Gastric Stromal Sarcoma Research Articles

Adrenal Cortical Adenoma

The Carney triad is the combination of gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma. Herein, we describe the clinical, imaging, pathologic, and follow-up findings from 14 patients for a fourth component of the syndrome, adrenal adenoma. The adrenal neoplasm was asymptomatic and usually a late finding. Results of adrenocortical function tests were normal. Computed tomography revealed low-density adrenal masses that were consistent with adenomas. Bilateral lesions were present in 4 patients. In 13 of the 14 patients who underwent surgery, resected adrenal glands and biopsy specimens featured 1 or more circumscribed, yellow tumors, up to 3.5 cm in diameter, composed of well-differentiated polygonal cells with clear vacuolated cytoplasm and a smaller component of eosinophilic cells. The extratumoral cortex had combinations of normal histologic features, discrete clear cell micronodules, zonal clear cell hypertrophy, and marked atrophy. The lesion in the 14th patient was different, grossly and microscopically resembling the usual sporadic cortisol-secreting adenoma. After the tumor was excised, the patient required glucocorticoid support. None of the tumors recurred or metastasized. Fourteen additional patients had unilateral or bilateral adrenal tumors consistent with adenomas detected by imaging studies.

Carney triad versus Carney Stratakis syndrome: two cases which illustrate the difficulty in distinguishing between these conditions in individual patients

Carney triad is a usually sporadic association of pulmonary chondroma, gastrointestinal stromal tumours, and paraganglioma. The majority of patients have two of these tumours, the gastric and pulmonary tumours being the most common combination. Carney Stratakis syndrome is an association of familial paraganglioma and gastric stromal sarcoma and it is considered to be a distinct condition from Carney triad as it is dominantly inherited and not associated with pulmonary chondroma. We report two unrelated patients each with two components of Carney triad. A pathological mutation in succinate dehydrogenase subunit B gene was identified in one and a variant in the same gene was identified in the other. This report demonstrates the difficulty in distinguishing between Carney triad and Carney Stratakis syndrome due to the rarity of the individual components. The fact that most patients with Carney triad have only two components of the Triad, and the long interval often seen between the occurrence of the first and the second component makes it difficult to differentiate confidently between the two conditions. Molecular information should improve the diagnosis of Carney triad.

Incomplete Carney triad--a review of two cases

A curious association of three rare tumours was described by Carney in 1977. 'Carney's triad' characteristically includes multifocal pulmonary chondroma, gastric stromal sarcoma and extra-adrenal paraganglioma. Patients may exhibit complete or incomplete expression of the triad. Carney acknowledged that, of 79 patients, only 17 possessed all three tumours. We report here two patients with incomplete expression of Carney's triad.

The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney–Stratakis syndrome): molecular genetics and clinical implications

Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumours (GISTs) and pulmonary chondromas (PCH). A number of other lesions have been described in the condition including pheochromocytomas, oesophageal leiomyomas and adrenocortical adenomas; CT is a novel form of multiple endocrine neoplasia (MEN), a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. We recently reported an international series of patients with CT, 34 females and three males (median age of presentation 21 years) who did not carry SDHA, SDHB, SDHC, SDHD, KIT or PDGFRA gene mutations. Comparative genomic hybridization revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbours the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumours despite their different tissue origin and histology; the findings were consistent with a common genetic aetiology of these two tumours in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney-Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. We conclude that CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumours. The above have clinical implications (i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumours are usually resistant to treatment with currently available tyrosine kinase inhibitors and may be part of a syndrome such as CT or CSS; and (ii) for patients with an inherited PGL syndrome, family history should be explored to identify any other tumours in the family, and in particular other endocrine lesions and GISTs.

New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors

Over the course of the last 10 years, we have studied the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are developmental, hereditary and associated with adrenal hypoplasia or hyperplasia, multiple tumors and abnormalities in other endocrine glands. On the basis of this work, we propose an hypothesis on how adrenocortical tumors form and the importance of the cyclic AMP-dependent signaling pathway in this process. The regulatory subunit type 1-alpha (RIalpha) of protein kinase A (PKA) (the PRKAR1A gene) is mutated in most patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD). Phosphodiesterase-11A (the PDE11A gene) and -8B (the PDE8B gene) mutations were found in patients with isolated adrenal hyperplasia and Cushing syndrome, as well in patients with PPNAD. PKA effects on tumor suppression and/or development and the cell cycle are becoming clear: PKA and/or cAMP act as a coordinator of growth and proliferation in the adrenal cortex. Mouse models in which the respective genes have been knocked out see m to support this notion. Genome-wide searches for other genes responsible for adrenal tumors and related diseases are ongoing; recent evidece of the involvement of the mitochondrial oxidation pathway in adrenocortical tumorigenesis is derived from our study of rare associations such as those of disorders predisposing to adrenomedullary and related tumors (Carney triad, the dyad of paragangliomas and gastric stromal sarcomas or Carney-Stratakis syndrome, hereditary leiomyomatosis and renal cancer syndrome) which appear to be associated with adrenocortical lesions.

Pulmonary Chondroma: A Tumor Associated With Carney Triad and Different From Pulmonary Hamartoma

The Carney triad is the clinical association of gastric stromal sarcomas, pulmonary cartilaginous tumors, and extra-adrenal paragangliomas. The pulmonary tumors are its second commonest component and have been misinterpreted clinically and pathologically as metastases from the gastric tumors and pulmonary cartilaginous hamartomas, respectively. They have not been previously described in detail in the pathology literature or compared with pulmonary cartilaginous hamartomas. Forty-two patients with pulmonary cartilaginous tumors as a component of Carney triad were identified. Clinical, radiographic, and pathologic findings in the cases were tabulated. Hematoxylin and eosin-stained sections of the neoplasms were evaluated for a series of histologic features. A subgroup of 41 tumors from the latter was compared with those in a group of pulmonary cartilaginous hamartomas. Patients with Carney triad group were predominantly young women. Their pulmonary neoplasm(s) were usually asymptomatic, often multiple, well circumscribed, medium-sized (mean diameter=2.8 cm), and composed almost exclusively of cartilage and bone surrounded by a fibrous pseudocapsule. The cartilage was usually myxoid, less frequently hyaline, and commonly calcified, ossified, or both. They showed no fat, smooth muscle or entrapped respiratory epithelium, tissues that were common in pulmonary hamartoma (P<0.0001). None of the tumors metastasized or was fatal. The pulmonary neoplasms in the Carney triad are well-differentiated benign cartilaginous tumors that are best designated as chondromas. They differ pathologically from pulmonary cartilaginous hamartomas on the basis of the presence of a thin fibrous pseudocapsule, frequent bone metaplasia, and calcification, and also the absence of entrapped epithelium and fat.

Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD

Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.

Potential tumor markers for human gastric cancer: an elevation of glycan:sulfotransferases and a concomitant loss of α1,2-fucosyltransferase activities

Several reports indicate a complexity in glycosyltransferase activities which lead to several tumor associated carbohydrate structures in gastric carcinoma. The present study was aimed to identify the carbohydrate associated transferases which exhibit the most marked and consistent change of activity in gastric tumorigenesis. We examined the levels of fucosyl, beta-galactosyl-, beta-N-acetylgalactosaminyl, sialyl- and glycan:sulfotransferase activities, which generate the outer ends of oligosaccharide chains in tumorous and adjacent normal gastric tissues of the same patient in ten gastric carcinoma cases by using well defined specific synthetic acceptors utilized in our several earlier published studies as referenced in the text (e.g. Chandrasekaran et al. in J Biol Chem 279:10032-10041, 2004; Biochemistry 44:15619-15635, 2005; Carbohydr Res 341:983-994, 2006). Among glycosyltransferases only alpha1,2-fucosyltransferase (FT) was unique in showing a remarkable 40-90% decrease of activity in seven cases. Uniquely several fold elevation of Gal3Sulfo-T(2) (1.9 --> 156.7 fold) and Gal3Sulfo-T(4) (2.4 --> 149.0 fold) activities in all ten cases and moderate elevation of GlcNAc6Sulfo-T (1.3 --> 37.5 fold) activities in nine cases were identified. Poorly differentiated Signet ring cell carcinoma expresses mainly Gal3Sulfo-T(2) activity whereas poorly differentiated adenocarcinoma express predominantly Gal3Sulfo-T(4) activity and also GlcNAc6Sulfo-T activity. But, very low level of these sulfotransferase activities were identified in moderately differentiated gastric carcinomas as well as non-epithelial gastric stromal sarcoma. Up regulation of glycan:sulfotransferase activities and down regulation of alpha1,2-fucosyltransferase activity are apparently associated with human gastric tumorigenesis.

Phase I and pharmacokinetic study of Yondelis™ (Ecteinascidin-743; ET-743) administered as an infusion over 1 h or 3 h every 21 days in patients with solid tumours

Yondelis™ (ET-743) is a novel anticancer agent isolated from the marine ascidian Ecteinascidia turbinata. ET-743 possesses potent antitumour activity and a novel mechanism of action at the level of gene transcription. We conducted two sequential phase I dose escalation and pharmacokinetic studies of ET-743 given as a 1- or a 3-h intravenous (i.v.) infusion. Seventy-two adults with metastatic or advanced solid tumours received ET-743 in escalating doses between 50 and 1100 μg/m2, initially as a 1-h infusion, and later at doses between 1000 and 1800 μg/m2 as a 3-h infusion every 3 weeks. The maximum tolerated dose (MTD) of ET-743 was 1100 μg/m2 for the 1-h infusion schedule and 1800 μg/m2 when given as a 3-h infusion. Dose-limiting toxicities (DLTs) were fatigue, neutropenia and thrombocytopenia. Transient non-cumulatives grade 3–4 increase in transaminases (not considered DLT) and grades 3–4 nausea and vomiting were frequently observed. Other toxicities (maximum grade 3) included anaemia, increased lactate dehydrogenase (LDH), bilirubin and alkaline phosphatase serum levels, and phlebitis; there were no toxic deaths. One pCR (melanoma), CR (uterine leiomyosarcoma), one PR (colon stromal sarcoma) and a MR (37% tumour shrinkage, gastric stromal sarcoma) were observed. A further 9 patients with colorectal, mesothelioma, bile duct carcinoma and bladder cancer had SD which lasted for six or more treatment cycles. ET-743 pharmacokinetics were linear with the 3-h infusion schedule. The haematological and hepatic toxicities of ET-743 were dose-dependent and not cumulative. Based on the current trial, the recommended dose of ET-743 for phase II studies is 1650 μg/m2 given as a 3-h infusion.

Recommendations for Reporting of Extra-Adrenal Paragangliomas

The Association of Directors of Anatomic and Surgical Pathology (ADASP) has proposed recommendations for surgical pathology reporting of malignant tumors. Recommendations for reporting of extra-adrenal paragangliomas are outlined herein. The Association of Directors of Anatomic and Surgical Pathology (ADASP) has requested various committees to propose recommendations for the content and scope of the surgical pathology report for common or uncommon tumors. The following recommendations were developed by an ad hoc committee composed of Ernest E. Lack, MD, (Chair), Ricardo V. Lloyd MD, PhD, J. Aidan Carney, MD, PhD, James M. Woodruff MD, and a group of pathologists with expertise or special interest in paragangliomas. These recommendations are reviewed and approved by the council of the ADASP and then circulated to the entire membership of the ADASP for their input. Thus, an interim consensus on reporting is reached among those with interest and expertise in a particular area or field of pathology; clearly, it is recognized that classification of tumors, diagnostic criteria, and terminology may undergo change in the future.

Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad.

Paragangliomas may be inherited in an autosomal dominant manner either alone (as in PGL1, PGL2, and PGL3 syndromes) or as a component of a multiple tumor syndrome (as in von Hippel-Lindau disease and neurofibromatosis type 1). In this article, we describe 12 patients (7 male and 5 female) with an average age of 23 years from five unrelated families that manifested paraganglioma and gastric stromal sarcoma; the tumors were inherited in an apparent autosomal dominant manner, with incomplete penetrance. Seven patients had paraganglioma, four had paraganglioma and gastric stromal sarcoma, and one had gastric stromal sarcoma. The paraganglioma was multicentric and the gastric stromal sarcoma multifocal. Because of the rarity of gastric stromal sarcoma and its multifocality, the young age of the patients, and the unlikelihood of coincidental co-occurrence of paragangliomas and gastric stromal sarcomas, we suggest that a new syndrome exists with these two main components, a condition that is familial and distinct from the Carney triad.

Stromal sarcoma of the stomach: therapeutic considerations.

To present our experience of the surgical treatment of primary gastric stromal sarcomas and to compare it with reported results. Retrospective study. University hospital, Germany. 17 patients (13 men and 4 women, median age: 58 years) who were operated on for stromal sarcomas of the stomach from April 1987 to March 1999. Extent of resection, morbidity and mortality, histopathological features, survival. Stromal sarcomas made up 0.8% of all gastric malignancies. Abdominal pain and gastrointestinal bleeding were the main symptoms. 16/17 were resected succesfully. The main type of resection was total gastrectomy (n = 11, in 6 cases as extended gastrectomy), followed by wide local excision of the stomach wall (n = 4), and proximal gastrectomy (n = 1). Of all resections 10 were radical (R0) and 6 were palliative (R1/R2). 5 patients developed complications. One patient died postoperatively. Median tumour size was 70 mm (range 30-230). The serosa was penetrated in 11 cases, lymph node metastases were found in 3 patients, and distant metastases in 8. Overall median survival was 19 months (2-64) and 5 patients survived 5 years. After radical resection (n = 10) median survival was 39 months (2-64) and the above mentioned 5 patients survived 5 years. Stromal sarcomas of the stomach are rare, the resection rate is high and the type of resection varies with the extent of the tumour. Wide local excision may be sufficiently radical. Long-term results after radical resection seem to be better than those after gastric adenocarcinoma.

The Carney Eponym

To the Editor: The recent article on the Carney triad1Carney JA Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney triad): natural history, adrenocortical component, and possible familial occurrence.Mayo Clin Proc. 1999; 74: 543-552Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar and, particularly, the editorial by Dr Appelman2Appelman HD The Carney triad: a lesson in observation, creativity, and perseverance [editorial].Mayo Clin Proc. 1999; 74: 638-640Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar prompted me to remind readers that there are 2 separate syndromes with the eponym Carney. The association of gastric sarcoma, pulmonary chondroma, and paraganglioma is distinct from the constellation of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. The former is usually referred to as the “Carney triad,” the latter as the “Carney complex”3Carney JA Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas.Semin Dermatol. 1995; 14: 90-98Crossref PubMed Google Scholar; however, the triad often includes other components, and often2Appelman HD The Carney triad: a lesson in observation, creativity, and perseverance [editorial].Mayo Clin Proc. 1999; 74: 638-640Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar 2 of the factors that make up the triad are absent. The terms triad, complex, and syndrome are often interchanged, even in Appelman's editorial: “This complex has subsequently been designated the ‘Carney triad.’ … The Carney triad has 3 anatomic components, but from the beginning, it was obvious that this was more than a triad because it had 2 unusual clinical features, female sex and young age, thus making it a syndrome.”2Appelman HD The Carney triad: a lesson in observation, creativity, and perseverance [editorial].Mayo Clin Proc. 1999; 74: 638-640Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar In the literature, Carney does not seem to have attempted to publicize the existence of these 2 separate entities. In their Dictionary of Medical Syndromes, Magalini and Magalini4Magalini SI Magalini SC Dictionary of Medical Syndromes. 4th ed. Lippincott-Raven, Philadelphia, Pa1997Google Scholar have recognized them as Carney I and Carney II. It would be helpful if Carney would acknowledge his 2 eponymic syndromes and suggest ways in which the medical literature could keep them distinct. Perhaps Carney would be willing to share his appellation with others, as other prolific physicians such as Osier and Weber have done. The Carney Eponym: In ResponseMayo Clinic ProceedingsVol. 74Issue 10PreviewDr Tashima raises the issue of nomenclature of 2 multi-organ tumorous conditions that I have described. Full-Text PDF

Combined RxFISH/G-banding allows refined karyotyping of solid tumors.

Chromosome banding analysis of solid tumors often yields incomplete karyotypes because of the complex rearrangements encountered. The addition of fluorescence in situ hybridization (FISH) methods has helped improve the accuracy of solid tumor cytogenetics, but the absence of screening qualities from standard FISH approaches has proved a severe limitation. We describe the cytogenetic analysis of ten solid tumors using G-banding followed by cross-species color banding (RxFISH), a FISH-based screening technique giving a chromosome-specific banding pattern based on the genomic homologies between humans and gibbons. The addition of RxFISH analysis in all cases led to the identification of previously unidentified intra- as well as interchromosomal rearrangements, thus giving a much more certain and detailed karyotype. In two gastric stromal sarcomas, a tumor type for which no cytogenetic data were hitherto available, numerical chromosomal aberrations dominated, but one of the tumors also carried an unbalanced 7;17-translocation with the same breakpoint in chromosome 17 as that seen in endometrial stromal sarcomas.

Gastric Stromal Sarcoma, Pulmonary Chondroma, and Extra-adrenal Paraganglioma (Carney Triad): Natural History, Adrenocortical Component, and Possible Familial Occurrence

To investigate the natural history of the triad of gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma, a rare syndrome of unknown cause primarily affecting young women. Mayo Clinic records, the world literature, and the author's files were searched for patients with all or 2 of the 3 tumors. Seventy-nine patients, 67 women and 12 men, were identified, 17 (22%) with the 3 tumors and 62 (78%) with 2 tumors. Forty-two (53%) had gastric and pulmonary tumors, the most common combination. The longest interval between detection of the first and second components was 26 years (mean, 8.4 years; median, 6 years). Follow-up ranged from 1 year to 49 years (mean, 20.6 years; median, 20 years). Sixty-four patients (81%) were alive, 19 (24%) apparently free of disease and 45 (57%) with residual or metastatic tumors. Thirty-two patients (41%) had had 1 or more local recurrences of the gastric sarcoma; the longest interval to first recurrence was 36 years. Twenty-one survivors (27%) had hepatic metastatic gastric sarcoma with follow-up of 1 year to 25 years (mean, 9.3 years; median, 7 years). Fifteen patients (19%) were dead, 10 (13%) of whom died of the disorder. Ten patients (13%) had nonfunctioning adrenocortical tumors. Two patients each had a sibling with 1 component of the triad. The triad is a chronic, persistent, and indolent disease. Benign adrenocortical tumors are a component of the condition. The disorder may be familial.

Stromal sarcoma of the stomach--a report of 20 surgically treated patients.

Twenty patients with gastric stromal sarcomas underwent surgery at the University Hospital of Hamburg-Eppendorf from 1979 to 1995. Symptoms were nonspecific. Exact preoperative diagnosis was difficult because of submucosal tumor growth. Operations varied from excision of the gastric wall to extended gastrectomy (pancreas, spleen, partial liver resection). In 16 cases, tumor could be resected with wide margins (R0). In four cases, tumor was found at the resection line (R1). After a median follow-up of 69 months, 12 patients with R0 resections (including tumors with poor differentiation or infiltration of surrounding organs) lived tumor free, and two died due to other causes. All four patients with R1 resections died because of tumor disease within 40 months. All patients had a mean survival time of 59 months and a 5-year-survival rate of 69%. Our series shows that not all gastric malignancies have a dismal prognosis, but that gastric stromal sarcomas have a favorable follow-up if resected with wide margins at initial surgery.

Gastric stromal sarcomas: correlation of MR imaging and histopathologic findings in nine patients.

To define the appearance of gastric stromal sarcomas at magnetic resonance (MR) imaging. Nine patients with gastric stromal sarcoma underwent MR imaging with the following sequences: nonenhanced and gadolinium-enhanced breath-hold, T1-weighted, spoiled gradient-recalled echo (n = 9); fat-suppressed, T2-weighted, fast spin echo (n = 9); and breathing-independent, half-Fourier rapid acquisition with relaxation enhancement (n = 6). Lesion morphology, signal intensity features, and relationships to the gastric wall and surrounding organs were retrospectively evaluated. The diagnosis of gastric stromal sarcoma was histologically proved in all patients. The nine tumors were solitary, multilobulated, shaped irregularly, predominantly exophytic, and large (diameter range, 7-28 cm [mean, 15.8 cm]). The epicenters of all lesions were extrinsic to the stomach, and all lesions arose from the gastric cardia or body. Regions of necrosis and hemorrhage were detected in all cases. Marginal definition on MR images corresponded to histologic grade: High-grade neoplasms possessed ill-defined margins, and low-grade neoplasms demonstrated more well-defined margins. Relationships to surrounding organs depicted at MR imaging corresponded well with histopathologic findings. Gastric stromal sarcomas demonstrate characteristic MR imaging features, which correspond well with histopathologic findings. The direct multiplanar capability of MR imaging facilitates delineation of relationships of the tumors to the stomach and surrounding organs.