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.     

Long-term Outcomes of Laparoscopic Resection of Gastric Gastrointestinal Stromal Tumors

OBJECTIVE: Gastric gastrointestinal stromal tumors (GISTs) are rare neoplasms that require excision for cure. Although the feasibility of minimally invasive resection of gastric GIST has been established, the long-term safety and efficacy of these techniques are unclear. We hypothesized that complete resection of gastric GISTs using a combination of laparoscopic or laparoendoscopic techniques results in low perioperative morbidity and an effective long-term control of the disease. METHODS: Between August 1996 and June 2005, 50 consecutive patients undergoing laparoscopic or laparoendoscopic resection of gastric GISTs were identified in a prospectively collected database. Outcome measures included patient demographics and outcomes, operative findings, morbidity, and histopathologic characteristics of the tumor. Patient and tumor characteristics were analyzed to identify risk factors for tumor recurrence. RESULTS: Fifty patients, mean age 60 years (range, 34-84 years), underwent 47 local and 3 segmental laparoscopic gastric resections. GI bleeding and dyspepsia were the most common symptoms. Mean tumor size was 4.4 cm (range, 1.0-8.5 cm) with the majority of the lesions located in the proximal stomach. Mean operative time was 135 minutes (range, 49-295 minutes), the mean blood loss was 85 mL (range, 10-450 mL), and the mean length of hospitalization was 3.8 days (range 1-10 days). There were no major perioperative complications or mortalities. All lesions had negative resection margins (range, 2-45 mm). Nine patients had 10 or more mitotic figures per 50 high power fields, while 11 had ulceration and/or necrosis of the lesion. At a mean follow-up of 36 months, 46 (92%) patients were disease free, 1 patient was alive with disease, 1 patient with metastases died of a cardiac event, and 2 (4%) patients died of metastatic disease. No local or port site recurrences have been identified. Patient age, tumor size, mitotic index, tumor ulceration, and necrosis were statistically associated with tumor recurrence. The presence of 10 or more mitotic figures per 50 high power fields was an independent predictor of disease progression (P = 0.006). CONCLUSION: A laparoscopic approach to surgical resection of gastric GIST is associated with low morbidity and short hospitalization. As found in historical series of open operative resection, the tumor mitotic index predicts local recurrence. The long-term disease-free survival of 92% in our study establishes laparoscopic resection as safe and effective in treating gastric GISTs. Given these findings as well as the advantages afforded by minimally invasive surgery, a laparoscopic approach may be the preferred resection technique in most patients with small- and medium-sized gastric GISTs.     

Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up

Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. This study analyzed 1091 tumors originally classified as smooth muscle tumors of the small intestine (including jejunum or ileum and excluding duodenum), and found that 906 (83%) of these were GISTs. The GIST patients had 55:45 male-to-female ratio with a median age of 59 years (range, 13-94 years). Only 0.6% of tumors occurred before the age of 21 years and 13.6% before the age of 40 years. The tumors varied from 0.3 to 40 cm (median, 7.0 cm) and most commonly presented with GI bleeding or acute abdomen; 18% were incidentally detected. Histologically, the tumors were relatively monotypic with spindle cell (86%), epithelioid (5%), or mixed patterns (9%). Skeinoid fibers were present in 44% of cases, and their presence was associated with a favorable course. Most epithelioid tumors were malignant, and this morphology sometimes emerged from less cellular and less mitotically active spindle cell tumors, suggesting that it represented a transformation. KIT was immunohistochemically detected in 98%, CD34 in 40%, smooth muscle actin in 34%, desmin in 0.2%, and S-100 protein in 14% of the tumors tested. Outcome was strongly dependent on tumor size and mitotic activity, with an overall 39% tumor-related mortality, twice that for gastric GISTs. Only <3% of tumors <5 cm and < or = 5 mitoses/50 HPF metastasized, whereas 86% of tumors >10 cm and >5 mitoses/50 HPF metastasized. In stark contrast to corresponding gastric tumors, tumors >10 cm with mitotic activity < or = 5/50 HPF and those < or = 5 cm with mitoses >5/50 HPF had a high metastatic rate (>50%); tumors >5 cm < or = 10 cm with low mitotic rate had a 24% metastatic rate. The median survival times of patients with low mitotic rate tumors who died of disease decreased by increasing tumor size. KIT exon 11 mutations were detected in 90 cases, exon 9 mutation in 17 cases, and exon 17 mutation in 1 case; the presence of mutation or mutation type was not prognostically significant. There were no PDGFRA exon 12 or 8 mutations. Systematic data on prognosis of small intestinal GISTs of various size and mitotic activity categories can be helpful in management and surveillance of patients with these tumors.     

Exophytic gastrointestinal stromal tumor of the stomach. Report of two cases

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Most GISTs occur in the stomach (60-70%). Their diagnosis is established immunohistochemically and reveals that the tumor cells are immunoreactive for the antigens CD117 and CD34. The infiltration of the adjacent organs, the large tumor size (>5cm) and the mitosis count of the cells (>5/50 CHPFs) are typical characteristics of GIST malignancy. GISTs rarely infiltrate adjacent organs and usually push them back. The clinical behaviour of GISTs is highly variable and tumor size mitotic rate and location are prognostic determinants.The biologic behaviour of GIST is variable. The majority were previously thought to be benign due to their characteristically bland histopathologic features. However, it is becoming increasingly clear that with long follow-up, virtually all GISTs have the potential for malignant behaviour, even those 2 cm or less with bland histologic features. Thus, it is not appropriate to define any GIST as "benign" per se.We present two cases of exophytic gastric GIST which were recently treated successfully in our Clinic with “wedge” gastric resection. The margins were negative and there was neither rupture of the tumor, nor spillage.     

Gastrointestinal stromal tumors in the appendix: a clinicopathologic and immunohistochemical study of four cases.

Mesenchymal tumors of the appendix are very rare, and specific stromal tumors (i.e., gastrointestinal stromal tumors, GISTs) have not been reported in this location to date. Four GISTs were identified in the review of primary mesenchymal tumors of the appendix from the files of the Armed Forces Institute of Pathology from 1970 to 1998. There were also one benign schwannoma, one diffuse neurofibroma with neurofibromatosis 1, one leiomyosarcoma in a child with HIV infection, and one inflammatory fibroid polyp. The four appendiceal GISTs occurred in adult males 56-72 years of age (mean 63 years). Two tumors occurred in patients who had surgery for appendicitis-like symptoms: one was an incidental finding during surgery for a malignant gastric epithelioid GIST and one was an incidental autopsy finding. Only one of the two appendices operated for symptoms had acute inflammation, and a polypoid GIST projected outward from the proximal part of appendix. Three tumors were partially obliterating nodules, eccentrically expanding the appendiceal wall. All four were spindle cell tumors, and three of them contained extracellular collagen globules (skeinoid fibers); none had atypia or mitotic activity (<1/50 high power fields). Immunohistochemically, two tumors studied were positive for CD117 (KIT), and two were positive for CD34. The tumors were negative for alpha-smooth muscle actin and S-100 protein. Follow-up revealed death from cardiovascular disease in one case (4 years after appendectomy) and liver failure because of malignant gastric epithelioid GIST metastatic to liver in another case 15 years after the appendectomy. This report documents the rare occurrence of CD117-positive GISTs as primary appendiceal tumors.     

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.     

Prognostically favorable "mitotically active" smooth-muscle tumors of the uterus. A clinicopathologic study of ten cases

We evaluated the clinicopathologic features of 22 smooth-muscle tumors of the uterine corpus that had at least five mitoses per 10 high-power fields (HPF) in the most active areas. Ten women were alive and well without tumor recurrence 15 months to 11 years after diagnosis (median, 6 years); these patients were referred to as the "clinically benign" group. The other 12 women had "clinically malignant" disease: 9 died of recurrent or metastatic tumor 3 months to 4.5 years after diagnosis (median, 16 months), and 3 are alive with disease 4-12 months after diagnosis. Significant clinical and pathologic differences were observed between patients in the "benign" and "malignant" groups. We found that mitotic activity in the range of 5 to 15 mitoses per 10 HPF was not a reliable predictor of aggressive behavior in tumors that lacked marked cytologic atypia and that by all other clinical and pathologic criteria were leiomyomas. An unfavorable prognosis among the mitotically active neoplasms could be predicted by a constellation of clinicopathologic features, including postmenopausal status, a clinical or intraoperative impression of cancer by the surgeon, extension of tumor beyond the uterine corpus, size greater than 10 cm, marked cytologic atypia, invasive borders, necrosis, and mitotic counts exceeding 20 per 10 HPF.     

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.     

Multiple sporadic gastrointestinal stromal tumors (GISTs) of the proximal stomach are caused by different somatic KIT mutations suggesting a field effect

Multifocal gastrointestinal stromal tumors (GISTs) are observed in patients with germline KIT or PDGFRA mutations, and in those with neurofibromatosis 1. However, the pathogenesis of apparently sporadic multifocal gastric GISTs in adults is poorly understood. We analyzed 27 GISTs from 11 patients (mean age, 75 y) with 2 to 4 tumors each. All tumors represented incidental findings in surgical (n=8) and autopsy (n=3) specimens and were located in the gastric body or fundus within < or =4 cm distance from each other. The 8 surgical cases represented 10% of GISTs involving the proximal stomach in our case material. Tumor size ranged from 1.5 mm to 45 mm (mean, 9 mm). Histology revealed a uniform spindle cell morphology with a variable sclerosis/calcification and a low mitotic activity (<5 mitoses/50 high-power fields). All tumors were KIT+/CD34+. Nineteen of 22 tumors (79%) revealed mutations in KIT exon 11 (13 deletions and 6 point mutations). Individual lesions from the same patient displayed different mutations in all, but 1 case, thus ruling out germline mutations and neurofibromatosis 1. Our findings indicate that multifocal gastric GISTs in elderly patients are unrelated to hereditary GIST syndromes. Clustering of these lesions in the proximal stomach, their close proximity, and the demonstration of different KIT mutations in individual lesions from the same patient point to the existence of distinct subsets of interstitial cells of Cajal with a higher propensity for different somatic KIT exon 11 mutations, possibly as a result of a field effect involving premutational epigenetic alterations or yet unidentified etiologic factors.     

Our experience in the surgical treatment of gastrointestinal stromal tumors

The authors carry out a retrospective review of 30 patients with gastrointestinal stromal tumours (GISTs) who underwent surgical treatment over the period from 1974 to 2001. Sixteen were male and 14 female, with an average age of 60.9 years. Histologically, 19 tumours showed evidence of differentiation towards smooth muscle elements (10 benign and 9 malignant), 9 towards neural elements (3 benign and 6 malignant) and 2 iacked differentiation towards either cell type. Twenty-one tumours were located in the stomach, 1 in the duodenum, 3 in the jejunum and 5 in the ileum. The main symptoms were abdominal pain and abdominal masses, and the most sensitive diagnostic techniques were abdominal CT scan and endoscopy in gastroduodenal locations. In 21 gastric GISTs, the surgical procedures were local resection (15 cases), partial gastric resection (3 cases), subtotal gastrectomy (2 cases) and total gastrectomy (1 case). In 8 small bowel GISTs, we performed a typical intestinal resection while duodenal undifferentiated GIST was managed by pancreatico-duodenectomy. There was no operative mortality or morbidity. Among the 13 patients with benign GISTs, 1 died of causes unrelated to the disease, while 12 patients are still alive and in good health after a mean follow-up of 148.5 months (range: 6-262). Among patients with malignant muscular GISTs (6 gastric and 3 ileal), 3 with gastric tumours were lost to follow-up, 3 with gastric and 1 with ileal neoplasms are alive and free from disease after a median follow-up of 58 months (range 3-108), while 2 patients with ileal neoplasms died of metastatic disease 39 and 29 months after the surgical procedure. Among 6 patients with malignant neural GISTs (2 gastric, 2 jejunal and 2 ileal) 1 with a gastric tumour and 1 with a jejunal tumour were lost to follow-up, while 3 are still alive and in good health after a median follow-up of 67.6 months (range 19 to 94); another with jejunal disease developed liver metastases 14 months after small bowel resection and died 12 months later. The two patients with undifferentiated GIST both died of liver metastasis 38 months after pancreatico-duodenectomy and 43 months after total gastrectomy. The most frequent symptoms were abdominal pain and a palpable mass, but no specific signs were detected. In gastroduodenal lesions endoscopy plays a very important diagnostic role and CT scan is the most sensitive diagnostic technique in the evaluation of location, size, invasion of adjacent organs and metastases. Prognostic prediction on the basis of histological findings is difficult and in our experience undifferentiated tumours are always malignant.     

Retrogastral located gastrointestinal stromal tumor (GIST) as a sonographically detected rare incidental finding

Gastrointestinal stromal tumors (GIST) represent compared to carcinomas a rare group of neoplasias of the gastro-intestinal tract of unclear dignity. We report the example of a patient suffering from a big retrogastral located gastrointestinal stromal tumor which had been detected as an incidental finding without previous complaints. Because origin and dignity of the process could not definitely be diagnosed, total resection (R0-resection) without systemic lymphadenectomy of the process measuring 11.5 cm x 11 cm x 7 cm was performed. Mitotic activity and tumor-size are regarded as predictive factors of potenzial malignancy of GISTs. In general tumors with low mitotic activity of up to 5 mitoses per 50 high power fields (HPFs) and a diameter smaller than 5 cm are regarded as benign. In the presented case, up to 4 mitoses per 50 HPFs could be detected and thus, in connection with tumor-size, an uncertain biological behaviour of the process has to be expected. Since no generally accepted consensus on the treatment of the GISTs exists, also patients originally suffering from tumors regarded as borderline-malignant should undergo a close-meshed follow-up in regular intervals.     

Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases

Gastrointestinal stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, most commonly occur sporadically, but there seems to be some increased tendency for these tumors to develop in patients with neurofibromatosis 1 (NF1). The clinicopathologic profile, KIT, and PDGFRA mutation status and long-term prognosis of patients with GIST in NF1 are incompletely characterized. In this study, we analyzed 45 patients who had NF1 and GIST. There were 26 females and 19 males with a median age of 49 years (10 years lower than the median age of GIST patients in general). A great majority of tumors occurred in the jejunum or ileum, with multiple tumors occurring in 28 cases. Ten patients had a duodenal and one had a gastric GIST. The most common presentations were gastrointestinal bleeding and anemia, and many patients had intermittent bleeding over several years. The majority of the tumors were small and mitotically inactive; only 7 had mitotic activity >5/50 HPFs and 15 tumors were >5 cm. Associated Cajal cell hyperplasia was common. One patient had an intraabdominal peri-intestinal neurofibroma. Five of 35 patients with follow-up died of metastatic disease; all of these had a tumor >5 cm, mitotic rate >5/50 HPFs, or both; three of these tumors were located in the duodenum. The presence of multiple small tumors was not associated with progressive disease. Most patients with long-term follow-up enjoyed a good prognosis; 2 died of other NF1-associated tumors (malignant peripheral nerve sheath tumors, brain tumor). None of the 16 tumors from 15 patients had a KIT exon 9, 11, 13, or 17 or PDGFRA exon 12 or 18 mutation as is typically seen in sporadic GISTs, indicating that GISTs in NF1 patients have a different pathogenesis than sporadic GISTs.     

Myoepithelial carcinoma of the salivary glands: a clinicopathologic study of 25 patients

Salivary gland carcinomas displaying exclusively myoepithelial differentiation (myoepithelial carcinoma) are considered rare. Their histopathologic features, immunohistochemical profile, and clinical behavior are not well characterized. The authors reviewed the clinicopathologic features of 25 salivary gland tumors fulfilling two fundamental histologic criteria: unequivocally malignant and exclusively myoepithelial. For most of these, the original diagnosis was malignant mixed tumor. Thirteen men and 12 women aged 24 to 77 years (mean age, 55 yrs) participated in the study, and most presented with a painless mass. The parotid gland was the most common site (n = 15). Tumors ranged from 2.1 to 5.5 cm, arising either in association with a benign mixed tumor (n = 15) or de novo (n = 10). Histologically, all the tumors displayed infiltrative growth and most had a characteristic multinodular architecture with a cellular periphery and central necrotic/myxoid zones. Epithelioid, hyaline, spindle, clear, or mixed cell types were noted with accompanying myxoid and/or hyalinized extracellular matrix. Ten tumors were high grade cytologically and 15 were low grade. The mitotic rate ranged from three to 51 mitoses per 10 high-power fields. Necrosis was present in 15 tumors and perineural and vascular invasion were identified in 11 and four neoplasms respectively. Immunoreactivities included CAM5.2 (89%), AE1:AE3 (100%), 34betaE12 (92%), cytokeratin 7 (21%), cytokeratin 14 (53%), vimentin (100%), S-100 protein (100%), smooth muscle actin (50%), calponin (75%), muscle-specific actin (31%), glial fibrillary acidic protein (31%), carcinoembryonic antigen (0%), and epithelial membrane antigen (21%). Ultrastructural examination of three tumors showed myoepithelial features. Ten patients developed recurrences, mostly multiple. Follow up of 17 patients showed that eight patients (47%) developed metastases (six high grade, two low grade) and five patients (29%) died of disease (four high grade, one low grade) after a mean of 32 months. Two patients were alive with disease (19 and 49 mos). Ten patients (59%) were without any evidence of disease after a mean of 42.2 months. Myoepithelial carcinomas exhibit a wide spectrum of cytomorphologic features and diverse clinical outcomes. As a result of their morphologic heterogeneity, they can be confused easily with many tumors. Myoepithelial carcinomas have been underrecognized in the past, primarily by being lumped under a broader category of "malignant mixed tumor." Awareness of their unique cytoarchitectural patterns and immunohistochemical profile is crucial for accurate identification.     

Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients

Adrenal cortical neoplasms in pediatric patients (<20 years) are rare. The clinical manifestations and biologic behavior of these lesions can be quite distinct from their histologically similar counterparts in the adult population, making pathologic criteria for distinguishing benign from malignant tumors equivocal. We undertook a study of 83 adrenal cortical neoplasms to determine if adult clinical and histologic features can be applied to pediatric patients in an outcome-based analysis. Most of the patients (50 girls and 33 boys) presented with hormone-related symptoms present for a mean of 6.8 months. The tumors ranged in size from 2 to 20 cm (mean 8.8 cm). Histologic parameters examined included capsular and/or vascular invasion, extraadrenal soft tissue extension, growth pattern, cellularity, necrosis, cytoplasmic eosinophilia, nuclear pleomorphism, nuclear-to-cytoplasmic ratio, prominent nucleoli, mitotic figures, atypical mitotic figures, bands of fibrosis, and calcifications. Immunophenotypically, there was reactivity with inhibin, vimentin, CK5, and focally with p53 and Ki-67. All patients underwent adrenalectomy, and 20 patients received adjuvant therapy. All patients with tumors classified as adenomas (n = 9) were alive, without evidence of disease (mean 14.7 years), whereas 21 patients with carcinomas had died with disease (mean 2.4 years). Only 31% of histologically malignant tumors behaved in a clinically malignant fashion. Features associated with an increased probability of a malignant clinical behavior included tumor weight (>400 g), tumor size (>10.5 cm), vena cava invasion, capsular and/or vascular invasion, extension into periadrenal soft tissue, confluent necrosis, severe nuclear atypia, >15 mitotic figures/20 high power fields, and the presence of atypical mitotic figures. Vena cava invasion, necrosis, and increased mitotic activity (>15 mitotic figures/20 high power fields) independently suggest malignant clinical behavior in multivariate analysis.     

胃肠道间质瘤的CT表现与病理分级的相关性研究

目的对不同分级胃肠道间质瘤（GIST）的计算机断层扫描（CT）征象进行对比分析,评价CT表现对GIST病理分级的作用。方法收集有完整CT及病理组织学资料的原发性GIST共58例,其中恶性41例,良性和交界性者17例,对照病理组织学与病理分级,分析其CT征象对GIST分级的作用。结果发生于小肠、直肠的GIST比来源于胃和食道的恶性可能性更大。50例GIST表现为向腔外及壁间生长,其中38例为恶性;肿瘤平均最大径为7.5 cm,最大径≥7.5 cm者共26例,其中恶性23例;呈分叶状生长的GIST 35例,其中恶性30例。所有良性或交界性的GIST边界清晰,19例恶性GIST边界不清或部分不清。所有的恶性GIST均呈不均匀强化,均见坏死,10例良性或交界性者不均匀强化,亦可见坏死。15例恶性GIST出现周围侵犯。5例肝转移,1例腹膜种植转移。肿瘤明显强化、肿瘤表面血管、瘤内粗大血管、肿瘤腔侧面黏膜强化环及肿瘤腔侧面出现溃疡这几个因素在两组之间差异均无统计学意义。结论 CT检查对GIST的术前诊断和病理分级的评估有重要的意义。     

Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: a novel form of tumor progression

Approximately 80% of advanced metastatic gastrointestinal stromal tumors (GISTs) respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, the majority of patients suffer disease progression at a median of 2 years due to drug resistance. In general, progressing GISTs retain their typical morphology. Herein, we report 5 cases of progressing metastatic GIST with heterologous rhabdomyoblastic differentiation after TKI treatment. Histologic, immunohistochemical, and mutational analyses were performed on histologically classic GISTs and components with rhabdomyoblastic differentiation. There were 3 men and 2 women (ranging from 35 to 66 y of age). Three tumors were localized at presentation (2 stomach and 1 small bowel) and 2 presented with metastases. All localized primary tumors were high risk. Two tumors showed spindle cell morphology and 3 were epithelioid, including 1 with marked pleomorphism. After resection of the 3 localized primary tumors, intra-abdominal (2 patients) and liver (1 patient) metastases developed. All patients were treated with imatinib and showed partial clinical responses (4 patient) or stable disease (1 patient). Four patients subsequently progressed; 2 patients were treated with sunitinib after progression with minor responses. Four patients underwent surgical debulking. At last follow-up (range: 20 to 87 mo), 2 patients died of disease, 2 were alive with metastatic disease resistant to TKIs, and 1 was alive without evidence of disease. In all cases, rhabdomyoblastic differentiation was identified adjacent to areas with classic GIST morphology in at least 1 metastatic site; in 1 case, the primary tumor (after treatment with TKIs) showed heterologous differentiation. The rhabdomyoblastic components showed strong and diffuse positivity for desmin and expressed myogenin, whereas KIT was negative in the rhabdomyoblastic component in all cases. Primary KIT mutations were detected in both the conventional GIST and rhabdomyoblastic components from all patients: KIT exon 11 mutations in 4 cases and a platelet-derived growth factor receptor alpha gene exon 18 deletion in 1 case. No secondary mutations of the type associated with TKI resistance were identified in the rhabdomyoblastic areas. This is the first report of rhabdomyoblastic differentiation occurring in GISTs that progressed on TKI therapy. It is associated with loss of KIT expression, but retention of the receptor tyrosine kinase mutation of the precursor GIST. The rhabdomyoblastic differentiation can represent a diagnostic pitfall. The molecular mechanisms for this form of TKI-resistant clonal evolution remain to be determined.     

Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up

Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. In this study, we analyzed 1869 cases originally classified as smooth muscle tumors of the stomach and found that 1765 (94%) of these were GISTs. The GISTs had a slight male predominance (55%) with a median age of 63 years. Only 2.7% of tumors occurred before the age of 21 years and 9.1% before the age of 40 years. The tumors varied from 0.5 to 44 cm (median, 6.0 cm) and most commonly presented with GI bleeding; 12% were incidentally detected. Several histologic variants were recognized among the spindle cell tumors (sclerosing, palisaded-vacuolated, hypercellular, and sarcomatous) and of epithelioid tumors (sclerosing, dyscohesive, hypercellular, and sarcomatous). Outcome was strongly dependent on tumor size and mitotic activity. Only 2% to 3% of tumors <10 cm and <5 mitoses/50 HPFs metastasized, whereas 86% of tumors >10 cm and >5 mitoses/50 HPFs metastasized. However, tumors >10 cm with mitotic activity <5/50 HPFs and those <5 cm with mitoses >5/50 HPFs had a relatively low metastatic rate (11% and 15%). A small number of patients survived intra-abdominal metastasis up to over 20 years. Tumor location in fundus or gastroesophageal junction, coagulative necrosis, ulceration, and mucosal invasion were unfavorable factors (P <0.001), whereas tumor location in antrum was favorable (P <0.001). KIT expression was detected in 91% of the cases, CD34 in 82%, smooth muscle actin in 18%, and desmin in 5%; the latter two were favorable (P <0.001). KIT exon 11 mutations were detected in 119 cases; patients with point mutations fared better than those with deletions (P <0.01). PDGFRA exon 18 mutations (total 86 cases) were common in epithelioid GISTs and most commonly represented a D842V point mutation; none of these was prognostically significant. The above results may be helpful for setting the criteria for adjuvant treatment such as Gleevec.     

原癌基因c-kit突变在胃肠道基质瘤临床预后中的意义

目的 探讨c—kit基因突变对胃肠道基质瘤（GIST）的发病及在临床病理和预后中的意义。方法 采用聚合酶链反应单链构象多态性技术（PCR—SSCP）方法检测106例GIST中c-kit基因突变的情况，并对其中的57例进行临床随访。结果全组基因突变率为45．3％（48／106）；良性GISTc-kit基因突变率为4．9％（2／41），恶性GISTc—kit基因突变率为70．8％（46／65），c-kit基因突变阳性组的1，3，5年生存率及中位生存期均明显低于突变阴性组。对肿瘤大小、肿瘤性坏死、浸润程度、核分裂象计数、核异型性等指标的比较，突变阳性组和阴性组均存在显著差异（P〈0．005）。邻近组织的侵袭及肿瘤的转移、复发的发生率突变阳性组均明显高于突变阴性组。结论 c—kit基因突变在GIST的发生发展中可能发挥着重要作用，可以作为判断GIST患者临床预后的一个重要指标。     

Fibrosarcoma-malignant fibrous histiocytoma of the breast. A clinicopathological study of 32 cases.

We report the clinical and pathologic features of 32 sarcomas of the breast with features spanning the spectrum of fibrosarcomas-malignant fibrous histiocytomas. Neoplasms were categorized as high- or low-grade lesions depending on a combination of the degrees of atypia and mitotic activity. The majority of high-grade lesions had marked (3+) nuclear atypia and at least five mitotic figures per 10 hpf. High-grade lesions with moderate (2+) nuclear atypia had a mitotic activity of six or more mitotic figures per 10 hpf. All low-grade lesions had five or fewer mitotic figures per 10 hpf, and none had a score of the nuclear grade times mitotic figures of more than 10. The average mitotic activity in low-grade lesions was two mitotic figures per 10 hpf; the high-grade lesions had 12 mitotic figures per 10 hpf. Sixty-nine percent of the low-grade fibrosarcomas-malignant fibrous histiocytomas showed mild (1+) cytologic atypia, and 69% of the high-grade lesions showed severe (3+) cytologic atypia. The herringbone pattern was associated with a more favorable prognosis than the malignant fibrous histiocytoma pattern. Compared to the high-grade lesions, low-grade fibrosarcomas-malignant fibrous histiocytomas were slow-growing, produced fewer recurrences, and did not metastasize. Of the 16 women with low-grade lesions, all were free of tumor at last contact, despite recurrence in more than half of the patients. In contrast, 31% of the patients with high-grade lesions died of tumor, and 13% were alive with disease. Twenty-five percent of women with high-grade lesions developed distant metastases.