Myofibroblasts in human pathology

It is believed that preoperative biopsy sampling for superficial-type colorectal tumors should be avoided because submucosal fibrosis caused by biopsy sampling makes EMR impossible. However, few studies have reported the influence of biopsy sampling on colorectal endoscopic submucosal dissection (ESD). This study aimed to examine the effect of biopsy sampling on submucosal fibrosis and treatment outcomes of ESD for laterally spreading tumors (LSTs).

Between April 2005 and September 2015, 441 consecutive patients underwent colorectal ESD in Osaka City University Hospital. Using propensity score matching and inverse probability of treatment weighting (IPTW), we retrospectively evaluated risk factors for severe submucosal fibrosis and treatment outcomes for patients with LSTs, with or without preoperative biopsy sampling.

A total of 428 LSTs resected using ESD were enrolled. After matching, there were 136 matched pairs of lesions that did or did not undergo biopsy sampling. Preoperative biopsy sampling increased severe fibrosis compared with that in the non–biopsy sampling group (20.6% vs 11.0%; P = .03) and was significantly associated with severe fibrosis after matching (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.07-4.10; P = .03). After adjustment with IPTW, biopsy sampling also increased the risk of severe fibrosis (OR, 2.33; 95% CI, 1.17-4.63; P = .02). However, no significant differences were observed between the 2 groups in treatment outcomes.

Preoperative biopsy sampling for colorectal LSTs might cause severe submucosal fibrosis but has no adverse influence on clinical outcomes of ESD.

Osteosarcoma (OS) is a bone malignancy that affects children and adolescents. It is a highly aggressive tumor and typically metastasizes to lungs. Despite aggressive chemotherapy and surgical treatments, the current 5 year survival rate is 60–70%. Clinically relevant models are needed to understand OS pathobiology, metastatic progression from bones to lungs, and ultimately, to develop more efficacious treatment strategies and improve survival rates in OS patients with metastasis. The main goal of this study was to develop and characterize an in vivo OS model that will allow non-invasive tracking of tumor progression in real time, and aid in studying OS pathobiology, and screening of potential therapeutic agents against OS. In this study, we have used a multi-modality approach using bioluminescent imaging, electron microscopy, micro-computed tomography, and histopathology to develop and characterize a preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model, using 143B human OS cell line. The results of this study clearly demonstrate that the BOOM model represents the clinical disease as evidenced by a spectrum of changes associated with tumor establishment, progression and metastasis, and detection of known OS biomarkers in the primary and metastatic tumor tissue. Key novel findings of this study include: (a) multimodality approach for extensive characterization of the BOOM model using 143B human OS cell line; (b) evidence of renal metastasis in OS orthotopic model using 143B cells; (c) evidence of Runx2 expression in the metastatic lung tissue; and (d) evidence of the presence of extracellular membrane vesicles and myofibroblasts in the BOOM model.

Hepatocyte growth factor (HGF) plays important roles in tumor development and progression. It is currently thought that the main action of HGF is of a paracrine nature: HGF produced by mesenchymal cells acts on epithelial cells that express its receptor c-MET. In this investigation, we explored the significance of c-MET expression in myofibroblasts, both in culture and in patients with lung adenocarcinoma. We first showed that human myofibroblasts derived from primary lung cancer expressed c-MET mRNA and protein by reverse transcription-polymerase chain reaction and Western blot analysis. Proliferation of myofibroblasts was stimulated in a dose-dependent manner by exogenously added recombinant human HGF whereas it was inhibited in a dose-dependent manner by neutralizing antibody to HGF. The addition of HGF in the culture medium stimulated tyrosine phosphorylation of c-MET. The c-MET protein was immunohistochemically detected in myofibroblasts in the invasive area of lung adenocarcinoma. Finally, the prognostic significance of c-MET expression in stromal myofibroblasts was explored in patients with small-sized lung adenocarcinomas. c-MET-positive myofibroblasts were observed in 69 of 131 cases (53%). A significant relationship between myofibroblast c-MET expression and shortened patient survival was observed in a whole cohort of patients including all pathological stages (two-sided P = 0.0089 by log-rank test) and in patients with stage IA disease (two-sided P = 0.0019 by log-rank test). These data suggest that the HGF/c-MET system constitutes an autocrine activation loop in cancer-stromal myofibroblasts. This autocrine system may play a role in invasion and metastasis of lung adenocarcinoma.

Soft tissue tumors of the penis are uncommon.We report here the clinicopathologic features of a penile epithelioid sarcoma (ES), review the literature concerning this unusual location and focalize our attention on its differentiation.The 34-year-old patient was admitted for abrupt urinary retention due to the growth of a firm and painful plaque on the left side of the shaft, three years previously clinically diagnosed as Peyronie's disease.Magnetic nuclear resonance revealed an infiltrating lesion of both corpora cavemosa.Histology of bioptic fragments showed a nodular malignant spindle and epithelioid cell tumor with focal necrosis and relatively high mitotic rate.Based on the immunohistochemical data (cytokeratin⁺, vimentin⁺, EMA⁺, CD34⁺, and S100⁻), the diagnosis of ES was strongly considered.Penectomy was undertaken and the diagnosis confirmed by both light and ultrastructural microscopy.The 22 month follow up was free of recurrences and metastases.Although not dissimilar from the 10 previously described ES of the penis in terms of natural history and histology, the tumor reported here showed myogenic features as revealed by both immunohistochemistry (immunoreactivity for muscle specific actin) and ultrastructure (intercellular junctions, discontinuous basal lamina, pinocytotic vesicles and thin filaments with intercalated dense bodies).Although previously observed in ES of other sites, this feature has never been established in ES of the penis.

Myofibroblasts are spindle cells having ultrastructural features in common with smooth muscle cells and fibroblasts. In the last few years, tumours have been described in which myofibroblasts represent not only a reactive mechanism but also a true neoplastic component. They constitute new nosologic entities which might be termed “myofibroblastic tumours”. Tumours with benign and, rarely, malignant behaviour are reported to belong to this group of lesions. Recently, a third tumour type with borderline biological course, named “inflammatory myofibroblastic tumour” (IMT), has been identified, a condition that has been regarded as a benign and reactive disorder for a long time. Only in recent reports has been demonstrated that, in spite of an apparently benign morphological pattern, some cases of IMT have a malignant course.

In this connection, DNA analysis by flow cytometry is a valuable diagnostic tool, because it allows identification of the ploidy status, a procedure that is often useful for predicting the nature and the biological behaviour of the lesion. In this study, 11 cases of myofibroblastic tumours were examined retrospectively by evaluating clinicopathological features and DNA ploidy status by flow cytometry. The diagnosis of myofibroblastic tumour was confirmed by performing histology, immunohistochemistry, and electron microscopy in all patients. In detail, these 11 cases were composed of 1 benign myofibroblastoma, 1 myofibrosarcoma and 9 IMTs. Among these myofibroblastic tumours, all those with local recurrence or distant metastases (one myofibrosarcoma and three IMT) showed an aneuploid cell population demonstrable by flow cytometric analysis, whereas the other cases with benign course (one benign myofibroblastoma and six IMT) exhibited an euploid DNA content. These data suggest the following: a) Besides the rare myofibroblastomas and myofibrosarcomas, IMTs represent a larger group of lesions with potentially different biological and clinical course. b) DNA flow cytometric analysis is a reliable tool that supports histopathological examination in characterizing those cases of IMT that, though being malignant, mimic benign lesions. Consequently, it establishes the basis for a different therapeutic approach according to the euploid or aneuploid DNA content.

In order to assess the characteristics of its stromal cells and the distribution of extracellular matrix proteins, we investigated, immunohistochemically and ultrastructurally, term, first and second trimester human umbilical cords. A differential distribution pattern of the various cytoskeletal proteins of stromal cells and extracellular matrix proteins was observed in different zones of the stroma, the subammotic stroma, Wharton's jelly, and the vessels' adventitia. All three zones showed immunoreactivities for collagen types I, III and VI and for basement membrane molecules such as collagen type IV, laminin and heparan sulphate proteoglycan. Immunoreactivities for these extracellular matrix molecules were observed around cleft-like territories (stromal clefts) in the Warton's jelly which were occupied by homogeneous ground substance but void of collagen fibrils and basal lamina molecules. Moreover, between the stromal clefts, slender cells were found which immunohistochemically and ultrastructurally corresponded to various stages of myofibroblastic differentiation. In earlier stages of gestation, stromal cells with a less complex expression pattern prevailed. The stromal clefts and the contractile cells together might serve as a system regulating the turgor of the cord.