.010) and the patient's disease-specific death (DSD) (p = 0.007). A 1-cm increase in tumor diameter enhanced the likelihood of metastasis by 1.26 (OR = 1.26; 95% confidence interval [CI], 1.05-1.53). Tumors originating from the central nervous system (CNS) showed a greater tendency toward local recurrence (LR) (p = 0.039) and DM (p = 0.05). Radiotherapy had no association with LR, DM, or DSD. The 10-year disease-specific survival rate was 82.7%. CONCLUSIONS: Tumor size and histopathologic diagnosis are the predictors of SFT's aggressive behavior. Cellular SFTs behave as aggressively as the malignant form of the tumor. A SFT grading based on SFT cellularity would contribute to anticipation of its aggressive behavior.

Probabilistic classification of tumour habitats in soft tissue sarcoma.

The purpose of this work is to propose a method to characterize tumour heterogeneity on MRI, using probabilistic classification based on a reference tissue. The method uses maps of the apparent diffusion coefficient (ADC), T2 relaxation, and a calculated map representing high-b-value diffusion-weighted MRI (denoted simDWI) to identify up to five habitats (i.e. sub-regions) of tumours. In this classification method, the parameter values (ADC, T2 , and simDWI) from each tumour voxel are compared against the corresponding parameter probability distributions in a reference tissue. The probability that a tumour voxel belongs to a specific habitat is the joint probability for all parameters. The classification can be visualized using a custom colour scheme. The proposed method was applied to data from seven patients with biopsy-confirmed soft tissue sarcoma, at three time-points over the course of pre-operative radiotherapy. Fast-spin-echo images with two different echo times and diffusion MRI with three b-values were obtained and used as inputs to the method. Imaging findings were compared with pathology reports from pre-radiotherapy biopsy and post-surgical resection. Regions of hypercellularity, high-T2 proteinaceous fluid, necrosis, collagenous stroma, and fibrosis were identified within soft tissue sarcoma. The classifications were qualitatively consistent with pathological observations. The percentage of necrosis on imaging correlated strongly with necrosis estimated from FDG-PET before radiotherapy (R2  = 0.97) and after radiotherapy (R2  = 0.96). The probabilistic classification method identifies realistic habitats and reflects the complex microenvironment of tumours, as demonstrated in soft tissue sarcoma.

Early detection of metastases using whole-body MRI for initial staging and routine follow-up of myxoid liposarcoma.

OBJECTIVE: To define the role of whole-body MRI (WBMRI) for initial staging and routine follow-up of myxoid liposarcoma (MLS). MATERIALS AND METHODS: A retrospective review of all the patients with MLS who underwent WBMRI for initial staging and routine follow-up at our institution between October 1, 2006, and September 30, 2016 was performed. Patient demographics, clinical presentation, imaging findings, tumor histology, and occurrence and location of metastatic disease were recorded. Thirty-three patients who underwent a total of 150 WBMRI examinations were included in the study. RESULTS: Nine patients (27%) were diagnosed with metastases between 0 and 60 months (median 10; interquartile range, 7-13) from the diagnosis of the primary tumor. The initial site of metastatic disease was extrapulmonary in all patients. Only two patients developed pulmonary metastases, which were diagnosed by CT chest 9 and 29 months after the diagnosis of extrapulmonary metastases. The first metastasis was diagnosed by WBMRI in seven patients (78%), by thoracic CT in one patient, and by abdominal CT in one patient. Eight of nine patients (89%) were asymptomatic at the time of diagnosis of the metastases. In seven patients (78%), WBMRI demonstrated metastases included within the field of view of, but occult on a contemporaneous CT scan. CONCLUSION: Our 10-year institutional experience demonstrates that WBMRI facilitates early detection of extrapulmonary MLS metastases before the onset of clinical symptoms and pulmonary metastases. WBMRI also depicts extrapulmonary metastases that are occult on CT scans. The current surveillance strategies are insufficient for screening for extrapulmonary MLS metastases.

The role of immunohistochemistry in the diagnosis of flat urothelial lesions: a study using CK20, CK5/6, P53, Cd138, and Her2/Neu.

Although differentiating reactive urothelial atypia from urothelial carcinoma in situ (CIS) relies primarily on histologic evaluation, confirming the morphologic impression using immunohistochemistry (IHC) has been increasingly used in routine clinical practice. The aims of this study are to confirm the utility of commonly used markers (CK20, P53) and to test the performance of CK5/6, CD138, and Her2/Neu in the diagnosis of CIS. Using a tissue microarray comprising 52 cases of normal/reactive urothelium and 45 cases of CIS, the IHC evaluation of 5 markers was undertaken. Although the individual specificity of CK20, P53, and Her2/Neu was high (94%, 90%, and 93%, respectively), their sensitivity for CIS detection was lower, with the most sensitive marker being HER2/Neu (63%). Whereas 78% of CIS shows positivity of at least 2 of those 3 markers, only 1 case of reactive urothelium shows positivity for 2 of those 3 markers. The discriminatory performance of CK5/6 and CD138 was poor. In conclusion, HER2/Neu can be added to a panel of CK20 and P53 to help differentiate reactive atypia from CIS in difficult cases. Positive staining for at least 2 of the 3 antibodies (CK20, P53, and HER2/Neu) is strongly associated with CIS. However, the histologic findings should be a primary determinant in the diagnosis of flat urothelial lesions, with IHC playing a supportive confirmatory role.

Value of Cellular Components and Focal Dedifferentiation to Predict the Risk of Metastasis in a Benign-Appearing Extra-Meningeal Solitary Fibrous Tumor: An Original Series from a Tertiary Sarcoma Center.

Histology has not been accepted as a valid predictor of the biological behavior of extra-meningeal solitary fibrous tumors (SFTs). Based on the lack of a histologic grading system, a risk stratification model is accepted by the WHO to predict the risk of metastasis; however, the model shows some limitations to predict the aggressive behavior of a low-risk/benign-appearing tumor. We conducted a retrospective study based on medical records of 51 primary extra-meningeal SFT patients treated surgically with a median follow-up of 60 months. Tumor size (p = 0.001), mitotic activity (p = 0.003), and cellular variants (p = 0.001) were statistically associated with the development of distant metastases. In cox regression analysis for metastasis outcome, a one-centimeter increment in tumor size enhanced the expected metastasis hazard by 21% during the follow-up time (HR = 1.21, CI 95% (1.08-1.35)), and each increase in the number of mitotic figures escalated the expected hazard of metastasis by 20% (HR = 1.2, CI 95% (1.06-1.34)). Recurrent SFTs presented with higher mitotic activity and increased the likelihood of distant metastasis (p = 0.003, HR = 12.68, CI 95% (2.31-69.5)). All SFTs with focal dedifferentiation developed metastases during follow-up. Our findings also revealed that assembling risk models based on a diagnostic biopsy underestimated the probability of developing metastasis in extra-meningeal SFTs.

Osteosarcoma Around a Ceramic-on-Ceramic Total Hip Arthroplasty.

Sarcoma arising at the site of a total hip arthroplasty (THA) is uncommon. We present a case report of a patient diagnosed with an osteosarcoma around a ceramic-on-ceramic THA and a narrative literature review of sarcomas around THA. A search of PubMed MEDLINE was performed from inception. Our case report was included in the analysis. A total of 13 studies were included in the review. We report the first case of a sarcoma around a ceramic-on-ceramic hip implant. All cases in the literature reported poor outcomes with an average time from index THA to diagnosis of 9.3 ± 8.2 years. Sarcomas around THA are extremely rare. Despite the rarity of the diagnosis, osteosarcoma must be considered in the differential diagnosis when investigating a periprosthetic mass.

Annular bullous pemphigoid: A case report and review of literature.

Bullous pemphigoid is an autoimmune blistering disease that primarily affects the geriatric population. It often presents as urticarial erythematous plaques, which evolve into subepidermal blisters accompanied by pruritus. Although rare, clinical variants of bullous pemphigoid have been documented. We present a rare case of annular bullous pemphigoid in a 50-year-old male and offer a brief review of the literature. Only five other case reports, including three in adults, have described this unusual presentation, which can mimic other autoimmune blistering diseases, including linear IgA bullous dermatosis and pemphigus herpetiformis. Therefore, histopathology and immunologic studies were essential in properly diagnosing this patient. Our case supports that annular blistering lesions can be a clinical variant of bullous pemphigoid.

Clinical Benefit from Lenvatinib and Pembrolizumab Observed in Mullerian Adenosarcoma: A Case Report.

A 32-year-old woman with chemorefractory mullerian adenosarcoma showed clinical benefit in response to administration of lenvatinib plus pembrolizumab. In this case report, we describe the course of her illness and her response to this treatment.

Rare case of extra-peritoneal brown fat (hibernoma) mimicking dumbbell-shaped liposarcoma.

Hibernomas are a very rare and benign soft tissue tumour that originate from brown adipose tissue. While they are not histologically malignant, they may be indistinguishable from aggressive tumours such as liposarcomas on imaging. It is, therefore, important to consider it as a differential diagnosis when a suspicious fatty lesion is seen on imaging. This may prevent unnecessary invasive surgery and patient stress. This paper illustrates the clinical presentation, radiological features, and histological diagnosis of a patient with a rare dumbbell-shaped hibernoma in the pelvis.

Long-standing necrobiotic xanthogranuloma limited to the skin: A case report.

Necrobiotic xanthogranuloma is a rare non-Langerhans cell histiocytosis with a known association with monoclonal gammopathies and malignant conditions. There is a lack of consensus regarding the management of necrobiotic xanthogranuloma. In this case report, the patient is diagnosed with a long-standing necrobiotic xanthogranuloma limited to the skin. Although all initial investigations were reassuring, the patient remains at a higher risk of developing a malignant condition. The goal of the authors is to highlight the need for clearer investigation and follow-up guidelines.

Two Cases of Polyethylene Granuloma After Distal Femoral Endoprosthesis With All-Polyethylene Tibia.

Limited literature exists on complications specific to the all-polyethylene tibial component in distal femoral replacement (DFR). Unlike in primary arthroplasty with polyethylene components, polyethylene granuloma has not been reported in DFR with an all-polyethylene tibia. Here, we report 2 cases of polyethylene granuloma in patients with primary bone sarcoma who underwent DFR with an all-polyethylene tibia. Radiologically, evidence of intraosseous granuloma formation and periprosthetic osteolysis was observed at the anterior tibial metaphysis. Both patients underwent an operative debridement of polyethylene granuloma and necrotic tissues, followed by a revision to a long-stem, cemented metal-backed tibia with impacted allograft to fill the defect. Polyethylene granuloma should be considered a differential diagnosis in the presence of a periprosthetic lytic lesion after DFR with an all-polyethylene tibial component.

Comparison of quantitative and qualitative scoring approaches for radiation-induced pulmonary fibrosis as applied to a preliminary investigation into the efficacy of mesenchymal stem cell delivery methods in a rat model.

OBJECTIVES: Compare a quantitative, algorithm-driven, and qualitative, pathologist-driven, scoring of radiation-induced pulmonary fibrosis (RIPF). And using these scoring models to derive preliminary comparisons on the effects of different mesenchymal stem cell (MSC) administration modalities in reducing RIPF. METHODS: 25 rats were randomized into 5 groups: non-irradiated control (CG), irradiated control (CR), intraperitoneally administered granulocyte-macrophage colony stimulating factor or GM-CSF (Drug), intravascularly administered MSC (IV), and intratracheally administered MSC (IT). All groups, except CG, received an 18 Gy conformal dose to the right lung. Drug, IV and IT groups were treated immediately after irradiation. After 24 weeks of observation, rats were euthanized, their lungs excised, fixed and stained with Masson's Trichrome. Samples were anonymized and RIPF was scored qualitatively by a certified pathologist and quantitatively using ImageScope. An analysis of association was conducted, and two binary classifiers trained to validate the integrity of both qualitative and quantitative scoring. Differences between the treatment groups, as assessed by the pathologist score, were then tested by variance component analysis and mixed models for differences in RIPF outcomes. RESULTS: There is agreement between qualitative and quantitative scoring for RIPF grades from 4 to 7. Both classifiers performed similarly on the testing set (AUC = 0.923) indicating accordance between the qualitative and quantitative scoring. For comparisons between MSC infusion modalities, the Drug group had better outcomes (mean pathologist scoring of 3.96), correlating with significantly better RIPF outcomes than IV [lower by 0.97, p = 0.047, 95% CI = (0.013, 1.918)] and resulting in an improvement over CR [lower by 0.93, p = 0.037, 95% CI = (0.062, 1.800]. CONCLUSION: Quantitative image analysis may help in the assessment of therapeutic interventions for RIPF and can serve as a scoring surrogate in differentiating between severe and mild cases of RIPF. Preliminary data demonstrate that the use of GM-CSF was best correlated with lower RIPF severity. ADVANCES IN KNOWLEDGE: Quantitative image analysis can be a viable supplemental system of quality control and triaging in situations where pathologist work hours or resources are limited. The use of different MSC administration methods can result in different degrees of MSC efficacy and study outcomes.

SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria.

Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca2+) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca2+ channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca2+ transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca2+-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers.

Aneurysmal bone cyst in thoracolumbar spine.

Aneurysmal bone cysts (ABC) are rare, benign primary bone tumors. Although benign, they can be locally aggressive resulting in erosion of bone and surrounding tissues over time. In later stages, depending on the clinical urgency, immunotherapy or surgical resection remain treatment options. This report illustrates a case of a 32-year-old female who presented with chronic worsening low back pain without neurological deficits. Radiological imaging revealed a large destructive mass arising from the thoracic spine invading into the central canal, causing critical central stenosis and cord compression. Histopathology revealed ABC. This case highlights the importance of including ABCs and other 'benign'/locally aggressive lesions in the differential of patients with insidious musculoskeletal complaints. This case also demonstrates that one can be neurologically asymptomatic despite having critical central canal stenosis and cord compression if the causative lesion is slow growing. Understanding this allows us to arrange for most appropriate management.

CD44 Promotes PD-L1 Expression and Its Tumor-Intrinsic Function in Breast and Lung Cancers.

The PD-L1 (CD274) immune-checkpoint ligand is often upregulated in cancers to inhibit T cells and elicit immunosuppression. Independent of this activity, PD-L1 has recently been shown to also exert a cancer cell-intrinsic function promoting tumorigenesis. Here, we establish this tumor-intrinsic role of PD-L1 in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Using FACS-assisted shRNA screens, we identified the cell-surface adhesion receptor CD44 as a key positive regulator of PD-L1 expression in these cancers. Mechanistically, CD44 activated PD-L1 transcription in part through its cleaved intracytoplasmic domain (ICD), which bound to a regulatory region of the PD-L1 locus containing a consensus CD44-ICD binding site. Supporting this genetic interaction, CD44 positively correlated with PD-L1 expression at the mRNA and protein levels in primary tumor samples of TNBC and NSCLC patients. These data provide a novel basis for CD44 as a critical therapeutic target to suppress PD-L1 tumor-intrinsic function. SIGNIFICANCE: CD44 is a potential target to suppress PD-L1 function in TNBC. This finding has the potential to open a new area of therapy for TNBC.