Shigeyuki Kuratsu

INFLUENCE OF LOCAL RECURRENCE ON THE PROGNOSIS OF SOFT-TISSUE SARCOMAS

We have investigated the significance of local recurrence on survival in 173 patients with localised soft-tissue sarcomas of the limbs and of the trunk. The overall survival rates at five and ten years were 75.2% and 68.0%, respectively. After definitive surgery at our hospitals, there was local recurrence in 25 patients (14.5%). After inadequate operations elsewhere, there was a higher incidence of late local recurrence (28.3%), in comparison with those with primary tumours treated by us (9.0%), or patients referred to us immediately after inadequate surgery elsewhere (10.2%). Because of small numbers these differences in the survival rates were not statistically significantly different. Univariate survival analysis showed that local recurrence after definitive surgery (p = 0.006) together with the histological grade (p = 0.0002), the size of the tumour (p = 0.002), its depth in relation to deep fascia (p = 0.003), and the surgical margin (p = 0.0001) were the significant prognostic factors. Local recurrence at the initial presentation did not affect survival. Multivariate analysis showed that local recurrence after definitive surgery also lost its apparent prognostic significance.

Clinical implications of serum C-reactive protein levels in malignant fibrous histiocytoma.

Paraneoplastic syndromes (PNSs) associated with mesenchymal tumors are uncommon. Previous reports sporadically described inflammatory PNSs with elevated serum C‐reactive protein (CRP) levels and leukocytosis in patients with inflammatory malignant fibrous histiocytoma (MFH) of soft tissue; however, the relationship between other subtypes of MFH and PNS has not been extensively investigated. Forty‐six patients with primary MFH of soft tissues who underwent radical surgery were retrospectively analyzed. These patients were divided into 2 groups according to preoperative serum CRP level: normal (<1.0 mg/dl) and elevated (≥1.0 mg/dl). The correlation between serum CRP level and several clinicopathologic factors was analyzed. Correlation between preoperative serum CRP level and metastasis‐free and overall survival was also investigated by univariate and multivariate analyses. Elevated preoperative serum CRP levels were found in 65% of patients with a mean of 3.7 mg/dl. There were statistically significant relationships regarding tumor size, depth, histologic subtypes, grade, stage and metastatic rate among normal and elevated CRP groups (p < 0.001, p < 0.02, p < 0.005, p < 0.001, p < 0.001 and p < 0.05, respectively). When the tumor was removed, the elevated CRP level subsided into the normal range and other abnormal laboratory findings diminished in all cases. In 11/14 relapsed cases that showed elevated CRP preoperatively, the serum CRP level re‐elevated with tumor relapse. The normal CRP group showed significantly more favorable prognosis than the elevated CRP group in metastasis‐free and overall survival on univariate analysis (p < 0.02, p < 0.05, respectively). Patients with MFH frequently present with an inflammatory PNS, such as elevated serum CRP level, which can be a useful marker of disease activity and a valuable prognostic indicator.

Angiogenesis in Malignant Fibrous Histiocytoma

The significance of neovascularization for tumor growth and metastasis has recently been postulated for human cancers; increased microvessel density correlates with increased frequency of metastasis. In the present study, microvessel density was examined in 42 cases of malignant fibrous histiocytoma (MFH). Microvessels were defined as lumens surrounded by anti-factor-VIII-related antigen (FVIII-RA)-antibody-stained endothelium, and counted in a x 400 field. The number of microvessels varied from 4 to 79 (median 14.5). When cases were divided into groups with less than or greater than 20 microvessels, there were no prominent differences in age distribution, sex ratio, size of tumor, depth of tumor, and histologic subtypes between the two groups. The number of microvessels in 19 cases with and 22 cases without metastasis was 19.4 +/- 14.9 and 19.6 +/- 17.4, respectively. Angiogenesis is apparently not a key factor in the formation of metastasis by MFH.

Soft tissue sarcoma of the pleural cavity.

Seventeen cases of soft tissue sarcoma (STS) developing in the pleural cavity were collected from Japanese hospitals, and their clinical and pathologic findings summarized. Eight of the 17 patients had a 15‐year to 50‐year (mean, 28.8) history of chronic pleural inflammatory disease (pleuritis, pyothorax, and pulmonary tuberculosis) before the onset of the pleural sarcoma. Histologically, malignant fibrous histiocytoma was the most common tumor type (11 cases), followed by angiosarcoma (four). The age at diagnosis of the sarcoma ranged from 15 to 74 years (mean, 58); the male‐to‐female ratio was 3.3:1. In the eight cases of sarcoma associated with chronic pleural inflammatory disease, male preponderance was more marked (7:1). The commonest presenting symptom was chest pain. A mass could be detected by chest roentgenograms in 13 patients and computed tomographic scans in 15 patients. No patient had distant metastases at first admission. Thirteen patients were treated by surgery, chemotherapy, and/or radiation therapy. Thirteen of the 17 patients died 1 to 87 months (mean, 14.2) after therapy for STS. The actuarial 1‐year survival rate was 38.5%. These findings suggest that long‐standing pleural inflammation might be an etiologic factor for development of pleural STS.

Neoadjuvant and adjuvant chemotherapy with high-dose ifosfamide, doxorubicin, cisplatin and high-dose methotrexate in non-metastatic osteosarcoma of the extremities: a phase II trial in Japan

Abstract From 1997 to 2003, 40 patients (all <40 years of age) with non-metastatic osteosarcoma of the extremities were treated with OOS-D and definitive surgery. Two cycles of doxorubicin 90 mg/m2 plus cisplatin 120 mg/m2 and ifosfamide 15 g/m2 were given as neoadjuvant chemotherapy, and two cycles of doxorubicin/cisplatin and ifosfamide, and two cycles of high-dose methotrexate (10–12 g/m2) were given post-operatively. All patients underwent limb salvage surgeries, and 66% showed good response to neoadjuvant chemotherapy. With a median follow-up period of 117 months, 31 of the evaluable 40 patients were continuously disease-free, 7 were currently alive with no evidence of disease, and 2 died of disease. There was no local recurrence. The 5-year event-free and overall survival rates were 83 and 98%, respectively. The 10-year event-free and overall survival rates were 80 and 95%, respectively. The major form of toxicity was haematological one.

Skeletal metastasis in patients with gastric cancer

To clarify metastatic patterns, and histologic and radiologic features in skeletal metastases from gastric cancer, 48 patients were retrospectively analyzed. The mean age of the patients at the time of diagnosis of gastric cancer was 59 years. In 31 patients with a history of the radical surgery, the mean interval between surgery and diagnosis of skeletal metastasis was 14 months. The mean duration between diagnosis of skeletal metastasis and death was 60 days. Scintigraphic assessment showed that solitary osseous lesions were found in four patients, whereas the remaining 44 had multiple skeletal lesions. In 28 patients with bone-only metastases with absence of visceral metastases, a higher incidence of thoracolumbar metastases at the level nearest the stomach was found. The incidence of skeletal metastasis in each histologic type was intestinal in 19 and diffuse in 29. Radiologic examination revealed that the ratio between the presence and the absence of osteosclerosis was 1:2. Osteosclerosis was seen in three of 19 patients with intestinal type metastasis, whereas with the diffuse type 13 of 29 patients had osteosclerosis.

SKELETAL METASTASES FROM SOFT-TISSUE SARCOMAS

We reviewed 277 patients with soft-tissue sarcoma (STS) treated between 1975 and 1995 to study the incidence, distribution, time of appearance, and radiological findings of skeletal metastases. Of these, 28 (10.1%) had metastases within a mean period of 18.6 months after admission. The incidence of skeletal metastases differed among the histological subtypes of sarcoma; alveolar soft-part sarcoma, dedifferentiated liposarcoma, angiosarcoma, and rhabdomyosarcoma tended to show higher incidences. The regional bones close to the primary tumour were affected in 13 (46.4%) of the 28 patients, and the axial bones in 18 (64.3%). Radiologically, the metastatic bony lesions predominantly showed osteolytic changes, and there were pathological fractures in 21 of 44 lesions.

DNA Ploidy Pattern and Cell Cycle Stage of Tumor Cells in Soft-Tissue Sarcomas: Clinical Implications

Staining and counting of argyrophilic nucleolar organizer region (AgNOR), segments of DNA with ribosomal genes, is useful for estimation of the proliferative activity in soft tissue sarcoma (STS). The precise role of AgNOR in STS, however, is still uncertain. In the present study, ploidy pattern and stage of cell cycle were analyzed in 151 cases of STS in the extremities and trunk, and their correlation with AgNOR and utility as independent prognostic factors were estimated. For this, microspectrophotometric and flow-cytometric analyses were done on paraffin-embedded material from 84 and 111 cases, respectively. Fifty-five percent cases showed an aneuploid pattern with a less favorable prognosis. The range of the DNA index and percentage of cells in S + G2M phase were 0.89-2.04 (mean +/- SD, 1.23 +/- 0.32) and 5.4-83.7% (mean +/- SD, 32.95 +/- 17.92), respectively. Tumors having less than 40% cells in the S + G2M phase showed a favorable prognosis compared to those over 40%. Both the ploidy pattern and stage of the cell cycle showed a good correlation with the AgNOR count: a high frequency of cases having aneuploidy and S + G2M phase in the AgNOR high count group. These findings provide a theoretical base for explaining the utility of AgNOR for the estimation of proliferative activity. In multivariate analysis, only AgNOR counts were a prognostic factor among histologic factors reflecting proliferative activity of tumors. The DNA ploidy pattern and the stage of the cell cycle was proved not to be an independent factor for prognosis.

Florid periosteal reaction and focal fibrocartilaginous dysplasia

Abstract Focal fibrocartilaginous dysplasia (FFCD) is a rare condition causing tibia vara in childhood. It is characterized by progressive tibia vara in young children with a characteristic radiographic lesion. This paper is thought to be the first to describe FFCD exhibiting florid periosteal reaction at the time of presentation with a subtle faint osteolytic lesion in the diametaphysis of the proximal tibia.

Usefulness of Argyrophilic Nucleolar Organizer Staining for Predicting Prognosis of Patients with Recurrent Soft Tissue Sarcoma

Local recurrence of tumor is a common phenomenon in soft tissue sarcoma (STS) and may be accompanied by an increase in malignant potential. In the present study, an increase of proliferative activity in recurrent tumors compared to primary tumors was observed using a silver stain for nucleolar organizer regions (AgNOR), and its implication for predicting prognosis is assessed. 44 patients with STS showing local tumor recurrence were selected. Local recurrence was defined as new tumor growth more than 2 months after the initial surgery in the same region where the primary tumor occurred. All patients received surgery, followed in 11 patients by adjuvant radiotherapy and/or chemotherapy. The histologic subtype was malignant fibrous histiocytoma in 22 cases, synovial sarcoma in 5, leiomyosarcoma in 4, liposarcoma in 3, malignant schwannoma in 3, and others in 7. The interval between initial surgery and local recurrence ranged from 2 to 72 months. No patients changed from one histological subtype to another. Histological changes included an increase in mitosis, cellularity, and sclerosis in 43.2, 31.8, and 27.3%, respectively. The AgNOR count (mean +/- SD) in recurrent tumors (7.22 +/- 2.59) was significantly higher than that in primary tumors (5.58 +/- 2.28; p < 0.0057), clearly showing a tendency for an increase in proliferative activity during recurrence. The 5-year survival rate of patients with a marked increase (> 4) in AgNOR count (16.7%) was worse than with minor to moderate increases (60.0%; p < 0.02). Marked AgNOR increase was more frequently observed in the tumors located in the head and neck and retroperitoneum (40%) than in other sites (9%). Irrespective of the primary site of tumors, a marked AgNOR increase resulted in an unfavorable prognosis. Multivariate analysis of change in histologic factors including AgNOR, cellularity, mitotic counts, pleomorphism, myxoid change, necrosis, sclerosis, and tumor size showed that increase of AgNOR counts was significant (p < 0.05). The present findings suggest that AgNOR counts can be used as a prognostic factor in recurrent STS.