Malignant Fibrous Histiocytoma Tumor Research Articles

Management of extremity malignant fibrous histiocytoma: A 10-year experience

Summary Background Malignant fibrous histiocytoma (MFH) is a common soft-tissue sarcoma in adults, which commonly affects the extremities, trunk, head, and neck. Of these regions, the extremities are more often affected. However, only a few studies have specifically investigated the clinical behavior and prognosis of this malignancy, especially in East Asian populations. Aims and objectives We collected data on MFH cases for a period of 10 years and present our experience here in treating patients with extremity MFH. Materials and methods This study was a retrospective analysis of patients with extremity MFH treated in the Department of Plastic Surgery at National Cheng Kung University Hospital between January 2004 and December 2013. Data on patient profiles, surgical resection, radiotherapy, and chemotherapy were all reviewed. The patients were followed up regarding their local recurrences and survivals. Results Thirteen patients (6 men and 7 women) were enrolled in this study. The mean age of the patients was 57.9 years (range, 33–82 years). The sizes of the clinical tumors ranged from 1.7 to 15 cm in a maximal linear dimension (mean, 7.3 cm), and 76.9% of the tumors developed in the lower extremities. The average follow-up time was 63.5 months. One patient received limb amputation, and 12 patients were treated with limb salvage including marginal or wide excisions. Adjuvant radiotherapy was performed in 10 patients whose tumor sizes exceeded 5 cm or who exhibited inadequate excision or recurrence. Chemotherapy was performed in six patients who exhibited a distant metastasis or vessel invasion. The local and distant recurrence rates were 53.8% and 30.8%, respectively. A total of 42.9% of patients with local recurrence developed distant metastases. The surgical margin was the only significant factor of local disease control, and distant metastasis was the only factor relevant to the overall survival (OS). Conclusion An adequate resection margin during treatment for the primary MFH tumor achieves optimal results for local disease control. It influences the OS rate, because local-recurrence-related distant metastasis is significantly associated with high mortality.

Primary pulmonary malignant fibrous histiocytoma.

Malignant fibrous histiocytoma (MFH) is one of the most common adult soft tissue sarcomas. MFH is very aggressive and is most often found in the extremities and the retroperitoneum, but it can manifest at other sites. Though the lungs are the most common sites of metastasis, they rarely present there as a primary tumor. Our report describes a rare case of a primary MFH tumor in the lung. Careful diagnostic procedure should be followed to ensure the tumor does not have extrapulmonary origins. Though MFH is highly invasive and deadly, surgical excision of the tumor has been shown to be successful.

Transcutaneous application of CO2 enhances the antitumor effect of radiation therapy in human malignant fibrous histiocytoma.

Sarcomas are relatively resistant because of hypoxia. We previously demonstrated that the transcutaneous CO(2) therapy reduced hypoxic conditions in human malignant fibrous histiocytoma (MFH). Therefore, we hypothesized that transcutaneous CO(2) therapy could enhance the antitumor effect of radiation therapy in human MFH. Our purpose was to evaluate the effects of transcutaneous CO(2) therapy on the antitumor efficacy of X-ray irradiation using MFH. First, in an in vitro study, we assessed apoptotic activity and reactive oxygen species (ROS) production using flow cytometric and immunoblot analysis at 24 h after X-ray irradiation under three different oxygen conditions (normoxic, reoxygenated and hypoxic). In addition, in the in vivo study, 24 male athymic BALB/c nude mice with MFH tumors that were inoculated in the dorsal subcutaneous area were randomized into four groups: control, CO(2), X-ray irradiation and combination (CO(2) and X-ray irradiation). Treatments were performed twice weekly for 2 weeks, four times in total. Tumor volume was calculated. All tumors were excised and apoptotic activity, ROS production, related proteins and HIF-1α expression were assessed using flow cytometric and immunoblot analysis. The in vitro study revealed that X-ray irradiation induced increased apoptosis and ROS production in MFH cells under normoxic and reoxygenated conditions relative to hypoxic conditions (P<0.01). In the in vivo study, tumor volume in the combination group was reduced to 28, 42 and 47% of that in the control, CO(2), and X-ray groups, respectively (P<0.05). Apoptotic activity and ROS production in the combination group were strongly increased with decreasing HIF-1α expression relative to the control, CO(2) and X-ray groups. The transcutaneous CO(2) system enhanced the antitumor action of X-ray irradiation and could be a novel therapeutic tool for overcoming radio-resistance in human malignancies.

Transcutaneous Application of Carbon Dioxide (CO2) Enhances Chemosensitivity by Reducing Hypoxic Conditions in Human Malignant Fibrous Histiocytoma

Background: Tumor hypoxia is a common feature of various human malignancies. Hypoxia contributes to tumor progression, and is a major cause of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF)-1 is a key transcription factor in hypoxic responses, and regulates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, and invasion. We previously demonstrated that transcutaneous application of carbon dioxide (CO2) induced oxygenation in the treated tissue in vivo, therefore, we hypothesized that transcutaneous CO2 exposure could enhance the chemosensitivity by reducing hypoxia in a tumor tissue. The aim of this study was to examine the effect of oxygenation by transcutaneous application of CO2 on the therapeutic efficacy of doxorubicin (DOX) to treat human malignant fibrous histiocytoma (MFH) in vivo. Methods: In this study, we utilized a murine model of human MFH, and mice were randomly divided into four groups: control, CO2, DOX and combination (CO2 + DOX) treatment groups to examine the effect of transcutaneous application of CO2 on the hypoxic condition, and to assess the therapeutic effect of combination therapy using transcutaneous CO2and DOX treatment in vivo. Results: Transcutaneous application of CO2 treatment decreased HIF-1α expression in human MFH tumor tissues, suggesting that our transcutaneous CO2 treatment reduced the hypoxic conditions. Furthermore, transcutaneous CO2 treatment alone had an antitumoral effect, and increased the chemotherapeutic effect of DOX on MFH tumor growth in vivo, with no observable effects on body weight. Conclusions: Our findings in this study strongly indicate that our transcutaneous CO2 system has antitumor effects and can enhance the chemosensitivity of tumor cells by reducing the local hypoxic conditions.

Recurrence of a Simultaneous Tumor of the Parotid Gland and Scalp Skin Malignant Fibrous Histiocytoma

Malignant fibrous histiocytoma (MFH) is one of the most common soft-tissue sarcomas and generally arises in elderly patients. Most often, MFH occurs in the extremities and the retroperitoneum; MFH of the head and neck region is only reported in 3% of all cases. The distant metastasis appears in one third of all cases, and those cases mainly involve the lung, regional lymph nodes, the liver, or bones. The main treatment of MFH of the head and neck is radical excision of the tumor with modified or radical neck dissection. Recurrences of MFH are commonly seen and identified within the first 2 years of treatment. We report a case of simultaneous MFH tumors of the parotid gland and of the scalp skin in an elderly male patient. The patient underwent a wide surgical excision of the lesion and referred to the oncology department for further treatment. However, 1 month after chemoradiotherapy had commenced, there was a recurrence of the tumor over the skin on the right parotid region.

Protein kinase Cδ in tumorigenesis of human malignant fibrous histiocytoma

Protein kinase Cδ (PKCδ), an isoform of PKC, has been shown to act as a critical mediator of tumor progression and apoptosis; however, its role in musculoskeletal tumors is still unknown. In the current study, we examined the expression of PKCδ in human musculoskeletal tumor tissue samples, and investigated the effects of siRNA downregulation of PKCδ on human malignant fibrous histiocytoma (MFH) cell proliferation, migration, and apoptosis, to elucidate its functional roles in musculoskeletal tumorigenesis. Of note, real-time PCR analysis revealed that mRNA expression of PKCδ in high-grade musculoskeletal MFH tumors was significantly lower than that in benign schwannomas. siRNA downregulation of PKCδ significantly increased human MFH cell proliferation and migration, and markedly suppressed apoptosis. These findings suggest that PKCδ has a negative effect on tumorigenesis and/or acts as a pro-apoptotic kinase in human MFH cells. The data presented here could be applied in the development of new therapeutic avenues, with the elevation of PKCδ expression being one potential strategy to prevent MFH progression. Thus, PKCδ may be a potent therapeutic target for human MFH.

Characterization and Signaling in a Primary Human Malignant Fibrous Histiocytoma Cell Line

ABSTRACTSarcomas are rare tumors, and malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma found in adults. Increasing evidence suggests a possible role for AKT activation in soft tissue sarcoma. In the present study, we established a primary human MFH cell line (named MSUMFH cells) from a fresh surgically resected MFH tumor. These cells morphologically resembled human normal fibroblasts that are the presumptive cells of origin of MFH tumor cells. As there is, unfortunately, no standard marker other than morphology to identify MFH at the cellular level, we compared MSUMFH cells to primary nonmalignant fibroblasts and the primary tumor specimen to characterize its signaling. AKT was hyperactivated in both the MSUMFH cell line and original primary MFH tumor cells compared to normal fibroblasts. The AKT hyperactivity in the MSUMFH cell line was not accompanied by activation of focal adhesion kinase (FAK) or downregulated expression of PTEN, each of which is a putative upstream regulator of AKT. In contrast, this AKT hyperactivation required PI-3K and Src in MSUMFH cells. This PI-3K and Src-dependent AKT-activated MSUMFH cell line that we established in this study may be beneficial for the future cell-based study of MFH biology.

Analysis of Multiple Sarcoma Expression Datasets: Implications for Classification, Oncogenic Pathway Activation and Chemotherapy Resistance

BackgroundDiagnosis of soft tissue sarcomas (STS) is challenging. Many remain unclassified (not-otherwise-specified, NOS) or grouped in controversial categories such as malignant fibrous histiocytoma (MFH), with unclear therapeutic value. We analyzed several independent microarray datasets, to identify a predictor, use it to classify unclassifiable sarcomas, and assess oncogenic pathway activation and chemotherapy response.Methodology/Principal FindingsWe analyzed 5 independent datasets (325 tumor arrays). We developed and validated a predictor, which was used to reclassify MFH and NOS sarcomas. The molecular “match” between MFH and their predicted subtypes was assessed using genome-wide hierarchical clustering and Subclass-Mapping. Findings were validated in 15 paraffin samples profiled on the DASL platform. Bayesian models of oncogenic pathway activation and chemotherapy response were applied to individual STS samples. A 170-gene predictor was developed and independently validated (80-85% accuracy in all datasets). Most MFH and NOS tumors were reclassified as leiomyosarcomas, liposarcomas and fibrosarcomas. “Molecular match” between MFH and their predicted STS subtypes was confirmed both within and across datasets. This classification revealed previously unrecognized tissue differentiation lines (adipocyte, fibroblastic, smooth-muscle) and was reproduced in paraffin specimens. Different sarcoma subtypes demonstrated distinct oncogenic pathway activation patterns, and reclassified MFH tumors shared oncogenic pathway activation patterns with their predicted subtypes. These patterns were associated with predicted resistance to chemotherapeutic agents commonly used in sarcomas.Conclusions/SignificanceSTS profiling can aid in diagnosis through a predictor tracking distinct tissue differentiation in unclassified tumors, and in therapeutic management via oncogenic pathway activation and chemotherapy response assessment.

Epidermal Growth Factor Receptor Overexpressed Malignant Fibrous Histiocytoma Associated With Recurrent Meningothelial Meningioma -Case Report-

A 71-year-old woman presented with a rare case of malignant fibrous histiocytoma (MFH) associated with recurrent meningothelial meningioma. The neuroimaging findings were consistent with a diagnosis of recurrent meningioma. Surgical removal was performed. Histological and immunohistochemical examinations detected meningothelial and MFH tumor components. The MFH component showed diffuse 3+ staining for epidermal growth factor receptor protein, predominantly located on the cell membrane and to a lesser extent within the cytoplasm. However, a fluorescein isothiocyanate analysis detected no amplification of epidermal growth factor receptor gene.

3D-Histological evaluation of surgery in dermatofibrosarcoma protuberans and malignant fibrous histiocytoma: Differences in growth patterns and outcome

Aims To evaluate the microscopic growth pattern of dermatofibrosarcoma protuberans (DFSP) and malignant fibrous histiocytoma (MFH) and the long-term outcome using 3D-histologic surgery with paraffin sections to cover complete margins and to detect subclinical spreads very sensitively. Methods One hundred and one patients have been included comprising 70 DFSP, 31 MFH. Data from 87 patients treated since 1992 were collected prospectively. Results Mean clinical tumor-size was 45 mm, mean histological tumor size 65 mm. A mean excision margin of 19 mm achieved negative margins. The histological infiltration shows an asymmetrical pattern with horizontal or vertical extension either cord-, sector- or multiple-like up to 70 mm in length, detectable by 3D-histology. Age and localization differed significantly between DFSP and MFH lesions. MFH tumors had a significantly deeper infiltration than DFSP. The mean follow up was 60 months. In 70 patients with DFSP one local recurrence after 62 months occurred, but no metastasis. 31 patients with MFH developed 8 local recurrences, and 4 metastases (lymph nodes and/ or lungs); 3 of them died of the disease, all 3 had a postoperative status of R1 ( p = 0.001). Conclusions There are significant differences in growth pattern and clinical outcome between DFSP and MFH. DFSP can be cured by surgery following 3D-histology with paraffin sections. MFH is significantly more malignant. After local R0-resection proofed by 3D-histology higher cure rates can be achieved.

Radiation response: An additional unique signature of myxoid liposarcoma

Purpose Historically, myxoid liposarcoma (MLS) has been reported to show a marked clinical response to radiotherapy (RT), but objective data to support that contention have been lacking. We performed a retrospective analysis of the response of a group of MLS tumors to preoperative RT using tumor dimensions calculated from pretreatment imaging and the subsequent surgical specimen obtained approximately 1 month after RT. Methods and materials Data were abstracted from the Princess Margaret Hospital prospective database on a series of patients with MLS who had undergone preoperative RT between 1991 and 1999. A group of malignant fibrous histiocytoma (MFH) patients treated on the same protocol served as controls. Pretreatment and posttreatment three-dimensional measurements were obtained; comparison tumor volume measurements were estimated using the ellipsoid formula, and the analysis was also repeated using the maximal tumor dimension. Identical measurement procedures were used for the MLS (experimental) and MFH (control) cases. Results A total of 16 MLS tumor specimens were available for analysis, and 16 MFH cases were randomly chosen for comparison. The mean pretreatment and posttreatment volume of the MLS tumors was 415 and 199 cm 3, respectively ( P = <0.0001). The mean pretreatment and posttreatment volume of the MFH tumors was 264 and 273 cm 3, respectively ( p = 0.804). The proportional reduction in the median tumor volume was 59% and −7% for MLS and MFH tumors, respectively. Both the absolute and the proportional reduction in volume for MLS tumors vs. MFH tumors was statistically significant ( p = 0.006 and p = 0.002, respectively). Conclusion These results provide the first objective data to support the idea that MLS tumors show a statistically significant reduction in size when treated with RT and that this response is greater than that of MFH tumors given the same RT. These results may be relevant to the management of MLS with combined RT and surgery in difficult anatomic situations in which adequate surgical excision is not feasible. They also confirm another unique characteristic of this unusual subtype of soft tissue sarcoma.

Cytogenetic findings in a case of dedifferentiated chondrosarcoma

Cytogenetic analysis of a case of dedifferentiated chondrosarcoma with a malignant fibrous histiocytoma (MFH) component revealed a near-triploid karyotype with multiple copies of chromosome 7, deletion of chromosome arm 9p, and a derivative chromosome 19 [add(19p)] in each metaphase. Whereas numerical anomalies of chromosome 7 have been frequently reported in chondrosarcoma, deletion 9p and add (19p) have been observed in MFH. A putative MFH tumor suppressor gene could be present in a critical region on chromosome bands 9p21~p22.

Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience.

Malignant fibrous histiocytoma (MFH) is a controversial entity. In the current study, the authors reviewed their institutional experience with these tumors to characterize their clinical features in pediatric patients and assess the impact of surgical resection on outcome. The records of the 28 patients who were diagnosed with MFH or MFH variants of soft tissue between January 1971 and December 2000 were reviewed and the tumors were reclassified according to the World Health Organization guidelines. Seventeen patients had MFH; 10 patients had angiomatoid fibrous histiocytoma (FH), and 1 patient had a plexiform fibrohistiocytic tumor. The median age of patients at the time of diagnosis was 7.3 years. The most common primary tumor site was the extremity (n = 14). Metastatic disease (to the lung) was present in only three patients, each of whom had MFH. Of the 17 MFH tumors, 13 were high grade, 8 were invasive, and 6 measured > 5 cm. All angiomatoid FH tumors and the plexiform fibrohistiocytic tumor were noninvasive, and 10 measured < or = 5 cm. Surgical treatment was comprised of wide local excision with clear margins (n = 18), amputation (n = 3), excision with positive or indeterminate surgical margins (n = 4), partial resection (n = 2), or biopsy only (n = 1). Primary reexcision was performed for 21 patients. The 5-year survival and event-free survival (EFS) estimates for patients with MFH were 76.5% +/- 11.2% and 70.6% +/- 12.1%, respectively; the 5-year survival and EFS estimates were 100% +/- 0% for patients with angiomatoid FH or plexiform fibrohistiocytic tumor. Compared with partial resection or excision, wide local excision or amputation was found to have a positive impact on the probability of EFS in patients with localized disease (P = 0.008). All four patients with metastatic or unresectable MFH had died by the time of last follow-up. MFH should be distinguished from angiomatoid FH and plexiform fibrohistiocytic tumors, both of which are less aggressive. Wide local excision is the treatment of choice, regardless of the histology or grade of the tumor. Patients with metastatic or unresectable MFH appear to have a poor outcome and would benefit from more effective therapies.

Malignant fibrous histiocytoma. Proliferative compartment and heterogeneity of "histiocytic" cells.

To elucidate the precise origin and characteristics of the proliferating cells in malignant fibrous histiocytoma (MFH), the authors analyzed 33 MFH tumors, using immunohistochemical techniques with a panel of 12 antibodies. All three types of MFH cells (spindle cells, polygonal cells, and bizarre giant cells) stained positively for mesenchymal antigens (FU3 and vimentin) but did not stain for macrophage/histiocyte markers (HAM 56 and CD68). Therefore, the MFH cells may not represent true histiocytes, although they may be mesenchymal-derived cells behaving as "facultative histiocytes" with superficial resemblance to actual histiocytes. Normal histiocytes in the stroma tested positive for macrophage/histiocyte antigens; the most common cells were HAM 56-positive cells constituting 30-80% of nonneoplastic stromal cells, followed by those positive for CD68 (10-50%), Mac 387 (less than 2%), and S-100 protein (less than 1%). Our results indicate the presence of heterogeneity of "histiocytic" cells in MFH. Proliferating-cell nuclear antigen (PCNA) was expressed not only in the spindle and polygonal MFH cells but also in the bizarre giant cells. These findings suggest that all three types of MFH cells participate in the proliferative compartment of MFH. Uneven PCNA staining of the irregular nuclear segments of the bizarre giant cells may result in abnormal DNA synthesis, possibly contributing to the marked diversity of nuclear morphology in MFH. Touton-type and osteoclast-like giant cells did not stain for PCNA but stained positively for histiocytic markers. Therefore, these giant cells may lack proliferative activity and probably result from normal histiocytes fusing together.

Production of monocyte chemoattractant protein-1 by malignant fibrous histiocytoma: Relation to the origin of histiocyte-like cells

Human malignant fibrous histiocytoma (MFH) comprise both fibroblast-like cells and histiocyte-like cells. We previously showed that the latter are not neoplastic cells, but are infiltrating macrophages. Since migration of blood monocytes into the tumor might be a response to a locally elaborated monocyte chemoattractant, we designed experiments to determine if the fibroblast-like tumor cells produced a chemoattractant for human monocytes. Malignant fibrous histiocytoma from three patients was put into culture. Cells of all three lines had a spindle shape, and showed no reactivity with antibodies against macrophages (MAC387), HLA-DR (LN3), or leukocyte common antigen. Immunohistochemically, they stained with antibody against human monocyte chemoattractant protein-1 (MCP-1). Culture supernatants of the three cell lines had chemotactic activity for monocytes. This activity was due to MCP-1, since it was absorbed by an anti-MCP-1 column. The production of MCP-1 by MFH tumor lines was confirmed by immunoprecipitation of metabolically labeled MCP-1. These results suggest that the histiocyte-like cells are the infiltrated macrophages that originate from blood monocytes attracted by tumor-derived MCP-1.

Immunohistochemical study of 4-hydroxyaminoquinoline 1-oxide-induced rat malignant fibrous histiocytoma

The primary focus of this experiment was on the investigation of localizations of alpha 1-antitrypsin (alpha 1-AT), alpha 1-antichymotrypsin (alpha 1-ACT), fibronectin (FN) and lysozyme (LY) in tumor cells of experimental malignant fibrous histiocytoma (MFH). The induction of MFH was conducted by injecting Fischer 344 rats with 4-hydroxyaminoquinoline 1-oxide (4-HAQO). In 46 out of 50 rats, tumors were generated, all of which were diagnosed as MFH and classified into 5 subtypes, according to their histological properties. The presence of alpha 1-AT, alpha 1-ACT and FN in all MFH tumor cells was observed in the tumor cells of various types. Especially, fibroblast-like, histiocyte-like and Touton and/or Epulis type giant cells showed strong reactivity. However, positive reaction of LY in MHF tumor cells was very weak, or the reaction was negative. These findings are consistent with those of human MFH.

DNA sequence amplification in malignant fibrous histiocytoma tumors

DNA sequence amplification in malignant fibrous histiocytoma tumors