Gastrointestinal stromal tumors: Clinicopathological study of Chinese cases

In the present study, we reviewed 73 Chinese cases of gastrointestinal stromal tumor (GIST), and analyzed factors in evaluating malignant potential, in particular focusing on Ki-67 index and p53 expression to determine whether these can be used as prognostic indicators in GIST. The p53 positive rate was 50.7% and it was significantly higher in malignant (25/35; 71.43%) than in benign cases (13/38; 34.21%). A Ki-67 labeling index of >10% was also significantly different between malignant (23/35; 65.71%) and benign cases (14/38; 36.84%). In the cases in which the patient died, 15/21 and 14/21 cases showed expression of p53 and Ki-67, respectively; both had a higher expression than in surviving cases. Comparing the cases positive for both Ki-67 and p53 with those positive for Ki-67 or p53 alone, and those negative for both Ki-67 and p53, the latter demonstrated the best prognosis. The study also indicated that the malignant potential of GIST is correlated with the mitotic index (> or =1/10 high-power fields; HPF), tumor size (> or =5 cm), high cellularity, tumor invasive growth, tumor location, tumor hemorrhage and tumor necrosis.     

胃肠道间质瘤76例的临床病理及免疫组织化学特征

目的：探讨胃肠道间质瘤（GIST）的临床表现、病理组织形态学和免疫组织化学特点及良恶性参考指标。方法：用CD117、CD34等抗体,通过免疫组织化学EnVision法对原发性消化道间叶源性肿瘤进行研究,确诊76例GIST,并结合随访资料,对其生物学行为进行分析。结果：本组GIST均为成年人,年龄32－81岁（平均54岁）,男性39例,女性37例,发生于胃34例,小肠23例,结肠2例,直肠17例,最常见症状为腹部肿块、腹部胀痛不适及消化道出血。黏膜下生长者3例,浆膜外生长者25例,余48例主要位于肌壁。大体上,肿瘤较易出现出血、坏死、囊性变等继发性改变。镜下观察,梭形细胞型46例,上皮样细胞型9例,梭形／上皮样细胞混合型21例,呈交叉束状、弥漫片状、栅栏状、漩涡状、小巢状、器官样及假菊形团样排列,瘤细胞胞质空亮、淡伊红、轻至中度嗜伊红及略嗜碱,核梭形、卵圆、圆形或镰状。CD117和CD34多为弥漫强阳性,阳性率分别为98．7％、68．4％,α-平滑肌肌动蛋白（ α-SMA）、肌特异性肌动蛋白、S-100、蛋白基因产物9．5呈片状或局灶阳性,阳性率分别为25．0％、19．7％、23．7％、17．1％,波形蛋白均阳性,结蛋白、胶质纤维酸性蛋白、神经丝蛋白均阴性。76例GIST中,良性9例,交界性19例,恶性48例。良性及交界性获访20例均健在,恶性组获访34例,10例无瘤生存,10例复发及转移,14例死亡。各组之间术中黏连、瘤体直径大于5cm、核分裂象大于5／50HPF差异有显著性意义,肿瘤性坏死、核分裂象大于10／50HPF、细胞密集明显异型者均在恶性组。恶性组内,肿瘤性坏死或核分裂象大于5／50HPF者3年生存率的差异有显著性意义。结论：GISF好发于中老年人,肿瘤细胞形态多变,排列结构多样;免疫组织化学特征为CD117、CD34阳性,结蛋白阴性;除转移和浸润外,肿瘤性坏死、核分裂象大于10／50HPF、细胞密集明显异型等提示恶性,此外,术中粘连、瘤体直径大于5cm、核分裂象大于5／50HPF可作为良恶性参考指标。     

Gastrointestinal stromal tumors: DNA flow-cytometric study of 58 patients with at least five years of follow-up

Flow-cytometrically measured DNA content of 58 surgically resected gastrointestinal stromal tumors (GIST) was correlated with the lesions' histopathologic features and patients' survival. Aneuploid DNA patterns were found in 43 cases (74%), including 33 (76.7%) histologically malignant and 10 (23.3%) in the indeterminate category. DNA ploidy pattern was significantly correlated with mitotic count (less than 5/10 high power field (HPF) versus greater than or equal to 5/10 HPF, P = 0.04) and histologic grade (malignant versus indeterminate, P = 0.02). DNA content was not related to tumor size, site, or histologic patterns (epitheliod versus spindle). The patients' survival was significantly correlated with DNA content (P less than 0.001), histologic grade (indeterminate versus malignant, P = 0.02), and mitotic rate (less than 5/10 HPF versus greater than or equal to 5/10 HPF, P = 0.01). Multivariate regression analysis showed that DNA ploidy is an independent parameter in predicting the clinical outcome for patients with GIST.     

Increased c-kit (CD117) expression in malignant mammary phyllodes tumors.

Mammary phyllodes tumors are uncommon stromal neoplasms, and are divided into benign, borderline and malignant groups basing on histologic criteria. While benign phyllodes tumors may recur, borderline phyllodes tumors show higher propensity to recur locally and rarely metastasize, and malignant phyllodes tumors show even higher chances of local recurrences or distant metastases. c-kit is a proto-oncogene that encodes a tyrosine kinase receptor (CD117) and is a marker for gastrointestinal stromal tumors (GIST). With the advent of therapeutic agent targeted at this receptor for GIST, we investigated 179 phyllodes tumors (101 benign, 50 borderline, 28 malignant) for c-kit expression using immunohistochemistry. The staining was compared to the degree of malignancy, and to the degree of stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. The overall positive rate for c-kit was 29% (52/179) and 17% (17/101), 24% (12/50) and 46% (13/28), respectively, for benign, borderline malignant and frank malignant phyllodes and the differences between all categories were significant (chi2=13.844, P=0.001). In mammary phyllodes tumors, there was increasing c-kit expression with increasing degree of malignancy, up to 46% in malignant cases. This provides strong evidence that c-kit receptor mediated tyrosine kinase involvement in the pathogenesis of phyllodes tumors, and the therapeutic agent, STI571, Glivec, may be a potentially useful drug for its management.     

Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review

This paper reviews data on the prognosis of gastrointestinal stromal tumors (GISTs). These tumors are specific KIT-expressing and KIT-signaling-driven mesenchymal tumors, many of which have KIT-activating mutations. GISTs occur in the entire gastrointestinal (GI) tract and may also arise from the omentum, mesenteries, and retroperitoneum. They range from small benign tumors to sarcomas at all sites of occurrence. A KIT tyrosine kinase inhibitor, STI-571 (imatinib [Gleevec]; Novartis, Basel, Switzerland), has recently shown promise in the treatment of metastatic GISTs. Understanding the natural history of GIST before introduction of STI-571 will help assess the impact and position of this new treatment. The frequency of benign versus malignant GISTs varies between sites. Benign GISTs outnumber malignant GISTs in the stomach, whereas malignant GISTs are more common in the intestines. Tumors that have metastasized at presentation have a very poor prognosis. Traditionally, the 3 key prognostic factors have been mitotic rate, tumor size, and site. Tumors that are small (< or =2 cm) and show mitotic activity not exceeding 5 mitoses per 50 high-power fields (HPFs) have an excellent prognosis, probably independent of site, although this has not been shown specifically for all sites. In the stomach, most epithelioid GISTs are benign, provided that mitotic counts do not exceed 5/50 HPFs. However, a small proportion of tumors apparently lacking mitotic activity do metastasize. Tumors with a mitotic rate >5/50 HPFs usually have a malignant behavior. The Ki67 index may help identify tumors with malignant potential, but large site-specific series are not yet available. Genetic markers, including DNA-copy number changes, telomerase activity, and KIT mutation status, may be useful in more accurately identifying tumors with malignant potential.     

良性和恶性嗜铬细胞瘤的区别

目的　分析良性和恶性嗜铬细胞瘤在组织形态、免疫组织化学、DNA倍体、11q13和 1p的杂合子缺失 (LOH)及微卫星不稳定性 (MSI)方面的差别 ,试图找出能区别良、恶性或预测恶性潜能的指标。方法　对 2 2例临床确诊为良性 (12例 )或恶性 (10例 )的嗜铬细胞瘤 :(1)分析组织形态 ;(2 )免疫组织化学观察Ki 6 7、p5 3、嗜铬粒素A、S 10 0、增殖细胞核抗原及survivin表达 ;(3)用流式细胞术分析DNA倍体 ;(4 ) 12例附有正常组织的肿瘤 (7例良性 ,5例恶性 )用显微切割获取肿瘤和正常组织 ,分别提取DNA ;用 8种引物进行PCR扩增 ,分析 11q13和 1p的LOH及MSI。结果　全组 2 2例肿瘤均未见不典型核分裂象 ,核分裂象数除 1例恶性肿瘤为 2 3/ 10HPF外 ,余均≤ 1/ 10HPF ,2例恶性肿瘤有广泛坏死。良性组Ki 6 7阳性细胞百分率明显少于恶性组 ,良性与恶性组平均Ki 6 7阳性细胞百分率之比为 0 73%∶2 4 % ,差异有显著意义 ,DNA倍体良性与恶性组差异无显著性。 11q13和 1pLOHMSI良性和恶性组的差别由于例数少 ,未能达到统计学意义。结论　仅Ki 6 7阳性表达 >3%具有区别良恶性或预测恶性潜能的意义     

Ovarian epithelial tumors of borderline malignancy]

Ovarian tumor is known to show histological variation. Each tumor shows various clinical behavior. Ovarian epithelial tumors consist of several types of histological findings. Epithelial tumors can be classified into benign, borderline malignancy and malignant for their biological behavior. Recently the therapeutic effectiveness against ovarian cancer is increasing in order to establish the operation technique and development of chemotherapeutic method with cisplatin. Therefore it is important that borderline malignant tumors which are said to have a good prognosis be defined from obviously malignant tumors to evaluate accurately the effectiveness of the therapy against the ovarian cancer. On the other hand, borderline malignant tumors with characters of a malignant tumor, must be distinguished from benign adenoma because long-term follow up is required. However, it is difficult to make an exact histological diagnosis of benign adenoma, borderline malignancy and malignancy because the histological criteria of borderline malignancy is lacking in concreteness. The histological criteria should be defined more clearly and concretely. For example, mitotic counts per 10 HPF of borderline malignancy and DNA ploidy. Next, because of good prognosis, we need a quick therapeutic guide line for borderline malignancy, especially for stage I and young women.     

Small intestinal stromal tumors: A clinicopathologic study of 31 tumors

The biologic behavior of gastrointestinal stromal tumors Is difficult to predict, and they can be best studied in a site-specific fashion. The alms of this study are to analyze the clinicopathologic parameters and assess the prognostic value of p53 (DO-7) and KI-67 (MIB-1) immunoreactivitles in small intestinal stromal tumors (SIST). The hlstopathologic features of 31 SIST were assessed and categorized Into two groups as follows. Group A (clinically aggressive) In which death due to tumor, metastasis, recurrence or relapsed melena were seen (n = 15) and group B (clinically benign; n = 16). For both groups, the period of follow-up was 30–144 months. p53 overexpression was observed In four tumors (31%) In group A, and In none in group B. For groups A and B, the mean Ki-67 index was 16.8 ± 12.5 and 8.4 ± 12.6, respectively. Statistical analysis revealed that the significant predictors of malignancy were high cellularity (odds ratio (OR) = 999; 95% confidence interval (Cl) = 0–999); p53 overexpression (OR = 999; Cl = 0–999); size of tumor ± 35 cm (OR = 18.0; Cl = 1.9–171.9); ± 35 mltoses/50 high-power fields (HPF) (OR = 17.1; Cl = 1.8–165.9); pleomorphism (OR = 17.1; Cl = 1.8–165.9); and necrosis (OR = 11.9; Cl = 2.2–65.1; P <0.05). High Ki-67 index (≥ 8.4) had a marginal Impact on risk (OR = 4.1; Cl = 0.8–20.2; P = 0.08). In conclusion, high cellularity, p53 overexpression, size of tumor ± 35 cm, ± 35 mitoses/50 HPF, pleomorphism and necrosis are important parameters for the prediction of malignancy in SIST.     

Grading of meningeal solitary fibrous tumors/hemangiopericytomas: analysis of the prognostic value of the Marseille Grading System in a cohort of 132 patients

The finding that meningeal solitary fibrous tumors (SFTs) and meningeal hemangiopericytomas (HPCs) are both characterized by NAB2‐STAT6 gene fusion has pushed their inclusion in the WHO 2016 Classification of tumors of the central nervous system (CNS) as different manifestations of the same entity. Given that the clinical behavior of the CNS SFT/HPC spectrum ranges from benign to malignant, it is presently unclear whether the grading criteria are still adequate. Here, we present the results of a study that analyzed the prognostic value of an updated version of the Marseille Grading System (MGS) in a retrospectively assembled cohort of 132 primary meningeal SFTs/HPCs with nuclear overexpression of STAT6. The median patient follow‐up was 64 months (range 4–274 months); 73 cases (55%) were MGS I, 50 cases (38%) MGS II and 9 cases (7%) were MGS III. Progression‐free survival (PFS) and disease‐specific survival (DSS) were investigated using univariate analysis: the prognostic factors for PFS included MGS, extent of surgery, radiotherapy, chemotherapy and mitotic activity ≥5/10 high‐power field (HPF). Moreover, MGS, radiotherapy, mitotic activity ≥5/10 HPF, and necrosis were the prognostic factors measured for DSS. In multivariate analysis, extent of surgery, mitotic activity ≥5/10 HPF, MGS I and MGS III were the independent prognostic factors measured for PFS while necrosis, MGS III and radiotherapy were the independent prognostic factors for DSS. In conclusion, our results show that assessing the malignancy risk of SFT/HPC should not rely on one single criterion like mitotic activity. Therefore, MGS is useful as it combines the value of different criteria. In particular, the combination of a high mitotic activity and necrosis (MGS III) indicates a particularly poor prognosis.     

Gastrointestinal mesenchymal tumors - immunophenotypic classification and survival analysis

The current definition of gastrointestinal tumors (GIST) as CD117-positive mesenchymal tumors of uncertain malignant potential fails to include a number of cases with similar histology. In an attempt to improve the classification of these neoplasms, we conducted an immunohistochemical analysis of 244 mesenchymal tumors with histological features of GIST. According to their immunophenotype, the tumors were classified as GISTs, which are characterized by CD117 (c-kit) expression; gastrointestinal CD117-negative CD34 positive stromal tumors (GINST); alpha-smooth muscle actin and/or desmin positive gastrointestinal leiomyogenic tumors (GILT); S-100 and glial fibrillary acidic protein positive gastrointestinal glial/schwannian tumors (GIGT); gastrointestinal neuronal/glial tumors (GINT), which are positive for S-100/glial fibrillary acidic protein plus neuronal/glial markers; and gastrointestinal fibrous tumors (GIFT), which are only vimentin positive. The most common type of tumors were GIST, followed in order of frequency by GINST, GILT, GIGT, GIFT, and GINT. GISTs did not show any preferential location, whereas GINSTs occurred almost exclusively in the stomach and duodenum, and GILTs preferentially in the large intestine. Over a median follow-up period of 71 months, malignant behavior, i.e., metastatic spread, was observed in all tumor types except GINTs. Malignancy was associated with distal gut location, high mitotic activity, large tumor size, and nuclear pleomorphism, though none of these criteria alone discriminated between benign and malignant. Kaplan-Meier analysis of disease-specific survival showed significant differences in the long-term outcome of the newly defined subgroups. We conclude that, despite strong morphological similarities, gastrointestinal mesenchymal tumors are heterogeneous in their immunophenotype and biology.     

Predicting Metastatic Risk of Gastrointestinal Stromal Tumors: Role of Cell Proliferation and Cell Cycle Regulatory Proteins

Gastrointestinal stromal tumors (GIST) are a heterogeneous group of neoplasms whose biologic behavior is difficult to predict. The aim of this study is to evaluate the prognostic value in GIST of some oncoproteins involved in regulation of cell proliferation. Tumor size, mitosis, necrosis, and p53, c-myc, and bcl-2 protein expression of 32 GIST were studied. Proliferative index was assessed with Ki67. The 32 cases were grouped into the following clinical categories: (1) clinically benign (BN) were defined as disease-free survival greater than 3 years (n=10); (2) clinically malignant (MN) in which local recurrence or metastasis occurred regardless of the follow-up time (n=15); and (3) clinically indeterminate (ID) owing to follow-up <3 years without metastasis or local recurrence (n=seven). Discriminant analysis was used to allocate any tumor to one of the two prognostic groups (BN or MN). In univariate analysis all six factors studied above proved to be of significant prognostic value. Using a multivariate stepwise discriminant analysis to take into account the interrelationship between factors, we found that c-myc expression was the most important prognostic factor, followed, in order of statistical weight, by size and Ki67. These were combined to define a discriminant score ([10.75 x c-myc]+[0.39 x size]+[0.078 x Ki67]-15.54=score), which was capable of correctly identifying tumors in our series whose known clinical behavior was BN or MN in 92% of the cases. The classification score was applied subsequently to the seven clinically ID cases: Three (42.9%) were predicted as BN, and four (57.1%) were predicted as MN. Both expression of oncoprotein c-myc and the proliferative index provide prognostic information in GIST, in addition to morphologically established prognostic factors such as size. These factors in a discriminant analysis proved to be useful for the clinical classification of GIST into BN or MN and to predict the clinical outcome of clinically ID tumors. Int J Surg Pathol 8(2):133-144, 2000     

Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade

Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (> or =5 cm), mitotic counts (> or =5/50 high-power fields), Ki-67 LI (> or =4.92%), cyclin A LI (> or =1.61%), and cdc2 LI (> or =1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.     

Overexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline ovarian tumors

Ovarian epithelial tumors are classically divided into benign, malignant, and borderline or of low malignant potential. It is controversial whether this last group of tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor. By inhibiting cdks, p21WAF1/CIP1 blocks the G-1 to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these tumors, we studied the expression of p53, Ki-67, MDM2, and p21WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these proteins in 19 cystadenomas (8 serous and 11 mucinous), 40 borderline tumors (31 serous and 9 mucinous), and 18 serous carcinomas of the ovary. p21WAF1/CIP1 was expressed in 7 of 19 (37%) benign cystadenomas, 32 of 40 (80%) borderline tumors (93.5% of serous and 33% of mucinous), and in 9 of 18 (50%) serous carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign cystadenomas, all borderline tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous carcinomas stained in more than 50% of tumor cells. p53 was absent in all but 1 of the cystadenomas, was expressed in 9 of 40 (22.5%) borderline tumors (25.8% of serous and 11% of mucinous), and in 10 of 18 (55%) carcinomas. All 11 implants of serous borderline tumors expressed p21WAF1/CIP1. Most serous borderline tumors expressed higher levels of MDM2 compared with the benign cystadenomas and carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline tumors of the ovary and their implants, which suggests that these cell cycle control proteins are important in these tumors and may be related to tumor progression. Low expression of p53 protein in serous borderline tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these tumors, in contrast with carcinomas, in which high expression of p53 has been related to mutations of this gene.     

Gastrointestinal stromal tumor of the digestive organs: a histopathologic study of 31 cases in a single Japanese institute

The author herein reports histopathologic features of 31 surgical cases of gastrointestinal stromal tumor (GIST) of the digestive organs. The 31 cases of GIST were diagnosed in our pathology laboratory. They consisted of 24 cases of gastric GIST, 1 case of hepatic GIST, 1 case of small intestinal GIST, 4 cases of colon GIST, and 1 case of rectal GIST. The age of the patients ranged from 56 year to 84 years with a mean of 71 years. Male to female ratio was 21:10. The presenting symptoms were gastrointestinal bleeding in 13 cases, abdominal pain and discomfort in 13 cases, and asymptomatic in 5 cases. Endoscopy and imaging modalities including US, CT and MRI were useful to detect the tumors in all cases, and biopsies confirmed the GIST diagnosis in 21 cases. The size of GIST ranged from 1 cm to 12 cm with a mean of 4.3 cm. Grossly, 23 cases were submucosal tumors, 6 serosa-side tumors, 1 solid tumor in the liver, and 1 rectal polyp. Histologically, 28 cases were of spindle cell type and 3 of epithelioid type. According to mitotic counts and tumor size, the malignant risk was very low in 4 cases, low in 14 cases, intermediate in 9 cases, and high in 4 cases. Immunohistochemically, all cases were positive for KIT and vimentin, 30 cases for CD34, and 4 cases for α-smooth muscle actin. None were positive for desmin and S100 protein. Ki-67 labeling ranged from 2% to 18%. P53 protein was negative in all cases. PDGFRA was positive in 20 cases among 24 cases examined. Genetic analysis using PCR-direct sequencing method was performed in 5 GISTs; all the 5 GISTs showed point mutations or deletions in KIT gene, but did not in PDGFRA gene. The 5 cases of GIST were positive for PDGFRA protein, suggesting that PDGFRA overexpression is not associated with PDGFRA gene mutations. Four of the 31 cases showed metastases. The chemotherapy was imatinib mesylate in 6 cases, and none in 25 cases. Four cases of high risk died of GIST, and 27 cases are alive now without tumors.     

Immunohistopathological and molecular genetic features of a case in which gastrointestinal stromal tumor recurred five times

Gastrointestinal stromal tumor (GIST) is a distinct group of mesenchymal neoplasms recently shown to exhibit differentiation toward interstitial cells of Cajal. Although previous studies have shown that the clinical outcome of patients with GIST is associated with mitotic activity, the proliferation index determined by the Ki-67 labeling index, immunophenotype (CD34 and/or p53) and mutation in exon 11 of the c-kit, a definitive discrimination between benign and malignant GIST has not yet been established. We report a patient in whom malignant GIST in the abdomen recurred five times. In this case, the primary GIST and the five recurrent GIST were associated with c-kit immunoreactivity, but the mitotic index of the GIST tended to be increasingly higher with subsequent recurrences. Mutational analysis of the c-kit revealed that the primary and recurrent GIST were mutant-negative. These data indicated that 'morphologically appearing benign' tumors with lower proliferative parameters may also have the capacity of metastasis and recurrence.     

Mitotically active leiomyomas of the uterus.

A series of 15 uterine smooth muscle tumors with histologic features of typical leiomyomas, except for the presence of mitotic activity exceeding 4 mitotic figures per 10 high-power fields (HPF), were studied. The patients' ages ranged from 25 to 50 years (median, 37 years). At least 60% of the tumors were submucosal. The maximum dimension of the tumors ranged from 1.3 to 8.0 cm (median, 3.8 cm). On gross examination, the tumors appeared to be generally unremarkable. By definition, none had cytologic atypia. Mitosis counts were performed in the most active areas by two methods. Counts ranged from 5 to 15 mitotic figures per 10 HPFs when the highest count in any single set of 10 HPFs was recorded (method A) and from 4.2 to 10.2 mitotic figures per 10 HPFs when the average count from 50 consecutive HPFs was determined (method B). Treatment included hysterectomy in eight patients, myomectomy followed by hysterectomy in one, and myomectomy only in six. All but one patient with evaluable endometria were in the secretory phase of the menstrual cycle. Follow-up periods ranged from 6 months to 10.5 years (mean, 2.5 years; median, 2.1 years). None developed local recurrences or metastases. The benign clinical behavior of such tumors warrants the designation of mitotically active leiomyoma rather than smooth muscle tumor of uncertain malignant potential or low-grade leiomyosarcoma.     

Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers

Bcl-2 and p53 gene products have been both linked to cell death by apoptosis. In the present study, we examined the relationship of Bcl-2 and p53 protein expression, p53 mutation and apoptosis in normal human ovaries and different types of human ovarian epithelial tumors by immunohistochemical localization, in situ terminal transferase-mediated dUTP nick end labeling and polymerase chain reaction-single strand conformation polymorphism. It was found that Bcl-2 expressed strongly in the surface epithelium of normal ovaries and benign and borderline ovarian tumors but weakly in the malignant tumors. On the contrary, strong protein expression of p53 was found in 54% (25/46) of the malignant epithelial tumors examined but similar expression of p53 was not observed in borderline and benign tumors and normal ovarian surface epithelium. A significant inverse correlation between Bcl-2 and p53 expression was found in the malignant ovarian tumors examined. p53 gene mutation at exons 5-11 was however not a pre-requisite for p53 expression in both borderline and malignant tumors. Apoptotic activities, as reflected by apoptotic indices, were low in normal ovarian surface epithelium and benign tumors but were increased in borderline and malignant tumors, with the highest average apoptotic index found in grade III malignant tumors. Statistical analyses showed a positive correlation between apoptosis and p53 expression, but similar correlation was not found between apoptosis and Bcl-2 expression. Our results also indicate that although expression of Bcl-2 is important during ovarian carcinogenesis, the Bcl-2 protein may have other roles to play apart from being a modulator of apoptosis in human ovarian epithelial cancers.     

Cystosarcoma phyllodes of the breast: histologic features, flow cytometric analysis, and clinical correlations.

The histologic features of 187 cases of cystosarcoma phyllodes of the breast were reviewed. The tumors were divided into histologically benign, borderline, and malignant categories. Correlation with clinical outcome was available in 100 cases. Overall rate of local recurrence was 28% (benign, 27%; borderline, 32%; malignant, 26%). Metastases occurred in eight of 100 cases (two borderline and six malignant). Although no histologic features were predictive of local recurrence, stromal overgrowth, mitotic rate greater than 15 per 50 high-power fields, and cytologically atypical stromal cells characterized seven of the eight tumors that metastasized. These features were not evident in the eighth case. Flow cytometric analysis of eight tumors (four benign, two borderline, and two malignant) showed discordance between histology and DNA content in three cases. There was slightly better correlation of histology and S-phase fractions. Based on these results demonstrating the difficulty in predicting clinical outcome, wide local excision remains an appropriate initial method of treatment. Simple mastectomy may be necessary for very large tumors and should be considered in histologically malignant tumors and cases with multiple recurrences, since some recurrent tumors in this series showed increasingly unfavorable histologic features.     

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors of the gastrointestinal tract. Activating KIT or PDGFRA (platelet-derived growth factor receptor alpha) mutations have been shown to be a major force in GIST pathogenesis. Recently, a previously undescribed N659K PDGFRA exon 14 mutation has been reported in GISTs. The purpose of this study was to evaluate the frequency of GISTs with PDGFRA exon 14 mutations and define the clinicopathologic profile of such tumors. In all, 200 GISTs negative for mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were evaluated for PDGFRA exon 14 mutations by PCR amplification and direct sequencing. Mutations were found in 11 of 119 (9%) gastric GISTs. None of the 81 GISTs from other than gastric location had such a PDGFRA mutation. A majority of these mutations (eight cases) represented simple 2125C>A or C>G missense mutations, leading to substitution of the lysine for asparagine (N659K). However, in two cases, 2123A>T missense mutations leading to substitution of the tyrosine for asparagine (N659Y) was found instead. Of 11 PDGFRA N659-mutant GISTs, 10 had pure epithelioid morphology. One tumor had mixed, predominantly spindle and focally epithelioid cell morphology. Frequency of PDGFRA N659-mutant GISTs among pure epithelioid GISTs was almost 19%. Immunohistochemically, the majority (64%) of these tumors lacked KIT expression or showed only focal scattered KIT positivity. Tumor size ranged from 2.5 to 16 cm (average 7.1 cm). Low mitotic activity, 5 cm tumors. Based on mitotic activity and tumor size, six tumors were classified as probably benign with very low malignant potential. Low to moderate malignant potential and high malignant potential was suggested in three and two tumors, respectively. In four cases with moderate or high malignant potential GISTs, a long-term follow-up (average 235.5 months) showed favorable course of disease.     

腹内胃肠道外间质瘤临床病理、免疫组织化学及分子遗传学研究

目的探讨腹内胃肠道外间质瘤(extra-gastrointestinal stromal tumors,EGIST)临床病理、免疫组织化学、分子遗传学特点及鉴别诊断。方法用CD117、CD34为主的一组抗体对消化道外腹腔软组织原诊断为平滑肌瘤、平滑肌母细胞瘤及平滑肌肉瘤等病例进行研究,获得9例EGLST,其中5例检测了c-kit基因11号外显子序列。结果患者中男性5例,女性4例,年龄38～72岁,平均61．7岁,其中肠系膜4例,网膜2例,腹膜后2例,1例位于脾门,肿瘤直径5～23cm,平均12．9cm。梭形细胞为主型7例,上皮型1例,混合型1例。此组抗体表达分别为CDll7(8／9)、CD34(5／9)、平滑肌肌动蛋白(d—SMA,3／9)、肌特异性肌动蛋白(MSA,4／9)、结蛋白(0／9)、s-100蛋白(1／9)、蛋白基因产物9．5(PGP9．5,1／9)。2例有c-kit基因11号外显子杂合性突变。交界性2例,分别存活8年和11年,恶性7例,1例无瘤生存4年,1例1年后死于肝转移,1例术后3年及4年两次复发,2例失访,2例随访中。结论消化道外腹腔软组织及腹膜后亦可发生符合GIST形态学、免疫表型及分子生物学特征的原发性间质瘤,生物学行为以交界性及恶性多见,肿瘤性坏死、核分裂象≥5／50HPF及细胞明显异型性对判断恶性有重要参考价值。需与相同部位的平滑肌肉瘤、恶性神经鞘膜瘤等鉴别。