A novel gene expression signature for bone metastasis in breast carcinomas

Metastatic cancer remains the leading cause of death for patients with breast cancer. To understand the mechanisms underlying the development of distant metastases to specific sites is therefore important and of potential clinical value. From 157 primary breast tumours of the patients with known metastatic disease, gene expression profiling data were generated and correlated to metastatic behaviour including site-specific metastasis, metastasis pattern and survival outcomes. We analysed gene expression signatures specifically associated with the development of bone metastases. As a validation cohort, we used a published dataset of 376 breast carcinomas for which gene expression data and site-specific metastasis information were available. 80.5 % of luminal-type tumours developed bone metastasis as opposed to 41.7 % of basal and 55.6 % of HER2-like tumours. A novel 15-gene signature identified 82.4 % of the tumours with bone metastasis, 85.2 % of the tumours which had bone metastasis as first site of metastasis and 100 % of the ones with bone metastasis only (p 9.99e-09), in the training set. In the independent dataset, 81.2 % of the positive tested tumours had known metastatic disease to the bone (p 4.28e-10). This 15-gene signature showed much better correlation with the development of bone metastases than previously identified signatures and was predictive in both ER-positive as well as in ER-negative tumours. Multivariate analyses revealed that together with the molecular subtype, our 15-gene expression signature was significantly correlated to bone metastasis status (p <0.001, 95 % CI 3.86-48.02 in the training set; p 0.001, 95 % CI 1.54-5.00 in the independent set). The 15 genes, APOPEC3B, ATL2, BBS1, C6orf61, C6orf167, MMS22L, KCNS1, MFAP3L, NIP7, NUP155, PALM2, PH-4, PGD5, SFT2D2 and STEAP3, encoded mainly membrane-bound molecules with molecular function of protein binding. The expression levels of the up-regulated genes (NAT1, BBS1 and PH-4) were also found to be correlated to epithelial to mesenchymal transition status of the tumour. We have identified a novel 15-gene expression signature associated with the development of bone metastases in breast cancer patients. This bone metastasis signature is the first to be identified using a supervised classification approach in a large series of patients and will help forward research in this area towards clinical application

No Pathogenic DICER1 Gene Variants in a Cohort Study of 28 Children With Congenital Pulmonary Airway Malformation

Background: Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1-associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis. Methods: In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0–18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples. Results: Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28). Conclusions: Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not. Level of Evidence: Level IV

Disturbed remodeling and delayed fracture healing in pediatric pycnodysostosis patients

Pycnodysostosis is an autosomal recessive disease caused by a gene mutation leading cathepsin K deficiency. Pathological fractures of the long bones are common, but guidelines on fracture treatment in these patients are still lacking. We have treated 5 fractures in 2 pediatric pycnodysostosis patients. We hypothesize that pycnodysostosis patients have an incomplete remodeling process in fracture healing because of cathepsin K deficiency. Therefore, to minimize the role of endochondral bone formation (indirect) after a fracture, it seems prudent to strive for direct bone healing (intramembranous) instead of indirect bone healing. Open reduction with internal fixation should be the goal

Benign and low-grade cartilaginous tumors: an update on differential diagnosis

Cartilaginous neoplasms hold considerable share in the routine diagnostics of bone tumor pathology. Benign cartilage forming tumors, that are in general more frequent than their malignant counterparts, may often pose diagnostic challenges. Distinction of a benign cartilaginous lesion from a low-grade malignant tumor can render difficulties especially in a small biopsy material. Considering the divergent therapeutic and prognostic implications, a careful assessment of histologic, radiologic and clinical findings/features is very important, and an experienced multidisciplinary team is indispensable to achieve an accurate diagnosis. This mini review focuses on the histomorphological findings of benign, locally aggressive and low-grade cartilaginous tumors referring to the latest edition of WHO Classification of Tumors of Soft Tissue and Bone Tumors (fifth edition, 2020). The focus of this article is on the differential diagnosis of benign cartilaginous lesions and their distinction from other cartilaginous lesions, especially their malignant counterparts. Histomorphology, in correlation with imaging findings, serve as the cornerstone in the diagnosis of cartilaginous tumors. Based on overlapping morphological and radiological features between the tumor types, including benign and malignant ones, their diagnosis can be challenging. Emerging molecular findings play a notable role in understanding the underlying mechanisms involved in their development, though their routine use in molecular diagnostics is limited to few indications. Likewise, the role of immunohistochemistry remains limited in the differential diagnosis of the cartilaginous tumors, emphasizing the need for joined histological and radiological evaluation

Benign and low-grade cartilaginous tumors: an update on differential diagnosis

Cartilaginous neoplasms hold considerable share in the routine diagnostics of bone tumor pathology. Benign cartilage forming tumors, that are in general more frequent than their malignant counterparts, may often pose diagnostic challenges. Distinction of a benign cartilaginous lesion from a low-grade malignant tumor can render difficulties especially in a small biopsy material. Considering the divergent therapeutic and prognostic implications, a careful assessment of histologic, radiologic and clinical findings/features is very important, and an experienced multidisciplinary team is indispensable to achieve an accurate diagnosis. This mini review focuses on the histomorphological findings of benign, locally aggressive and low-grade cartilaginous tumors referring to the latest edition of WHO Classification of Tumors of Soft Tissue and Bone Tumors (fifth edition, 2020). The focus of this article is on the differential diagnosis of benign cartilaginous lesions and their distinction from other cartilaginous lesions, especially their malignant counterparts. Histomorphology, in correlation with imaging findings, serve as the cornerstone in the diagnosis of cartilaginous tumors. Based on overlapping morphological and radiological features between the tumor types, including benign and malignant ones, their diagnosis can be challenging. Emerging molecular findings play a notable role in understanding the underlying mechanisms involved in their development, though their routine use in molecular diagnostics is limited to few indications. Likewise, the role of immunohistochemistry remains limited in the differential diagnosis of the cartilaginous tumors, emphasizing the need for joined histological and radiological evaluation

Inadequate detection of the FSHR complicates future research on extragonadal FSHR localization

Introduction: Recently, follicle stimulating hormone (FSH) through interaction with its receptor (FSHR) has been proposed to play a role in postmenopausal osteoporosis and cardiovascular disease, rather than the loss of estrogen. To explore this hypothesis, unravelling which cells express extragonadal FSHR on protein level is key. Methods: We used two commercial anti-FSHR antibodies and validated them by performing immunohistochemistry on positive (ovary, testis) and negative controls (skin). Results: The monoclonal anti-FSHR antibody could not identify the FSHR in ovary or testis. The polyclonal anti-FSHR antibody stained the granulosa cells (ovary) and Sertoli cells (testis), yet there was equally intense staining of other cells/extracellular matrix. Furthermore, the polyclonal anti-FSHR antibody also stained skin tissue extensively, suggesting that the antibody stains more than just FSHR. Discussion: The findings in this study may add accuracy to literature on extragonadal FSHR localization and warrants attention to the use of inadequate anti-FSHR antibodies to value the potential role of FSH/FSHR in postmenopausal disease