Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases.

Gastrointestinal stromal tumors (GISTs), the specific KIT-positive mesenchymal tumors of the gastrointestinal tract, have been sporadically reported in the rectum, but there are few clinicopathologic series. In this study we analyzed the clinicopathologic features of 133 anorectal GISTs, 3 intramural leiomyomas (LMs), and 8 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. Ninety-six GISTs were documented as KIT-positive and three additional ones as CD34-positive. Thirty-four tumors were included by their histologic similarity to KIT- or CD34-positive cases. GIST-specific c-kit gene mutations, mostly in exon 11, were documented in 18 of 29 cases (62%). The GISTs occurred in adults with the age range of 17-90 years (median 60 years) with a significant male predominance (71%). The tumors ranged from small asymptomatic intramural nodules to large masses that bulged into pelvis causing pain, rectal bleeding, or obstruction. They were mostly highly cellular spindle cell tumors; four tumors had an epithelioid morphology. The tumors coexpressed CD34 and KIT and were rarely positive for smooth muscle actin or desmin and never for S-100 protein. Seventy percent of patients with tumors >5 cm with more than 5 mitoses/50 high power fields (HPF) (n = 31) died of disease, whereas only one tumor <2 cm with <5 mitoses/50 HPF (n = 21) recurred and none caused death. Long latency was common between primary operation and recurrences and metastases; either one occurred in 60 of 111 patients with follow-up (54%). Distant metastases were in the liver, bones, and lungs. Three benign actin- and desmin-positive and KIT-negative intramural LMs, similar to those seen in the esophagus, were identified. There were eight LMSs, six of which formed a polypoid intraluminal mass and were actin-positive and KIT-negative. Despite high mitotic counts, only one LMS patient died of disease. A great majority of rectal smooth muscle and stromal tumors are GISTs, which have a spectrum from minimal indolent tumors to overt sarcomas. Intramural LMs are exceptional, and true LMSs are rare, and similar to colonic ones, often present as intraluminal polypoid masses that appear to have a better prognosis than GISTs with similar mitotic rates.     

胃肠间叶源性肿瘤210例临床病理及免疫组织化学分析

目的分析胃肠间叶源性肿瘤(GIMT)的临床病理及免疫组织化学(免疫组化)特征,探讨各项诊断指标在鉴别诊断中的价值。方法对北京大学人民医院原病理诊断为GIMT的病例进行回顾性分析,通过连续切片CD117、CD34、Desmin、SMA、PS100五联染色的方法观察免疫组化表型,结合临床、病理资料及苏木精-伊红染色,重新确认诊断。结果210例GIMT经复习后,确诊为胃肠间质瘤(GIST)127例(60.5%),平滑肌(肉)瘤33例(15.7%),神经源性肿瘤27例(12.8%),其他GIMT 23例(11.0%)。GIST与平滑肌肿瘤患者男女性别比例相当,神经源性肿瘤和其他GIMT男性高于女性。GIST的好发部位依次是胃(51.2%)、小肠(19.7%)、食管(11.0%)、结直肠(10.2%);平滑肌(肉)瘤好发部位为食管(15/33,45.5%),神经源性肿瘤好发于腹膜后(20/ 27,74.1%)。GIST常见的临床首发症状依次为消化道出血36例(28.3%)、腹痛27例(21.3%)、腹部包块24例(18.9%),GIST之外的GIMT均无消化道出血的首发症状。79.5%的GIST和72.7%的平滑肌(肉)瘤肿瘤局限;33.3%的神经源性肿瘤侵及邻近器官或组织;GIST之外的GIMT均无远处转移。GIST细胞形态中梭形细胞占72.5%,上皮样细胞占11.8%,多形性细胞占15.7%:平滑肌(肉)瘤的梭形细胞占94.0%。GIST免疫组化CD117染色阳性率93.7%,CD34阳性率69.3%。Desmin阳性率13.4%,SMA阳性率12.6%,PS100阳性率10.2%。平滑肌(肉)瘤Desmin阳性率78.5%、SMA阳性率63.6%,而CD117、CD34和PS100阴性。神经源性肿瘤88.9%为PS100弥漫强阳性表现。结论GIMT以GIST为主,GIST与平滑肌(肉)瘤、神经源性肿瘤在首发症状、好发部位、生物学行为和免疫表型等方面具有一定的差异,免疫组化检测是GIMT鉴别诊断的重要手段。     

Gastrointestinal stromal tumors express ras oncogene: a potential role for diagnosis and treatment

BACKGROUND: Gastrointestinal stromal tumors (GISTs) constitute the largest category of nonepithelial neoplasms of the gastrointestinal tract. Histologically, they have a spindle cell appearance but stain by immunohistochemistry for the proto-oncogene, c-kit (CD117). There is some evidence that phosphorylation of these receptors leads to a cascade that may activate the ras/mitogen-activated protein kinase pathway, which may, in turn, allow other oncogenes to become active. HYPOTHESIS: Immunohistochemical staining pattern of GISTs will aid in their differentiation from other spindle cell tumors and predict clinical outcome in patients. DESIGN AND SETTING: Retrospective review of patient records and paraffin block specimens of spindle cell tumors. PATIENTS: We have identified 65 patients with spindle cell tumors of the gastrointestinal tract at our institution in the past 10 years. Tumors were diagnosed by their morphology as leiomyomas, leiomyoblastomas, or leiomyosarcomas. MAIN OUTCOME MEASURES: CD117 and ras p21 were stained by immunohistochemistry on formalin-fixed, paraffin-embedded sections of normal and tumor tissues. RESULTS: Of the 65 patients, there were 23 patients diagnosed as having GIST confirmed by CD117 expression and 42 patients without GIST. Gastrointestinal stromal tumor samples of 17 (77%) of 22 patients stained positive for ras protein compared with 0 of 27 patients with leiomyomas (P<.001). CONCLUSIONS: To our knowledge, this study is the first to demonstrate that GISTs stain positive for ras p21. This molecular trait may be a useful diagnostic tool in addition to the c-kit (CD117) to separate GISTs from leiomyomas and leiomyosarcomas. In the future, ras inhibitors may potentially be a therapeutic to treat GISTs.     

Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases.

Gastrointestinal stromal tumor or smooth muscle tumor (GIST) is the designation for a major subset of gastrointestinal mesenchymal tumors that histologically, immunohistochemically, and genetically differ from typical leiomyomas, leiomyosarcomas, and schwannomas. Because GISTs, like the interstitial cells of Cajal, the gastrointestinal pacemaker cells, express CD117 (c-kit protein), the origin of GISTs from the interstitial cells of Cajal has been recently proposed. Comparison of GISTs primary in the omentum and mesentery to GISTs primary in the tubular gastrointestinal tract is of particular diagnostic and histogenetic interest in view of the possible similarity of these tumors with the GIST group. In this study, we analyzed 14 omental and 12 mesenteric primary mesenchymal tumors representing smooth muscle tumors or GISTs. These tumors were phenotypically compared with gastric and small intestinal GISTs, leiomyomas of the esophagus, and leiomyosarcomas of the retroperitoneum. Most (13 of 14) omental and mesenteric (10 of 12) tumors showed histologic features similar to GISTs with elongated spindle cells or epithelioid cells with high cellularity; most of these tumors showed low mitotic activity. Omental and mesenteric GISTs were typically positive for CD117 and less consistently for CD34. They often showed alpha-smooth muscle actin reactivity but were virtually negative for desmin and S-100 protein. One omental and two mesenteric tumors showed features of leiomyosarcoma with ovoid, less elongated nuclei, cytoplasmic eosinophilia; all these tumors had significant mitotic activity. These tumors were positive for alpha-smooth muscle actin and two of them for desmin, but all were negative for CD34 and CD117, similar to retroperitoneal leiomyosarcomas. Tumor-related mortality occurred in the group of mesenteric GISTs, but not in the group of omental GISTs. In contrast, all three patients with a true leiomyosarcoma of the omentum or mesentery had documented liver metastases or died of tumor. In summary, we show that tumors phenotypically identical with GISTs occur as primary tumors in the omentum and mesentery. The occurrence of CD117-positive tumors outside the gastrointestinal tract militates against an origin of these tumors exclusively from the interstitial cells of Cajal.     

Gastrointestinal stromal tumors,intramural leiomyomas,and leiomyosarcomas in the duodenum: a clinicopathologic,immunohistochemical, and molecular genetic study of 167 cases

In this study we analyzed the clinicopathologic features of duodenal smooth muscle or stromal tumors, including 156 GISTs, 6 leiomyomas (LMs), and 5 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. GISTs were documented as KIT positive (n = 109); 47 tumors were also included because of their histologic identity to KIT-positive cases. GIST-specific c-kit gene mutations were documented in exon 11 in 9 of 30 cases (30%) and exon 9 in 4 of 30 cases (13%). The GISTs occurred in patients with an age range of 10-88 years (median 56 years); 54% were male. Ten patients had neurofibromatosis type I; six of them had multiple GISTs. The GISTs ranged from small asymptomatic intramural or external nodules to large masses that extended into the retroperitoneum (median size 4.5 cm). They were mostly spindle cell tumors; three malignant GISTs had an epithelioid morphology, and 81 cases had skeinoid fibers. The tumors often coexpressed CD34 and KIT (54%) and were variably positive for smooth muscle actin (39%) and S-100 protein (20%) but never for desmin. A total of 86% of patients with tumors >5 cm with >5 mitoses/50 high power fields (HPF) (n = 21) died of disease, whereas no tumor <2 cm with <5 mitoses/50 HPF (n = 12) recurred or caused death. Long latency was common between primary operation and recurrences or metastases; either one occurred in 49 of 140 patients with follow-up (35%). No formula could accurately predict metastases, which occasionally developed even if mitotic activity was <5/50 HPF and size <5 cm. Metastases were in the abdominal cavity, liver, and rarely in bones and lungs but never in lymph nodes. Four actin- and desmin-positive and KIT-negative benign intramural LMs were similar to those more often seen in the esophagus. There were five LMSs, one of which formed a polypoid intraluminal mass; all were actin positive and KIT negative. The great majority of duodenal mesenchymal tumors are GISTs, which have a spectrum from small indolent tumors to overt sarcomas. LMs and LMSs are rare.     

Gastrointestinal stromal tumors (GIST) of the stomach as a cause of upper gastrointestinal bleeding

Gastrointestinal stromal tumors (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. GIST is currently defined as a gastrointestinal tract mesenchymal tumor containing spindle cells (less commonly epitheloid cells or rarely both) and showing CD 117 (c-kit protein) positivity in more than 95% of cases. Although they may arise throughout the gut, the commonest site are stomach (60-70%), small intestine (20-30%), colorectum (5%) and esophagus (up to 5%). Rarely, GISTs develop in the retroperitoneum, omentum or mesentery. GIST originates from the intestinal cell of Cajal (ICC). ICCs are located in and around the myenteric plexus and are thought to function as intestinal pacemaker cells. Historicaly, GIST were often misclassified as leiomyomas or leiomyosarcomas. Subsequently, it has been determined that GISTs have distinct ultrastructural features and immunophenotypical markers compared with smooth muscle and smooth muscle tumors. GIST predominantly occur in middle aged and older patients, with no significant difference in the sex incidence. Data from the recent population study suggest an incidence of about 10-22 cases per million persons per year. Clinical presentation of GIST varies widely, and depends on tumor size and location. GISTs that caused symptoms tended to be larger with an average size of 6cm versus 2cm for asymptomatic GISTs. Symptoms are most commonly related to mass effect or bleeding. GISTs can grow very large before producing symptoms. Commonest symptom of gastric GIST is manifest or occult bleeding. Abudant, life-threateting bleeding that require urgent surgery is rare. For patient with primary, localized, nonmetastatic GIST, complete surgical resection represents the only chance for cure. Lymhadenectomy is not necessary, because lymph node metastasis is very rare. The 5 year survival rate in patients with resected primary GISTs ranges from 48-65%. Conventional chemotherapy and radiation therapy is ineffective in the treatment of GIST. Imatinib mesilate (a tyrosine kinase inhibitor) was confirmed to be effective against metastatic or unresectable GISTs.     

Tumors of the Rectum and Anal Canal

This collective review includes all available case reports of smooth muscle (stromal) tumors of the rectum and anal canal in the world literature. When compiling this review we endeavored to present cumulative and recently collected data of both benign and malignant smooth muscle tumors found in the literature spanning the period from 1881 to 1996, which totaled 432 leiomyomas (LMs) and 480 leiomyosarcomas (LMSs) of the anus and rectum. The peak age of frequency for LMs was 40 to 59 years and 50 to 69 years for LMSs; men were slightly more likely to develop both benign and malignant anorectal smooth muscle tumors than women. Intraluminal growth of both LMs and LMSs was more frequently seen than extraluminal or intramural patterns, and tumors were more likely to be found in the rectum than in the anus. Patients with LMs presented most commonly with gastrointestinal (GI) bleeding, a palpable mass, or anorectal pain. As with smooth muscle tumors in other areas of the alimentary tract, symptoms likely persisted for less than 1 year prior to diagnosis. As was also the case for these neoplasms in other GI locations, LMSs tended to be larger than LMs. Approximately 20% of LMSs reported from 1881 to 1996 had metastasized at diagnoses. The local recurrence rate for resectable tumors was more than 80%, exceeding the propensity of LMSs in other areas of the GI tract to recur.     

胃肠间质瘤135例临床诊治分析

目的探讨胃肠道平滑肌肿瘤与胃肠间质瘤(GIST)的关系及外科治疗的效果。方法重新调出1993-2003年间收治的资料完整的86例胃肠道平滑肌瘤或平滑肌肉瘤患者的病理组织重新病理复检,结合2000年1月至2005年7月确诊GIST的71例病例资料进行分析。并完成随访。结果86例原诊断胃肠道平滑肌瘤或平滑肌肉瘤的患者共有78例完成免疫组化检测,有64例(82.1%)被纠正诊断为GIST。共计135例GIST患者中,男性65例,女性70例;平均发病年龄53岁。均接受手术治疗,130例(96.3%)为完全切除;术后总体5年生存率为79.7%。完全切除者术后总体生存率与首诊转移、肿瘤大小、核分裂和术后复发转移有关(P<0.01);无病生存率的多因素回归分析中发现,完全切除术后无病生存率与首诊已有转移和核分裂数有关(P<0.01)。结论既往胃肠道平滑肌肿瘤大部分应纠正诊断为GIST。GIST以外科治疗为主。完全切除很重要。首诊肿瘤转移和核分裂数是独立的预后因素。     

Gastrointestinal stromal tumors and leiomyosarcomas in the colon: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases

Gastrointestinal stromal tumors (GISTs), mesenchymal tumors largely specific for the gastrointestinal tract, have been well defined in the stomach and small intestine, but have not been extensively documented or contrasted with true smooth muscle tumors in the colon. This study was undertaken to determine the clinicopathologic features of GISTs of the colon, excluding the rectum, and to compare them with leiomyosarcomas (LMSs) of the same location. A total of 37 colonic GISTs and seven LMSs from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki were analyzed. The GISTs occurred predominantly in adults older than 50 years of age (median, 67 yrs), and most were histologically malignant; four small benign tumors (< or = 1 cm) were incidentally detected, and 10 others had minimal mitotic activity (five or fewer mitoses per 50 high-power fields). The colonic GISTs were typically transmural tumors with frequent intraluminal and outward bulging components. Histologically, they usually showed a spindle cell pattern (92%), whereas 8% were epithelioid. Most tumors (19 of 25) were positive for CD117 (KIT) and for CD34 (16 of 27); six tumors coexpressed alpha-smooth muscle actin and CD117; none showed desmin or S-100 protein. C-kit mutations in exon 11 were seen in 5 (36%) of 14 colonic GISTs. None of the patients with incidental small tumors had a recurrence, whereas 2 of 10 patients with tumors larger than 1 cm but minimal mitotic activity died of the disease with liver metastasis. Nearly all patients whose tumor was larger than 1 cm and showed more than five mitoses per 50 high-power fields died of disease; half had evidence of metastasis. LMSs were typically intraluminally bulging, polypoid masses that showed a histologic likeness to differentiated smooth muscle cells. They occurred in five men and two women with a median age of 61 years. Most LMSs were high-grade histologically and showed smooth muscle actin, desmin, or both. All were negative for CD34 and CD117 and lacked c-kit mutations. Five of the seven patients died of disease, and two had a long-term survival, despite high mitotic activity. These results show that KIT-positive GISTs are more common than LMSs of the colon, and these tumor groups have clinicopathologic differences that warrant their separation.     

h-Caldesmon expression effectively distinguishes endometrial stromal tumors from uterine smooth muscle tumors

Distinction of endometrial stromal neoplasms from cellular smooth muscle tumors of the uterus is sometimes difficult. Immunohistochemistry is often not helpful because muscle actins and desmin are expressed in both neoplasms. This study's goal was to determine whether h-caldesmon, a smooth muscle-specific isoform of a calcium, calmodulin, and actin binding protein, could effectively distinguish endometrial stromal tumors from uterine smooth muscle tumors. The authors analyzed immunohistochemical expression in 24 endometrial stromal neoplasms (21 sarcomas and three nodules), 29 leiomyosarcomas, 32 leiomyomas (10 "usual," 14 cellular leiomyoma, and eight "highly cellular" types), 40 myometria, and 25 endometria. h-Caldesmon was diffusely positive in all myometria, leiomyomata, and leiomyosarcomas. Of note, 16 leiomyosarcomas (55%) were positive for h-caldesmon in more than 50% of tumor cells. In five "highly cellular" leiomyomas, h-caldesmon expression was markedly decreased or absent in areas morphologically resembling endometrial stromal tumors, raising the possibility that these tumors may be mixed smooth muscle-endometrial stromal neoplasms. In contrast, h-caldesmon expression was absent in all endometria and endometrial stromal neoplasms apart from accompanying small vessels. Desmin was diffusely positive in all myometria and leiomyomata. The fraction of cells expressing desmin was greater than that of h-caldesmon in only 10% of leiomyosarcomas. Focal desmin expression was also present in eight of 25 (32%) endometria and 12 of 24 (50%) endometrial stromal neoplasms. h-Caldesmon appears to be a more sensitive and specific marker of smooth muscle differentiation in the uterus than desmin and may be a useful tool for distinguishing and classifying uterine mesenchymal tumors.     

Microscopic gastrointestinal stromal tumors in esophageal and intestinal surgical resection specimens: a clinicopathologic, immunohistochemical, and molecular study of 19 lesions

Microscopic gastrointestinal stromal tumors (GISTs) (synonyms: sporadic interstitial cell of Cajal hyperplasia, seedling GISTs, minimal GISTs) are common incidental findings in gastroesophageal resections (9% to 35%). To our knowledge, their frequency, clinicopathologic features, and molecular pathogenesis from nongastroesophageal sites have so far not been sufficiently analyzed. We studied 19 lesions from distal esophagus (n=8), gastroesophageal junction (n=2), sigmoid colon (n=5), and vermiform appendix, cecum, rectum, and small intestine (1 each). Microscopic GISTs were detected in 0.2%, 0.1%, and 0.01% of routinely processed resection specimens from sigmoid colon, vermiform appendix, and rectum, respectively. Patients were 11 men and 8 women with a mean age of 66 years (range, 57 to 86 y). Thirteen patients had GI cancers and 5 had diverticular disease. None has a family history of GIST or features of neurofibromatosis 1. Lesions were 0.5 to 4 mm in size (mean, 1.12 mm), were all spindled and had noncircumscribed infiltrating borders. All arose in the muscularis propria and 2 were predominantly subserosal. Immunohistochemistry revealed a CD117/CD34/smooth muscle actin-negative phenotype in 18/19 lesions. Three KIT exon 11 mutations (2 point mutations and 1 deletion, all involving W557) were detected in 3/12 lesions with successful molecular analysis. In conclusion, incidental microscopic GISTs are uncommon in intestinal resections (< or =0.1%), contrasting with their gastroesophageal counterparts (> or =9%). Somatic KIT mutations are early initiating molecular events in a subset of them. The remarkable variation in the incidence of microscopic GISTs at different GI sites suggests an origin from heterogeneous subsets of interstitial cells of Cajal with varying potentials for neoplastic transformation.     

Smooth muscle tumours of the upper gastrointestinal tract

Forty-six patients with smooth muscle tumours of the stomach and small intestine were treated surgically at the Princess Alexandra Hospital between 1970 and 1986. Leiomyomas were three times more common than leiomyosarcomas, but malignant tumours occurred more frequently in the small intestine than in the stomach. Gastric tumours tended to present with gastrointestinal bleeding, in contrast to intestinal lesions which presented predominantly with abdominal pain. Although leiomyomas tend to be smaller at operation than leiomyosarcomas, the size of a smooth muscle tumour is not reliable in discriminating between benign and malignant lesions. Therefore all smooth muscle tumours of the upper gastrointestinal tract should be excised as widely as possible, including local lymphatics in the dissection where practicable, so as to maximize the likelihood of radical extirpation of malignant lesions. Approximately one-third of patients with leiomyosarcomas have metastases at the time of surgery; the 5 year survival rate after surgical treatment of leiomyosarcomas of the upper gastrointestinal tract is less than 50%.     

True smooth muscle tumors of the small intestine: a clinicopathologic, immunhistochemical, and molecular genetic study of 25 cases

Gastrointestinal stromal tumors (GISTs) comprise a great majority of small intestinal mesenchymal tumors previously designated as smooth muscle tumors (SMTs), but true SMTs occur with a low-frequency encompassing both leiomyomas and leiomyosarcomas (LMSs). In this study, we analyzed 25 tumors in the spectrum of primary SMTs of the small intestine. Metastatic tumors and those with external attachment only were excluded. These tumors occurred in 15 men and 10 women of median age of 62 years (range: 18 to 80 y). There were 9 well-differentiated SMTs with no atypia and low mitotic activity [< or = 5/50 high-power fields (HPFs)] and these were considered leiomyomas. All 6 tumors examined were positive for SMA and desmin, and negative for KIT; all 3 tumors in female patients that were tested were negative for estrogen receptor. Two leiomyomas, a 5 mm, and another, 2 cm tumor, were examples of a muscularis mucosae leiomyomas. The other 7 were considered intramural leiomyomas; their median diameter was 4.5 cm (range: 0.8 to 9 cm). No patient with these tumors experienced recurrences or metastases, and 6 patients were alive with a median follow-up of 16 years (range: 9 to 28 y). Sixteen tumors had atypia and mitotic activity warranting the designation of LMS. One of these tumors, a 16 cm diverticular tumor, had mitotic activity of only 1/50 HPFs, and this tumor recurred 4 times. All other LMSs had > or =35 mitoses/50 HPFs. Four of 5 such LMSs with follow-up recurred or metastasized, and at least 3 patients died of disease; several others had a short survival but cause of death could not be determined. One patient, an 18-year-old woman, who died of LMS, was a survivor of a Wilms tumor radiated in infancy. All 6 LMSs studied for GIST-specific KIT and platelet-derived growth factor receptor alpha mutations showed wild-type sequences. This series demonstrates that primary small intestinal SMTs are rare (estimated frequency 1 SMT for 36 GISTs). A majority of these are mitotically active tumors with atypia warranting the diagnosis of LMS, and have a high malignant potential. The number of LMS cases is too small for stratification for risk assessment. True SMTs of small intestine should be separated from GISTs because of different pathogenesis and treatment.     

Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas

Although rare elsewhere in the gastrointestinal tract, leiomyomas (LMs) are the most common esophageal mesenchymal neoplasms. In contrast, gastrointestinal stromal tumors (GISTs) predominate in the stomach and intestines but have not been documented in the esophagus. This study was undertaken to determine the clinicopathologic features and frequency of esophageal GISTs compared with LMs and leiomyosarcomas (LMSs) of the esophagus. A total of 68 stromal/smooth muscle tumors from the Armed Forces Institute of Pathology and the Haartman Institute of University of Helsinki were reclassified by current histologic and immunohistochemical criteria. There were 17 GISTs, 48 LMs, and three LMSs. The esophageal GISTs occurred in 12 men and five women with a median age of 63 years (range, 49-75 years). All tumors were from the lowest third of the esophagus, and the most common complaint was dysphagia, whereas two tumors were detected incidentally. Histologically the tumors had an overall basophilic appearance and showed combinations of solid, myxoid, and perivascular collarlike patterns with a spindle cell histology in 13 patients and epithelioid histology in four patients. All tumors were positive for CD117 and for CD34, whereas two patients were also positive for alpha-smooth muscle actin (SMA) and three patients were positive for desmin. One patient showed a unique immunophenotype with coexpression of CD117, CD34, SMA, and desmin. Nine patients died of disease, including all who had a tumor larger than 10 cm, and also one patient whose tumor showed five mitoses per 50 high-power fields. In comparison, esophageal LMs (n = 48) occurred in a younger population (median age, 35 years) but, similar to the GIST group, men predominated (67%). All LMs were clinically indolent tumors with no tumor-related mortality. The LMs showed eosinophilic cytoplasm, and were positive for desmin and SMA, and negative for CD117 and CD34. All three LMSs were large high-grade tumors that showed muscle cell markers but no CD117. All patients died of disease. Esophageal GISTs showed mutations in exon 11 of c-kit as described previously in gastric and intestinal GISTs. The separation of GISTs from esophageal LMs is important diagnostically because the former group has a high risk of malignant behavior.     

Mutations in exon 11 of the c-kit gene in a myogenic tumor and a neurogenic tumor as well as in gastrointestinal stromal tumors. Utility of c-kit mutation as a prognostic biomarker for gastrointestinal mesenchymal tumor

BACKGROUND/AIMS: Gain-of-function mutations in exons 9, 11 and 13 of the c-kit gene in gastrointestinal stromal tumors (GISTs) have been identified, and it has been reported that the prognosis is worse for patients with mutation-positive GISTs than for those with mutation-negative GISTs. We studied c-kit mutations in gastrointestinal mesenchymal tumors. By chance, the c-kit mutation in exon 11 was found in myogenic and neurogenic tumors as well as in GISTs. Furthermore, we studied the clinical prognostic utility of these mutations. METHODS: Ten gastrointestinal mesenchymal tumors were stained with HE and immunohistochemically analyzed with alpha-smooth muscle actin, S-100 protein, CD34 and c-kit. In these tumors, as well as in 11 cases of leiomyomas, PCR-amplified DNA from the juxtamembrane (JM) domain of exon 11, the extracellular domain of exon 9 and the tyrosine kinase domain 1 of exon 13 showed a high frequency of c-kit mutation and was sequenced. RESULTS: Although c-kit mutations have previously been reported only in GISTs, we found c-kit mutations in the JM domain of exon 11 in one myogenic and one neurogenic tumor as well as in two GISTs. No c-kit mutation was seen in the 11 cases of leiomyomas. In addition, all four cases with c-kit mutation in exon 11 suffered a relapse sooner than the other cases without c-kit mutations. CONCLUSION: Clinically, the prognosis was worse for the patients with mutation-positive gastrointestinal mesenchymal tumors than for those with mutation-negative tumors. We therefore conclude that the gain-of-function mutation in exon 11 of the c-kit gene is an important prognostic factor for gastrointestinal mesenchymal tumors, including myogenic and neurogenic tumors as well as GISTs.     

Dissecting leiomyomas of the uterus other than cotyledonoid dissecting leiomyomas: a report of eight cases.

We report eight cases of benign uterine smooth muscle neoplasms with unusual growth patterns and intramural dissection. All the patients in our series were of reproductive age or perimenopausal (range, 36-51 years) and had an enlarged uterus or a pelvic mass, with the exception of one lesion that was found incidentally in a patient treated for uterine prolapse. Three also had abnormal uterine bleeding. On gross examination, the lesions had an unusual appearance and were often lobulated and irregular with indistinct margins. On microscopic examination of all the lesions in this study, a dominant benign smooth muscle tumor was associated with intramural dissection of the myometrium by fascicles of neoplastic smooth muscle. Of the eight cases showing intramural dissection, four were intramural dissecting leiomyomas; three were examples of intravenous leiomyomatosis; and one was a multinodular leiomyoma with hydropic degeneration. We excluded cotyledonoid dissecting leiomyomas from the study. In two of the three cases of intravenous leiomyomatosis, extrauterine extensions in continuity with the intramural components were noted at surgery and on gross examination. Intramural dissection of the myometrium by a benign smooth muscle tumor is one additional possibility to be considered in the differential diagnosis of leiomyosarcoma and low-grade stromal sarcoma.     

Gastro-intestinal stromal tumor (GIST): case report

Gastro-intestinal stromal tumors (GISTs), as currently defined, represent the largest category of primary non epithelial neoplasms of the gastrointestinal tract. They arise from mesenchymal cells located in the wall of the organ and show a remarkable variability in their differentiation pathways. For this reason there is relevant degree of confusion in their interpretation. On the basis of immunohistochemical and ultrastructural studies these neoplasms are divided into several categories: leiomyomas, schwannomas and less differentiated tumors referred as GIST. In the small bowel GIST are uncommon. Usually asymptomatic, they could be the cause of surgical emergencies like massive bleeding, obstruction, intussusception or perforation. Generally benign, an higher percentage of malignant cases are described in the small bowel. The Authors report a case of malignant GIST of the small intestine presented with bowel obstruction by ileal invagination. In this case, as usually it happens in malignant GIST, the final diagnosis was obtained by an abdominal surgical exploration.     

Gastrointestinal stromal tumors: five case reports and review of the literature

Being a rare entity, GISTs represents the most common subset of mesenchymal tumours that arise from the digestive tract. Their immunohistochemical and histopathologic features distinguish them from other gastrointestinal mesenchymal neoplasms. These tumours have been the matter of considerable debate in the literature regarding their histogenesis, criteria for diagnosis, prognostic features and treatment. GISTs express Kit protein that not only is a marker for diagnosis but has also permitted to identify a specific medical treatment. The exceptional interest aroused in the literature leads us to make a review about this subject reporting five cases treated in the last 2 years.     

Intramural leiomyomas of the bladder in asymptomatic men

Bladder leiomyomas are rare benign mesenchymal tumors, which account for less than 0.43% of all bladder tumors with approximately 200 cases described in the literature. These tumors may be classified into 3 different locations: endovesical, intramural and extravesical. Endovesical is the most common form, accounting for 63-86% of the cases, while intramural occurs in 3-7% and extravesical in 11-30%. The intramural form, especially small tumors, may not produce symptoms hardening detection. We report two cases of intramural bladder leiomyomas in asymptomatic men observed incidentally by transabdominal ultrasonography during the follow-up of benign prostatic hyperplasia. We discuss the diagnosis and management of these lesions.     

"Seedling" mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction

Gastrointestinal stromal tumors (GISTs) are the most common nonepithelial neoplasm of the gastrointestinal tract and show a predilection for the stomach. Most are detected because of symptoms, but some are incidental findings at autopsy or surgery for other reasons. Incidental GISTs tend to be smaller at diagnosis, but even small (<1 cm) GISTs have been shown to harbor activating KIT mutations at rates similar to advanced GISTs. However, the prevalence and characteristics of small GISTs in surgical resections of the esophagogastric junction (EGJ) remains unclear. We studied 150 esophagogastric resections for esophageal or EGJ carcinomas (100 with preoperative chemoradiation and 50 untreated cases) that had been extensively embedded for histologic examination (mean 30 sections/case). Number, size, morphology, and location of all GISTs and leiomyomas were recorded. All potential GISTs were evaluated with CD117 and CD34 immunohistochemistry, and a subset (35) leiomyomas with smooth muscle actin, desmin, and CD117. We found 18 incidental GISTs in 15 of 150 (10%) patients; 3 patients harbored 2 separate lesions. Prevalence of GIST was identical in treated (10 of 100) and untreated (5 of 50) cases. All (100%) showed positivity for both CD117 and CD34 and all were of spindle cell morphology. Lesions ranged from 0.2 to 3.0 mm in size (mean 1.3 mm). Eight (44%) were based in the outer muscularis propria, 7 (39%) in inner muscularis, and 3 (17%) between the muscle layers. The lesions tended to cluster near the EGJ, with 8 (44%) on the gastric side, 9 (50%) on the esophageal side, and 1 (6%) undetermined owing to overlying ulceration. Leiomyomas were even more common than GIST, occurring in 47% of patients (44% of treated and 52% of untreated, P=0.39), with a mean of 3 leiomyomas per patient (range 1 to 13) and mean size of 1.7 mm (range 0.2 to 12 mm). Unlike colorectal leiomyomas, most (91%) EGJ leiomyomas were located in the inner muscularis propria and only rarely (1%) in muscularis mucosa. These results suggest that GIST and leiomyoma are common incidental "seedling" lesions of the EGJ, found in 10% and 47% of patients undergoing surgery for esophageal carcinoma. The common occurrence of microscopic GISTs compared with the rarity of clinically manifest and malignant esophagogastric GISTs suggests that additional genetic or epigenetic alterations must happen for neoplastic progression.