[Giant cell-containing tumors of bone and differential diagnoses]. / Riesenzell-haltige Tumoren des Knochens und Differenzialdiagnosen.

Osteoclastic giant cells represent a common cellular component of lesions arising in bone. Highlighting this morphological finding, the current WHO classification of bone tumors defines a diagnostic group comprising aneurysmal bone cyst, giant cell tumor of bone and non-ossifying fibroma, which may display morphologic similarities while being distinct with regard to molecular and biological features. Starting with these tumors - putting a focus on lesions arising in bone - this article gives a survey of other (chondrogenic and osteogenic) tumors that frequently contain osteoclastic giant cells, which may, particularly in small biopsies, enter differential diagnosis. Overlapping features with selected giant cell-containing soft tissue tumors, which may be of differential diagnostic relevance in daily routine, are discussed.

The endometrial stem cell markers notch-1 and numb are associated with endometriosis.

Previous studies reported increased expression of the notch pathway-associated protein Musashi-1 in endometriosis. This case-control study investigates an association of the endometrial stem cell markers notch-1 and numb with endometriosis. Fifty-one endometriosis patients and 76 controls were recruited in the IVF unit and tertiary endometriosis referral centre of a university hospital. All subjects underwent transcervical endometrial biopsy and diagnostic laparoscopy. Expression of endometrial notch-1 and numb was assessed by immunostaining and correlated with clinical data. Association of stem-cell-marker expression with the presence of endometriosis was evaluated. Numb expression in the luminal epithelium was significantly higher in eutopic endometrium of endometriosis patients compared with controls (20.5% versus 16.5%, P = 0.033). Numb-positive single stromal cells were less frequent in endometrioma patients compared with other forms of endometriosis (0.3 versus 0.5 cells/visual field; P = 0.028). Notch-1 expression in endometrial glands was significantly higher in patients with deep infiltrating endometriosis compared with controls (39.1% versus 21.8%; P = 0.045). We conclude that stem cell markers notch-1 and numb of eutopic endometrium are associated with endometriosis and its clinical presentations, supporting the stem cell hypothesis of endometriosis. These findings could help develop promising research strategies applying endometrial stem cells as novel tools.

Granulomatosis with polyangiitis (Wegener's granulomatosis): a rare variant of sudden natural death.

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is the most common form of life-threatening small-vessel vasculitis. Although its exact pathogenesis remains unclear, GPA is believed to belong to the wide complex of autoimmune diseases due to the presence of anti-neutrophil cytoplasmatic antibodies with cytoplasmic staining pattern (c-ANCA) that is expressed in activated neutrophils. GPA predominantly manifests at the upper and lower respiratory tract and the kidneys, but the impairment of multiple organ systems is possible as well. The so-called classical clinical triad of GPA comprises sinusitis, pneumonia, and glomerulonephritis. Despite the fact that there is an elevated risk of mortality for patients suffering from GPA, sudden death due to GPA is a rare and difficult differential diagnosis of sudden natural death in forensic case work. In the present article, the rare case of a 41-year-old male, who died of a sudden death due to previously undiagnosed GPA, is demonstrated. The final diagnosis was feasible by close interdisciplinary collaboration, considering the entire body of findings obtained during autopsy, histopathological investigation, and analysis of the clinical records. Therefore, it remains necessary to point out that especially for rare causes of death, interdisciplinary collaboration is essential in order to concretize the cause of death and exclude rare differential diagnoses of sudden unexpected death of hospitalized patients in forensic case work.

Assessment of the Ferroptosis Regulators: Glutathione Peroxidase 4, Acyl-Coenzyme A Synthetase Long-Chain Family Member 4, and Transferrin Receptor 1 in Patient-Derived Endometriosis Tissue.

Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays a pivotal role in various diseases and is gaining considerable attention in the realm of endometriosis. Considering the classical pathomechanism theories, we hypothesized that ferroptosis, potentially driven by increased iron content at ectopic sites, may contribute to the progression of endometriosis. This retrospective case-control study provides a comprehensive immunohistochemical assessment of the expression and tissue distribution of established ferroptosis markers: GPX4, ACSL4, and TfR1 in endometriosis patients. The case group consisted of 38 women with laparoscopically and histologically confirmed endometriosis and the control group consisted of 18 women with other gynecological conditions. Our study revealed a significant downregulation of GPX4 in stromal cells of endometriosis patients (M = 59.7% ± 42.4 versus 90.0% ± 17.5 in the control group, t (54) = -2.90, p = 0.005). This finding aligned with slightly, but not significantly, higher iron levels detected in the blood of endometriosis patients, using hemoglobin as an indirect predictor (Hb 12.8 (12.2-13.5) g/dL versus 12.5 (12.2-13.4) g/dL in the control group; t (54) = -0.897, p = 0.374). Interestingly, there was no concurrent upregulation of TfR1 (M = 0.7 ± 1.2 versus 0.2 ± 0.4 for EM, t (54) = 2.552, p = 0.014), responsible for iron uptake into cells. Our empirical findings provide support for the involvement of ferroptosis in the context of endometriosis. However, variances in expression patterns within stromal and epithelial cellular subsets call for further in-depth investigations.

High expression of transcription factor POU2F1 confers improved survival on smokers with lung adenocarcinoma: a retrospective study of two cohorts.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide and its most important risk factor is tobacco smoking. While smoking is associated with inferior outcome in NSCLC patients, smoking also correlates with a higher tumor mutational burden. In contrast to adenocarcinomas (ADC) of non-smokers, that frequently harbor targetable gain-of-function mutations, NSCLC smokers largely present with non-targetable loss-of-function mutations of genes associated with DNA-damage repair. The transcription factor Pit-1, Oct1/2, Unc-86 (POU) domain class 2 transcription factor 1 (POU2F1) is a widely expressed bipotential stabilizer of repressed and inducible transcriptional states and frequently deregulated in cancer. Methods: Via immunohistochemistry, we evaluated POU2F1 protein expression on a tissue micro array of 217 operable stage I-III NSCLC patients. Findings were reproduced in a gene expression database of 1144 NSCLC patients, filtered for POU2F1 mRNA expression. After retroviral overexpression of POU2F1 in A549 cells, we evaluated for clonogenic growth and proliferation. Additionally, CRISPR-Cas9 mediated POU2F1 knockdown in A549 cells was likewise analyzed. Results: High protein expression of POU2F1 in 217 NSCLC patients resulted in improved outcome of smokers with ADC [hazard ratio (HR) 0.30 (0.09-0.99), P=0.035]. Moreover, gene expression analysis confirmed favorable outcome of high POU2F1 mRNA expression in smokers with ADC [HR 0.41 (0.24-0.69), P<0.001]. Other than that, retrovirally induced overexpression of POU2F1 in A549 cells significantly reduced both, clonogenic growth as well as proliferation of NSCLC cells, whereas CRISPR-Cas9 mediated knockdown of the protein did not have any impact. Conclusions: Our data suggest that high expression of POU2F1 mediates a less aggressive cancer phenotype in smokers with ADC NSCLC. Pharmacological induction of genes and signaling pathways controlled by POU2F1 may provide novel avenues for future targeted NSCLC therapies in smokers.

Evaluation of a novel classification system to predict local recurrence in sarcoma patients undergoing hemipelvectomy with iliosacral resection.

AIMS: Iliosacral sarcoma resections have been shown to have high rates of local recurrence (LR) and poor overall survival. There is also no universal classification for the resection of pelvic sarcomas invading the sacrum. This study proposes a novel classification system and analyzes the survival and risk of recurrence, when using this system. METHODS: This is a retrospective analysis of 151 patients (with median follow-up in survivors of 44 months (interquartile range 12 to 77)) who underwent hemipelvectomy with iliosacral resection at a single centre between 2007 and 2019. The proposed classification differentiates the extent of iliosacral resection and defines types S1 to S6 (S1 resection medial and parallel to the sacroiliac joint, S2 resection through the ipsilateral sacral lateral mass to the neuroforamina, S3 resection through the ipsilateral neuroforamina, S4 resection through ipsilateral the spinal canal, and S5 and S6 contralateral sacral resections). Descriptive statistics and the chi-squared test were used for categorical variables, and the Kaplan-Meier survival analysis were performed. RESULTS: Resections were S1 in 25/151 patients (17%), S2 in 70/151 (46%), S3 in 33/151 (22%), S4 in 77/151 (11%), S5 in 4/151 (3%), and S6 in 2/151 (1%). An internal hemipelvectomy was performed in 113/151 patients (75%), and 38/151 patients (25%) had an external hemipelvectomy. The predominant types of sarcoma were high-grade osteosarcoma in 48/151 patients (32%), chondrosarcoma in 41/151 (27%), Ewing sarcoma in 33/151 (22%), pleomorphic sarcoma in 17/151 (11%), and others in 2/151 (8%). LR was found in 24/151 patients (15%) with S3, S5, with S6 resections showing the highest rate of LR (p = 0.038). Overall, 19/151 patients (16%) had evidence of metastastic disease at the time of surgery and these patients showed poorer survival when compared to patients with no metastasis. CONCLUSION: The proposed classification can help to report and compare different surgical and reconstructive approaches in these difficult cases who are still have a considerable risk of LR. Cite this article: Bone Joint J 2022;104-B(2):290-296.

Tumor infiltrating T cells influence prognosis in stage I-III non-small cell lung cancer.

BACKGROUND: T cell infiltration in non-small cell lung cancer (NSCLC) is essential for the immunological response to malignant tissue, especially in the era of immune-checkpoint inhibition. To investigate the prognostic impact of CD4+ T helper cells (Th), CD8+ cytotoxic (Tc) and FOXP3+ regulatory T (Treg) cells in NSCLC, we performed this analysis. METHODS: By counterstaining of CD4, CD8 and FOXP3 we used immunohistochemistry on tissue microarrays (TMA) to evaluate peritumoral Th cells, Treg cells and Tc cells in n=294 NSCLC patients with pTNM stage I-III disease. RESULTS: Strong CD4+ infiltration was associated with higher tumor stages and lymphonodal spread. However, strong CD4+ infiltration yielded improved overall survival (OS) (P=0.014) in adenocarcinoma (ADC) and large cell carcinoma (LCC) but not in squamous cell carcinoma (SCC). A CD4/CD8 ratio <1 was associated with high grade NSCLC tumors (P=0.020). High CD8+ T cell infiltration was an independent prognostic factor for OS (P=0.040) and progression-free survival (PFS) (P=0.012) in the entire study collective. The OS benefit of high CD8+ infiltration was especially prominent in PD-L1 negative NSCLC (P=0.001) but not in PD-L1 positive tissue (P=0.335). Moreover, positive FOXP3+ expression in tumor infiltrating lymphocytes was associated with increased OS (P=0.007) and PFS (P=0.014) in SCC but not in ADC and LCC (all P>0.05). Here, prognostic effects were prominent in PD-L1 positive SCC (P=0.023) but not in PD-L1 negative SCC (P=0.236). CONCLUSIONS: High proportion of CD8+ Tc cells correlated with improved prognostic outcome in stage I-III NSCLC. Th cells and Treg cells have implications on outcome with respect to tumor histology and biology.

Prognostic impact of CD34 and SMA in cancer-associated fibroblasts in stage I-III NSCLC.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a crucial step in lung cancer pathogenesis. Among others, cancer-associated fibroblasts (CAFs) are reported to regulate this process. OBJECTIVES: To investigate the prognostic and clinical impact, we analyzed CD34+ and SMA+ CAFs in non-small cell lung cancer (NSCLC). METHODS: Retrospectively, immunohistochemistry was performed to study stromal protein expression of both CD34 and SMA in 304 NSCLC patients with pTNM stage I-III disease. All tissue samples were embedded on tissue microarrays (TMAs). RESULTS: Our analysis revealed an association for CD34+ CAFs with G1/2 tumors and adenocarcinoma histology. Moreover CD34+ CAFs were identified as an independent prognostic factor (both for progression free survival [PFS] and overall survival [OS] in stage I-III NSCLC). Besides, SMA+ expression correlated with higher pTNM-tumor stages and lymphatic spread (pN stage). In turn, SMA-negativity was associated with improved PFS, but no prognostic impact was found on OS. Of interest, neither CD34+ CAFs nor SMA+ CAFs were associated with the primary tumor size, localization and depth of infiltration (pT stage). CONCLUSIONS: CD34 was identified as an independent prognostic marker in pTNM stage I-III NSCLC. Moreover, loss of CD34+ CAFs might influence the dedifferentiation of the NSCLC tumor from its cell origin. Finally, SMA+ CAFs are more prevalent in NSCLC tumors of higher stages and lymphonodal positive NSCLC. KEY POINTS: Expression of CD34 on cancer associated fibroblasts (CAFs) is an independent prognostic factor in stage I-III NSCLC. SMA+ cancer associated fibroblasts are associated with higher tumor stages in NSCLC and might contribute to tumor progression in NSCLC.

The Association of the Long Prostate Cancer Expressed PDE4D Transcripts to Poor Patient Outcome Depends on the Tumour's TMPRSS2-ERG Fusion Status.

OBJECTIVES: To investigate the added value of assessing transcripts for the long cAMP phosphodiesterase-4D (PDE4D) isoforms, PDE4D5 and PDE4D9, regarding the prognostic power of the 'CAPRA & PDE4D7' combination risk model to predict longitudinal postsurgical biological outcomes in prostate cancer. PATIENTS AND METHODS: RNA was extracted from both biopsy punches of resected tumours (606 patients; RP cohort) and diagnostic needle biopsies (168 patients; DB cohort). RT-qPCR was performed in order to determine PDE4D5, PDE4D7, and PDE4D9 transcript scores in both study cohorts. By RNA sequencing, we determined the TMPRSS2-ERG fusion status of each tumour sample in the RP cohort. Kaplan-Meier survival analyses were then applied to correlate the PDE4D5, PDE4D7 and PDE4D9 scores with postsurgical patient outcomes. Logistic regression was then used to combine the clinical CAPRA score with PDE4D5, PDE4D7, and PDE4D9 scores in order to build a 'CAPRA & PDE4D5/7/9' regression model. ROC and decision curve analysis was used to estimate the net benefit of the 'CAPRA & PDE4D5/7/9' risk model. RESULTS: Kaplan-Meier survival analysis, on the RP cohort, revealed a significant association of the PDE4D7 score with postsurgical biochemical recurrence (BCR) in the presence of the TMPRSS2-ERG gene rearrangement (logrank p<0.0001), compared to the absence of this gene fusion event (logrank p=0.08). In contrast, the PDE4D5 score was only significantly associated with BCR in TMPRSS2-ERG fusion negative tumours (logrank p<0.0001 vs. logrank p=0.4 for TMPRSS2-ERG+ tumours). This was similar for the PDE4D9 score although less pronounced compared to that of the PDE4D5 score (TMPRSS2ERG- logrank p<0.0001 vs. TMPRSS2ERG+ logrank p<0.005). In order to predict BCR after primary treatment, we undertook ROC analysis of the logistic regression combination model of the CAPRA score with the PDE4D5, PDE4D7, and PDE4D9 scores. For the DB cohort, this demonstrated significant differences in the AUC between the CAPRA and the PDE4D5/7/9 regression model vs. the CAPRA and PDE4D7 risk model (AUC 0.87 vs. 0.82; p=0.049) vs. the CAPRA score alone (AUC 0.87 vs. 0.77; p=0.005). The CAPRA and PDE4D5/7/9 risk model stratified 19.2% patients of the DB cohort to either 'no risk of biochemical relapse' (NPV 100%) or the 'start of any secondary treatment (NPV 100%)', over a follow-up period of up to 15 years. Decision curve analysis presented a clear, net benefit for the use of the novel CAPRA & PDE4D5/7/9 risk model compared to the clinical CAPRA score alone or the CAPRA and PDE4D7 model across all decision thresholds. CONCLUSION: Association of the long PDE4D5, PDE4D7, and PDE4D9 transcript scores to prostate cancer patient outcome, after primary intervention, varies in opposite directions depending on the TMPRSS2-ERG genomic fusion background of the tumour. Adding transcript scores for the long PDE4D isoforms, PDE4D5 and PDE4D9, to our previously presented combination risk model of the combined 'CAPRA & PDE4D7' score, in order to generate the CAPRA and PDE4D5/7/9 score, significantly improves the prognostic power of the model in predicting postsurgical biological outcomes in prostate cancer patients.

Neovascular PSMA expression is a common feature in malignant neoplasms of the thyroid.

AIM: PSMA (prostate-specific membrane antigen) is physiologically expressed in normal prostate tissue and over expressed in prostate cancer cells, therefore constituting a potential target for antibody-based radioligand therapy. Very recent imaging findings reported PSMA-PET/CT uptake in various thyroid lesions. We were therefore encouraged to systematically analyse PSMA expression in different benign and malignant thyroid lesions. METHODS: Immunohistochemistry was used to detect PSMA expression in 101 thyroid lesions, while neovasculature was identified by CD34 immunostaining. RESULTS: PSMA expression in the neovasculature was significantly more frequent in malignant tumors (36/63; 57.1%) compared to benign diseases (5/38; 13.2%; p = 0.0001). In addition, PSMA expression levels in the neovasculature of poorly and undifferentiated thyroid cancers were significantly higher compared to differentiated thyroid tumors (p = 0.021). However, one case with a strong expression in follicular adenoma was identified. CONCLUSIONS: We conclude that neovascular PSMA expression is common in thyroid cancer but may also rarely be found in benign thyroid diseases, such as follicular adenoma. High expression in the tumor-associated neovasculature is predominantly found in poorly differentiated and undifferentiated (anaplastic) thyroid cancer. This knowledge is highly relevant when interpreting PSMA/PET-CT scans from patients with prostate cancer. In addition, our findings might provide a rationale for further evaluation of PSMA-targeted anti-neovascular or radioligand therapy in metastatic dedifferentiated thyroid cancer.