Comparison of clinical outcome between surgical treatment and particle beam therapy for pelvic bone sarcomas: A retrospective multicenter study in Japan.

BACKGROUND: Few studies have compared the clinical outcomes of patients with pelvic bone sarcomas treated surgically and those treated with particle beam therapy. This is a multicenter retrospective cohort study which compared the clinical outcomes of patients with pelvic bone sarcoma who underwent surgical treatment and particle beam therapy in Japan. METHODS: A total of 116 patients with pelvic bone sarcoma treated at 19 specialized sarcoma centers in Japan were included in this study. Fifty-seven patients underwent surgery (surgery group), and 59 patients underwent particle beam therapy (particle beam group; carbon-ion radiotherapy: 55 patients, proton: four patients). RESULTS: The median age at primary tumor diagnosis was 52 years in the surgery group and 66 years in the particle beam group (P < 0.001), and the median tumor size was 9 cm in the surgery group and 8 cm in the particle beam group (P = 0.091). Overall survival (OS), local control (LC), and metastasis-free survival (MFS) rates were evaluated using the Kaplan-Meier method and compared among 116 patients with bone sarcoma (surgery group, 57 patients; particle beam group, 59 patients). After propensity score matching, the 3-year OS, LC, and MFS rates were 82.9% (95% confidence interval [CI], 60.5-93.2%), 66.0% (95% CI, 43.3-81.3%), and 78.4% (95% CI, 55.5-90.5%), respectively, in the surgery group and 64.9% (95% CI, 41.7-80.8%), 86.4% (95% CI, 63.3-95.4%), and 62.6% (95% CI, 38.5-79.4%), respectively, in the particle beam group. In chordoma patients, only surgery was significantly correlated with worse LC in the univariate analysis. CONCLUSIONS: The groups had no significant differences in the OS, LC, and MFS rates. Among the patients with chordomas, the 3-year LC rate in the particle beam group was significantly higher than in the surgery group.

Perivascular epithelioid cell tumors (PEComas) of the bone and soft tissue: a Japanese Musculoskeletal Oncology Group (JMOG) multi-institutional study.

PURPOSE: Perivascular epithelioid cell tumors (PEComas) of the bone and soft tissues are rare mesenchymal neoplasms, some of which are malignant. However, their clinical and pathological characteristics remain unclear. This study was performed to investigate the clinical and pathological characteristics of PEComas in bone and soft tissues by leveraging information from the Japanese Musculoskeletal Oncology Group. METHODS: Nine patients, including four male and five female patients with a median age of 50 years, were retrospectively reviewed. PEComas of the visceral organs, including the uterus and retroperitoneum, were excluded. RESULTS: Eight tumors arose in the soft tissue and one in the bone, with a mean size of 8.8 cm. Four patients showed local recurrence or distant metastasis. The 1-year survival rate was 78%. Pathologically, eight tumors were classified as malignant and one as having uncertain malignancy potential. Half of the tumors showed high MIB-1 index values of > 30%. Immunohistochemically, the melanocyte marker HMB45 was expressed in 89% of the cases, and muscle-specific markers were expressed only in 30-50% of the cases. Transcription factor binding to IGHM enhancer 3 (TFE3) expression was positive in 100% of the patients. Tumors with high expression of TFE3 were classified as PEComas with malignant potential according to Folpe's classification. CONCLUSIONS: Bone and soft tissue PEComas may have a higher malignancy potential than other visceral PEComas and are more likely to develop as TFE3-rearranged PEComas.

Multicenter study on atypical femoral fractures in patients with bone metastases taking bone- modifying agents.

Bone-modifying agents (BMAs), with bone-resorptive inhibitory effects, such as zoledronic acid and denosumab, are widely used at higher doses for bone-related events caused by bone metastasis of malignant tumors. These drugs have been suggested to be associated with atypical femoral fractures (AFFs), and the relationship between BMAs and AFFs has attracted attention. To investigate the clinical features including bone union time of AFFs in patients administered BMA for bone metastasis, we conducted a retrospective multicenter study. Thirty AFFs from 19 patients were enrolled in this study. Thirteen patients had bilateral AFFs, and nineteen AFFs had prodromal symptoms. Eighteen AFFs underwent surgery after complete fracture, three failed to achieve bone union and required nonunion surgery, and 11 AFFs that achieved bone union had an average period until bone union of 16.2 months, which was much longer than that previously reported for ordinary AFFs. Seven patients discontinued the BMAs, but not due to AFFs. Stopping BMAs in patients with bone metastasis would make it difficult to secure their performance of activities of daily living, and AFF with BMA administration might require a longer time for union. Therefore, it would be important to prevent incomplete AFF from becoming complete AFF via prophylactic internal fixation.

Proximal-type epithelioid sarcoma in pubic region expressing L-type amino acid transporter 1: A case report.

Proximal-type epithelioid sarcoma is an aggressive malignant soft-tissue neoplasm, a "proximal" variant of epithelioid sarcoma, resistant to multimodal therapy and involved in early tumor-related death. Pertinent treatments are, therefore, continually being explored. A 24-year-old woman with nonmetastatic proximal-type epithelioid sarcoma, originating subcutaneously on the right side of the vulva, underwent surgical resection; the lesion recurred, however, leading to death 3 months after the second surgery. Here described is a case of proximal-type epithelioid sarcoma expressing L-type amino acid transporter 1 (LAT1) that transports essential amino acids and p-borono-L-phenylalanine (BPA)-the chemical compound used in boron neutron capture therapy (BNCT)-and is highly expressed in many malignant tumors. Recently, LAT1 has drawn attention, and relevant treatments have been studied-LAT1 inhibitor and BNCT. LAT1 expression in proximal-type epithelioid sarcoma may lead to cogent treatments for the disease.

Clinical Outcome of Patients with Pelvic and Retroperitoneal Bone and Soft Tissue Sarcoma: A Retrospective Multicenter Study in Japan.

This study aimed to retrospectively analyze the clinical outcomes of patients with pelvic and retroperitoneal bone and soft tissue sarcoma (BSTS). Overall, 187 patients with BSTS in the pelvis and retroperitoneal region treated at 19 specialized sarcoma centers in Japan were included. The prognostic factors related to overall survival (OS), local control (LC), and progression-free survival (PFS) were evaluated. The 3-year OS and LC rates in the 187 patients were 71.7% and 79.1%, respectively. The 3-year PFS in 166 patients without any distant metastases at the time of primary tumor diagnosis was 48.6%. Osteosarcoma showed significantly worse OS and PFS than other sarcomas of the pelvis and retroperitoneum. In the univariate analyses, larger primary tumor size, soft tissue tumor, distant metastasis at the time of primary tumor diagnosis, P2 location, chemotherapy, and osteosarcoma were poor prognostic factors correlated with OS. Larger primary tumor size, higher age, soft tissue tumor, chemotherapy, and osteosarcoma were poor prognostic factors correlated with PFS in patients without any metastasis at the initial presentation. Larger primary tumor size was the only poor prognostic factor correlation with LC. This study has clarified the epidemiology and prognosis of patients with pelvic and retroperitoneal BSTS in Japan.

Clinical Outcome of the Patients With Brain Metastasis from Soft Tissue Sarcomas.

BACKGROUND/AIM: This study aimed to evaluate the association of clinical characteristics with treatment outcomes to ascertain the appropriate treatment options for soft tissue sarcomas (STS) patients with brain metastasis (BM). PATIENTS AND METHODS: Medical records of STS patients with BM who were treated in our institutions were retrospectively reviewed, and analyzed to identify the factors associated with post-BM survival. RESULTS: Among the 509 STS patients, BM occurred in five patients (0.98%). The median survival after BM was 1.5 months. Histological subtypes of the primary lesions in the five BM patients were: two synovial sarcomas, one myxoid liposarcoma, one alveolar soft part sarcoma, and one rhabdomyosarcoma. Among the five BM patients, the post-BM survival of two patients, who underwent surgery and postoperative radiotherapy, was longer than that of the other patients (p<0.01). CONCLUSION: Combined surgery and postoperative radiotherapy effectively managed symptoms and prolonged survival in STS patients with BM.

BNCT for primary synovial sarcoma.

Synovial sarcoma is a rare tumor requiring new treatment methods. A 46-year-old woman with primary monophasic synovial sarcoma in the left thigh involving the sciatic nerve, declining surgery because of potential dysfunction of the affected limbs, received two courses of BNCT. The tumor thus reduced was completely resected with no subsequent recurrence. The patient is now able to walk unassisted, and no local recurrence has been observed, demonstrating the applicability of BNCT as adjuvant therapy for synovial sarcoma. Further study and analysis with more experience accumulation are needed to confirm the real impact of BNCT efficacy for its application to synovial sarcoma.

Prognostic influence of the treatment approach for pulmonary metastasis in patients with soft tissue sarcoma.

Soft tissue sarcomas (STSs) are rare heterogeneous malignancies of mesenchymal origin. Pulmonary metastases develop in approximately 50% of the patients with high-grade STS, being the major cause of mortality in patients with metastatic STS. Pulmonary metastasectomy has been reported to contribute to long-term survival; however, an appropriate treatment has not been established. We aimed to identify factors associated with post-metastasis survival in STS patients with pulmonary metastasis and determine the appropriate treatment for each patient. We retrospectively reviewed the records of metastatic STS patients treated between 2000 and 2017 and analyzed the clinico-pathologic variables to identify factors associated with the survival. The median survival after pulmonary metastasis was 20.6 months, and the 1-, 3-, and 5-year survival rates were 68.6%, 36.0%, and 25.1%, respectively. The survival was significantly greater in patients who underwent pulmonary metastasectomy than in those without surgery (38.9 months vs. 10.5 months; p < 0.0001). Among those who did not undergo surgery, the survival was significantly greater in patients who received chemotherapy than in those without chemotherapy (19.1 months vs. 6.3 months, p = 0.037). Multivariate analysis identified pulmonary metastasectomy as the most important prognostic factor for post-metastasis survival (Hazard ratio 5.623; 95% Confidence Interval 2.733-11.572; p < 0.0001). In conclusion, pulmonary metastasectomy was the most important prognostic factor for post-metastasis survival in patients with metastatic STS. In addition, chemotherapy could prolong survival in patients who were not eligible for pulmonary resection. Although we should carefully weigh the risks and benefits, appropriate treatment for pulmonary metastases could contribute to long-time survival.

Boron neutron capture therapy for clear cell sarcoma.

Clear cell sarcoma of tendons and aponeuroses (CCS) is a rare, malignant tumor arising in lower extremities with no effective treatment other than wide surgical resection. Here described is a case of primary CCS in the peroneal tendon of the right foot of a 54-year-old woman enrolled to undergo BNCT. The tumor mass post-BNCT disappeared totally without damage to other normal tissue, demonstrating, for the first time, the potential efficacy of BNCT in complete local control of CCS.

Predicting the survival of patients with bone metastases treated with radiation therapy: a validation study of the Katagiri scoring system.

BACKGROUND: The selection of radiation therapy dose fractionation schedules for bone metastases is often based on the estimation of life expectancy. Therefore, accurate prognosis prediction is an important issue. It is reported that the Katagiri scoring system can be used to predict the survival of patients with bone metastases. We aimed to assess prognostic factors and validate the Katagiri scoring system in patients who were treated with radiation therapy for bone metastases. MATERIALS/METHODS: We retrospectively reviewed data of all patients who were treated with radiation therapy for bone metastases between 2004 and 2013. Age, sex, Karnofsky performance status (KPS), Eastern Cooperative Oncology Group performance status (ECOG PS), primary site (lesions and characteristics), visceral metastases, laboratory data, previous chemotherapy, and multiple bone metastases were analyzed for associations with overall survival (OS). Katagiri scores were calculated for each patient and were used to compare OS. RESULTS: Out of the 616 patients included in this analysis, 574 had died and 42 remained alive. The median follow-up time for survivors was 42 months. Univariate analysis revealed that age (P = 0.604) and multiple bone metastases (P = 0.691) were not significantly associated with OS. Multivariate analysis revealed that sex, ECOG PS, KPS, primary characteristics, visceral metastases, laboratory data, and previous chemotherapy were significantly associated with OS. The survival rates at 3, 6, 12, and 24 months, categorized by Katagiri score, were as follows: score 0-3, 94.4, 77.8, and 61.1%, respectively; score 4-6, 67.7, 48.7, and 31.2%, respectively; and score 7-10, 39.1, 22.1, and 9.0%, respectively (P < 0.001). CONCLUSION: Sex, ECOG PS, KPS, primary characteristics, visceral metastases, laboratory data, and previous chemotherapy were significant predictors of survival in patients with bone metastases. The Katagiri scoring system was significantly correlated with OS and can help us select the optimal dose-fractionation.

Expression of transforming growth factor beta isoforms and their receptors in malignant fibrous histiocytoma of soft tissues.

PURPOSE: Transforming growth factor beta (TGF-beta) is a multifunctional growth factor that variably affects proliferation, differentiation, and extracellular matrix formation. Little information is currently available on the TGF-beta expression in malignant fibrous histiocytoma (MFH). The aims of the present study were to investigate the expression of TGF-beta isoforms and their receptors in human MFH specimens. EXPERIMENTAL DESIGN: The expression of TGF isoforms, and TGF-beta receptors (TGF-beta R1 and -beta R2) were immunohistochemically evaluated in 43 paraffin-embedded MFH specimens. Furthermore, the correlation of the TGF-beta and receptor expression with tumor proliferative activity assessed by MIB-1 indices was analyzed. RESULTS: Positive immunoreactivity for TGF-beta1, -beta2, and -beta 3 was identified in tumor cells of 42, 40, and 38 of the 43 MFHs, respectively. In each TGF-beta isoform immunostaining, the specimens were divided into two groups based on the number of positive tumor cells: those with low (<25%) and those with high (>==25%) immunoreactivity. There were no statistically significant differences in the MIB-1 indices between the two groups. Positive immunoreactivity for TGF-beta R1 and -beta R2 was identified in tumor cells of 36 and 24 of the MFHs, respectively. The specimens were divided into two groups based on their receptor expression patterns: those with both TGF-beta R1- and -beta R2-positive immunoreactivity (n = 23), and those with both or either TGF-beta R1- and -beta R2-negative immunoreactivity (n = 20). The MIB-1 indices in the both-TGF-beta R1- and -beta R2-positive group were significantly higher than those in the other group (P = 0.0102). There was no significant difference in pulmonary metastasis ratios between the two groups. CONCLUSIONS: These findings strongly suggest an association of the TGF-beta ligand/receptor system with a significantly higher MIB-1 index in human MFHs. Investigation of the TGF-beta R1 and -beta R2 coexpression might be useful in predicting tumor behavior of MFHs.

Boron neutron capture therapy (BNCT) as a new approach for clear cell sarcoma (CCS) treatment: Trial using a lung metastasis model of CCS.

Clear cell sarcoma (CCS) is a rare malignant tumor with a poor prognosis. In the present study, we established a lung metastasis animal model of CCS and investigated the therapeutic effect of boron neutron capture therapy (BNCT) using p-borono-L-phenylalanine (L-BPA). Biodistribution data revealed tumor-selective accumulation of (10)B. Unlike conventional gamma-ray irradiation, BNCT significantly suppressed tumor growth without damaging normal tissues, suggesting that it may be a potential new therapeutic option to treat CCS lung metastases.

Potential of boron neutron capture therapy (BNCT) for malignant peripheral nerve sheath tumors (MPNST).

Malignant peripheral nerve sheath tumors (MPNST) are relatively rare neoplasms with poor prognosis. At present there is no effective treatment for MPNST other than surgical resection. Nonetheless, the anti-tumor effect of boron neutron capture therapy (BNCT) was recently demonstrated in two patients with MPNST. Subsequently, tumor-bearing nude mice subcutaneously transplanted with a human MPNST cell line were injected with p-borono-L-phenylalanine (L-BPA) and subjected to BNCT. Pathological studies then revealed that the MPNST cells were selectively destroyed by BNCT.

Inhibitory effect of STI571 on cell proliferation of human malignant fibrous histiocytoma cell lines.

BACKGROUND: Malignant fibrous histiocytoma (MFH) is one of the most common high-grade sarcomas in bone and soft tissue and, due to its chemo-resistance, the prognosis of the disease is poor. ST1571 is a tyrosine kinase inhibitor that was initially developed as a BCR/ABL inhibitor for chronic myeloid leukemia patients. STI571 also selectively inhibits platelet-derived growth factor receptors (PDGFRs) and c-kit. We examined the expression of PDGFRs and c-kit in human MFH cell lines, and the effect of STI571 on cell proliferation. MATERIALS AND METHODS: Four human MFH cell lines (TNMY1, GBS-1, Nara-F and Nara-H) were used. mRNA expression of the receptor tyrosine kinases (PDGFRs and c-kit) was analyzed using reverse transcription-polymerase chain reaction, and the inhibitory effect of STI571 on cell proliferation was analyzed using the MTS assay technique. RESULTS: PDGFRalpha mRNA was expressed in TNMY1 and GBS-1, and PDGFRbeta and c-kit mRNAs were expressed in TNMY1, GBS-1 and Nara-F. All three of these mRNAs were absent in Nara-H. STI571 inhibited cell proliferation of TNMY1, GBS-1 and Nara-F in a dose- and time-dependent manner, but cell proliferation of Nara-H was not inhibited by ST1571 at concentrations of 10 microM or less. CONCLUSION: STI571 significantly inhibited proliferation of the three human MFH cell lines that expressed mRNAs of target receptor tyrosine kinases. The inhibitory effect of ST1571 on cell proliferation in these three cell lines might be due to decreased tyrosine kinase activity. STI571 might be a potent chemotherapeutic agent for human MFHs.

Amphiregulin and epidermal growth factor receptor expression in human malignant fibrous histiocytoma of soft tissues.

BACKGROUND: Amphiregulin is a member of the epidermal growth factor (EGF) system and a potent mitogen for various epithelial tissues. Little information, however, is currently available on the amphiregulin and EGF receptor (EGF-R) expression in mesenchymal malignancies of a fibrohistiocytic origin including malignant fibrous histiocytoma (MFH). MATERIALS AND METHODS: We investigated the amphiregulin and EGF-R expression in 43 human MFH tissues using immunohistochemical techniques. Furthermore, the correlation of the ligand and the receptor expression with tumor proliferative activity assessed by MIB-1 indices was analyzed. RESULTS: Positive immunoreactivity for amphiregulin and EGF-R was identified in 34 (79%) and 36 (84%) of the 43 MFH cases analyzed, respectively. Coexpression of amphiregulin and EGF-R was observed in 30 (70%) of the 43 MFHs analyzed. There were no significant differences in MIB-1 indices between both the amphiregulin and EGF-R-positive MFHs and the remaining MFHs. CONCLUSION: These results show that amphiregulin is expressed not only by epithelial tumor cells but also by MFH cells. Our data provide evidence indicating the presence of an autocrine mechanism of proliferation control involving the amphiregulin/EGF-R signaling system in human MFHs.

Expression of betacellulin, heparin-binding epidermal growth factor and epiregulin in human malignant fibrous histiocytoma.

BACKGROUND: Heparin-binding epidermal growth factor (HB-EGF), betacellulin (BTC) and epiregulin (EPR) are members of the EGF system and involved in the cell growth of various epithelial malignancies. There have been no reports on the HB-EGF, BTC and EPR expression in mesenchymal malignancies of fibrohistiocytic origin including malignant fibrous histiocytoma (MFH). MATERIALS AND METHODS: We investigated the expression of HB-EGF, BTC, EPR and EGF-receptor (EGF-R) in 43 human MFH tissue samples using immunohistochemical techniques. RESULTS: Positive immuno-reactivity for HB-EGF, BTC, EPR and EGF-R was identified in 28 (65%), 7 (16%), 43 (100%) and 36 (84%) out of the 43 MFH cases analyzed, respectively. Coexpression of HB-EGF/BTC, BTC/EPR and HB-EGF/EPR was observed in 6 (14%), 7 (16%) and 28 (65%) of the MFHs, respectively. Coexpression of HB-EGF/EGF-R, BTC/EGF-R and EPR/EGF-R was observed in 25 (58%), 6 (14%) and 36 (84%) of the MFHs, respectively. CONCLUSION: These results revealed that HB-EGF, BTC and EPR are expressed not only by epithelial tumor cells, but also by MFH cells. It is suggested that HB-EGF and EPR might be more important tumor growth regulators of MFH through autocrine or paracrine pathways, when compared with BTC.

Expression of stem cell factor and c-kit in human malignant fibrous histiocytoma cell line (TNMY1).

BACKGROUND: The expression of c-kit and/or its ligand, stem cell factor (SCF), has been related to tumor proliferation, in several tumor systems. MATERIALS AND METHODS: We analyzed the expression of the SCF/its receptor (c-kit) mRNA and the production of soluble SCF in a human malignant fibrous histiocytoma (MFH) cell line (TNMY1). RESULTS: Immunocytochemical analysis revealed that the TNMY1 cells were positive for both SCF and c-kit. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the TNMY1 cell line expressed mRNA for SCF and c-kit. By using an enzyme-linked immunosorbent assay (ELISA), the TNMY1 cells were found to produce relatively high amounts of soluble SCF. However, the addition of soluble SCF to the TNMY1 cells did not alter the in vitro growth ability of the cells. CONCLUSION: Our data showed that the MFH cells produced consistent amounts of SCF but did not demonstrate autocrine growth modulation. Thus, SCF secretion may have a paracrine activity in the growth of MFH cells.

Expression of stem cell factor and lack of c-kit expression in malignant fibrous histiocytoma of soft tissues.

BACKGROUND: Little information is available on the expression of stem cell factor (SCF) and its receptor c-kit in soft tissue tumors of a fibrohistiocytic origin, including malignant fibrous histiocytoma (MFH). MATERIALS AND METHODS: We investigated the endogenous expression of SCF and c-kit in 43 MFH tissue samples using immunohistochemical techniques. Furthermore, we examined the correlation of SCF expression in MFHs with proliferative activity assessed by mitotic indices and MIB-1 immunohistochemical staining. RESULTS: Positive immunoreactivity for c-kit was identified in tumor cells of only one MFH case, while the remaining 42 cases were negative. In the one positive case, immunohistochemical staining was focal. Positive immunoreactivity for SCF was identified in 31 out of 43 cases studied (72%, focal; 11, moderate; 6, diffuse; 14). There were no significant differences in the MIB-1 and mitotic indices between the SCF-positive and negative groups. CONCLUSION: Our data indicate that any direct autocrine effects of the SCF/c-kit system on cell growth regulation are precluded in most MFH cases studied, but it is speculated that SCF might indirectly influence tumor growth by promoting local neovascularization.

Immunohistochemical analysis of platelet-derived growth factor and its receptors in soft tissue malignant fibrous histiocytoma.

BACKGROUND: Little information is available regarding the expression of platelet-derived growth factor (PDGF) isoforms and their receptors in soft tissue malignant fibrous histiocytoma (MFH). MATERIALS AND METHODS: We investigated expression of PDGF isoforms and their receptors (PDGF-R alpha and -R beta) in 43 MFH tissue specimens using immunohistochemical techniques. Furthermore, we examined the correlation of PDGF expression in MFHs with proliferative activity assessed by MIB-1 immunohistochemical staining. RESULTS: Positive cytoplasmic immunoreactivity for PDGF-AA, -BB and -AB was identified in tumor cells of 28 (66%), 4 (10%) and 26 (61%), respectively, of the 43 MFHs analyzed. Positive cytoplasmic immunoreactivity for PDGF-R alpha and -R beta was identified in tumor cells of 41 (95%) and 32 (74%), respectively, of the MFHs. Thirty-four (79%) MFHs coexpressed one or more PDGF isoforms and their corresponding receptors. In PDGF-AA immunostaining, MIB-indices in the high immunoreactivity group (> 10% of tumor cells) were significantly higher than those in the low immunoreactivity group (< 10% of tumor cells) (p = 0.031). CONCLUSION: Our data provide evidence to support the presence of an autocrine/paracrine mechanism of proliferation control involving the PDGF ligand/receptor system in human MFHs.

Coexpression of hepatocyte growth factor and its receptor c-Met correlates with high MIB-1 proliferative index in malignant fibrous histiocytoma.

Hepatocyte growth factor (HGF) is a multifunctional cytokine that variably affects cell motility, proliferation, and morphogenesis. Little information is currently available on the HGF and its receptor c-Met expression in malignant fibrous histiocytoma (MFH). We immunohistochemically investigated the HGF and c-Met expression in 43 MFH tissue specimens. Furthermore, the correlation of the HGF and c-Met expression with tumor proliferative activity assessed by MIB-1 indices was analyzed. Our results showed that positive cytoplasmic immunoreactivity for HGF and c-Met was identified in tumor cells in 36 (84%) and 20 (47%) of the 43 MFH cases analyzed, respectively. Coexpression of HGF and c-Met was observed in 20 (47%) of the 43 MFHs, and was correlated with high MIB-1 proliferative indices (p = 0.0446). These findings strongly indicate that the HGF/c-Met signaling system plays an important role in promoting cell proliferation of human MFHs via an autocrine loop.