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Gastrointestinal Stromal Tumors (GIST) are a rare but important group of tumors arising within the gastrointestinal tract. For many years, these tumors were called leiomyomas, epithelioid leiomyomas, leiomyoblastomas, epithelioid leiomyoblastomas, and leiomyosarcomas, depending upon the histologic findings. With refinement in diagnostic pathology, the cell of origin has been found to be a mesenchymal stem cell, and not the smooth muscle cell as once thought. (See the outline below). Most of these tumors present with pain, obstruction, a mass lesion, or bleeding.

The pathologist is faced with the task of identifying prognostic factors that may provide guidance for treatment and survival. These tumors are unpredictable in behavior although several investigators have identified key clinical and histological parameters.


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INCIDENCE Rare-see site distribution below
AGE Usually >50 years
Gastrointestinal Stromal Tumors of the Stomach in Children and Young Adults: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 44 Cases With Long-Term Follow-Up and Review of the Literature.

Miettinen M, Lasota J, Sobin LH.

From the Departments of *Soft Tissue Pathology and daggerHepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC.

Am J Surg Pathol. 2005 Oct;29(10):1373-1381. Abstract quote  

Gastrointestinal stromal tumors (GISTs), specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are rare in children and young adults, and their clinicopathologic and molecular genetic profile is incompletely understood.

In this study, we analyzed 44 gastric GISTs occurring by the age of 21 years. There were 32 females and 12 males, youngest of whom were a 5-year-old boy and an 8-year-old girl. All but 1 of 25 patients under the age of 16 were girls. The patients most commonly received medical attention because of chronic, insidious gastrointestinal bleeding with anemia, less commonly with acute GI bleeding. Only 1 patient had Carney triad with pulmonary chondroma. None of the patients had family members with GIST. The tumors measured from 1.5 to 24 cm (median, 5.6 cm). A total of 21 tumors with specified location were in the antrum and 8 were in the gastric body. Histologically, 26 tumors were composed of epithelioid cells, 12 of spindle cells, and 6 of combination thereof. Mitotic activity varied form 0 to 65/50 HPF (median, 5/50). All but one of the 24 tumors tested were KIT-positive, and 20 were CD34-positive.

Eleven patients developed liver or abdominal metastases, and 6 of them died of tumor surviving 5.5 to 35.5 years (median, 16 years) after the first surgery; three of these tumors had a low mitotic activity and size <10 cm. Twenty-one patients were alive with no evidence for disease 7 to 41 years (median, 17 years) after the first surgery. None of the 13 tumors examined (7 of them 8- to 16-year-old females) had KIT exon 9, 11, 13, or 17 or PDGFRA exon 12 or 18 mutation as typically seen in adult GISTs.

Gastric GISTs in children have mainly epithelioid morphology, often occur in antrum, and have a somewhat unpredictable but slow course of disease. Their pathogenesis may differ from that of adult GISTs because no KIT or PDGFRA mutations were found; connection with Carney triad seems infrequent despite demographic and histologic similarities.
SEX Equal
Gastrointestinal Stromal Tumors: Insights From a New Familial GIST Kindred With Unusual Genetic and Pathologic Features.

O'riain C, Corless CL, Heinrich MC, Keegan D, Vioreanu M, Maguire D, Sheahan K.

From the Departments of *Histopathology, daggerSurgery, and double daggerGastroenterology, St. Vincent's University Hospital, Elm Park, Dublin, Ireland; and section signDepartments of Pathology and Medicine, Oregon Health and Science University, Portland, OR.

Am J Surg Pathol. 2005 Dec;29(12):1680-1683. Abstract quote  

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder. We report the second family to date with a germline point mutation in exon 17 of the KIT gene that leads to substitution of aspartic acid at position 820 with tyrosine (D820Y). One or more GISTs was documented in three generations of this kindred, and there was associated hyperplasia of the interstitial cells of Cajal (ICC). One affected family member complained of dysphagia and another suffered small intestinal diverticulosis with perforation, which may represent additional consequences of ICC hyperplasia.

Diffuse and nodular ICC hyperplasia associated with the latter family member's small intestinal diverticulosis is illustrated, providing supportive functional and morphologic evidence for the ICC being the cell of origin of GISTs. Skin hyperpigmentation was not observed. Analysis of a 17-cm malignant GIST in the index patient revealed that it was hemi/homozygous for the germline D820Y mutation, indicating loss of the remaining wild-type KIT allele with tumor progression. Two smaller lesions from this patient were heterozygous for the mutation.

This phenomenon has been observed in up to 8% of sporadic malignant GISTs but has not been documented in familial disease.



Secondary amyloidosis and gastrointestinal stromal tumors. A case report and discussion of pathogenesis.

Overstreet K, Barone RM, Robin HS.

PGY-3, Department of Pathology, University of California, San Diego, Calif, USA.

Arch Pathol Lab Med 2003 Apr;127(4):470-3 Abstract quote

A 69-year-old man presented with a malignant gastrointestinal stromal tumor associated with secondary amyloidosis.

The tumor had classic features of a malignant gastrointestinal stromal tumor with interlacing fascicles and whorls of spindled cells, numerous and conspicuous mitotic figures, and extensive coagulative necrosis. The cells stained diffusely for CD117 (c-Kit), confirming the diagnosis of gastrointestinal stromal tumor. The spleen, 1 adrenal gland, and part of the pancreas were removed en block with the stomach.

By microscopy, the spleen and adrenal gland were partially replaced with amyloid deposits confirmed by Congo red staining, electron microscopy, and immunohistochemistry. In contrast, neither the tumor nor the surrounding vasculature showed amyloid deposition. To our knowledge, this represents only the second case of systemic amyloidosis associated with a gastrointestinal stromal tumor.

This case is unique in that extensive, diffuse amyloid deposits were observed in the spleen, adrenal gland, and liver.

Gastrointestinal Stromal Tumors in Patients With Neurofibromatosis 1: A Clinicopathologic and Molecular Genetic Study of 45 Cases.

Miettinen M, Fetsch JF, Sobin LH, Lasota J.

From the Departments of *Soft Tissue Pathology and daggerHepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC.

Am J Surg Pathol. 2006 Jan;30(1):90-96. Abstract quote  

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.
NF1-Associated Gastrointestinal Stromal Tumors Have Unique Clinical, Phenotypic, and Genotypic Characteristics.

Andersson J, Sihto H, Meis-Kindblom JM, Joensuu H, Nupponen N, Kindblom LG.

From the *Lundberg Laboratory for Cancer Research, Department of Pathology at the Sahlgrenska Academy, Goteborg University, Goteborg, Sweden; and daggerDepartment of Oncology, Helsinki University Central Hospital, Helsinki, Finland.

Am J Surg Pathol. 2005 Sep;29(9):1170-1176. Abstract quote  

Gastrointestinal stromal tumors (GIST) have been reported to occasionally occur in patients with neurofibromatosis type 1 (NF1). This study aims to describe the phenotypic and genotypic characteristics of GIST in NF1 patients and attempts to elucidate the relationship between them.

We analyzed GIST arising in 15 NF1 patients (8 males and 7 females, 19-82 years of age). Eleven patients had multiple GISTs (3 to >100 tumors) ranging from 1 mm to 10 cm in size and predominantly involving the small intestine including the duodenum. Tumors were symptomatic in 8 patients and incidental findings in the remaining 7 patients.

Microscopically, the tumors cells were typically spindled and the mitotic rate low; 9 patients had tumors classified as very low or low risk and 6 as intermediate risk GIST. Nine patients were treated surgically and none developed metastases or died of disease. Immunohistochemical stains for CD117 were strongly positive in 47 of 50 GIST; they also accentuated hyperplastic foci (diffuse and focal) of the interstitial cells of Cajal that were often associated with microscopic GIST in the surrounding intestinal muscle wall. No KIT or PDGFRA mutations were detected in 24 GIST from 12 patients using dHPLC analysis and DNA sequencing.

We conclude that patients with NF1 have a high risk of developing GIST. NF1-associated GIST are also phenotypically and genotypically distinct from sporadic GIST, indicating that different pathogenetic mechanisms are involved in their evolution.
Gastrointestinal Stromal Tumors of Neurofibromatosis Type I (von Recklinghausen's Disease).

Takazawa Y, Sakurai S, Sakuma Y, Ikeda T, Yamaguchi J, Hashizume Y, Yokoyama S, Motegi A, Fukayama M.

From the *Department of Human Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; daggerDepartment of Pathology, Jichi Medical School, Tochigi, Japan; double daggerDepartment of Clinical Pathology, Sapporo Medical University Hospital, Sapporo, Japan; section signDepartment of Pathology, Obihiro Kosei General Hospital, Obihiro, Japan; parallelDepartment of Pathology, Aichi Medical University, Aichi, Japan; paragraph signDepartment of Pathology, Faculty of Medicine, Oita University, Oita, Japan; and #Department of Tumor Pathology, Gunma University Graduate School of Medicine, Gunma, Japan.
Am J Surg Pathol. 2005 Jun;29(6):755-763. Abstract quote  

Gastrointestinal stromal tumor (GIST), as well as the hyperplastic lesions of intestinal neural tissue and its supporting structures, is a gastrointestinal complication of type 1 neurofibromatosis (NF1) (von Recklinghausen's disease).

In the present study, we analyzed the histologic and immunohistochemical features, and the c-kit and PDGFRA gene mutations of 36 GISTs derived from 9 NF1 patients. Distinctively, multiple GISTs arose preferentially in the small intestine.

The histologic features of NF1-associated GISTs are almost similar to those of non-NF1 GISTs, but characteristically most of the NF1-associated GISTs contained skeinoid fibers. Thirty-three GISTs (92%) showed immunoreactivity for KIT, and 23 tumors (64%) showed diffuse or mosaic-like immunoreactivity for S-100 protein. Hyperplasic lesions, which may be the hyperplasia of interstitial cells of Cajal, were observed around some GISTs. Exons 9, 11, 13, and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene were amplified and directly sequenced. Point mutations of c-kit gene or PDGFRA gene were identified only in three (8%) and two (6%) tumors, respectively. NF1-associated GISTs, showing the dual differentiation of interstitial cells of Cajal and Schwann cells, develop in close association with the myenteric nerve structure of gastrointestinal tract of NF1 patients.

The point mutations of c-kit and PDGFRA gene may play a limited role in the tumorigenesis of NF1-associated GISTs.
Functioning Paraganglioma and Gastrointestinal Stromal Tumor of the Jejunum in Three Women: Syndrome or Coincidence.

Perry CG, Young WF Jr, McWhinney SR, Bei T, Stergiopoulos S, Knudson RA, Ketterling RP, Eng C, Stratakis CA, Carney JA.

From the Departments of *Medicine (Endocrinology) and daggerLaboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; the double daggerHuman Cancer Genetics Program, Department of Medicine, Ohio State University, Columbus, OH; and the section signSection on Endocrinology and Genetics, Developmental Endocrine Branch, National Institute of Child Health, Bethesda, MD. The current address of Dr. Perry is Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK.

Am J Surg Pathol. 2006 Jan;30(1):42-49. Abstract quote  

Functioning paraganglioma and gastrointestinal stromal tumor (GIST) are uncommon tumors that occur mostly in a sporadic and isolated form, occasionally as components of multiple neoplasia syndromes, either separately or together. Separately, they occur in several inherited syndromes including multiple endocrine neoplasia 2, and the GIST, lentigines, and mast cell tumor syndrome.

Together, they are variably prominent components of three syndromes: the familial paraganglioma and gastric GIST syndrome, neurofibromatosis type 1, and the Carney triad. The two former conditions are inherited as autosomal dominant traits; the latter does not appear to be inherited and affects young women predominantly. This article reports the nonfamilial occurrence of functioning paraganglioma and GIST of the jejunum in 3 women, 1 young (22 years) at initial presentation. The occurrences were unexpected because of the infrequency of the tumors. The neoplasms, respectively, did not show germline SDHA, SDHB, SDHC, and SDHD, and KIT mutations associated with familial paraganglioma and familial GIST.

The paraganglioma-jejunal GIST combination may be the harbinger of a rare genetic syndrome, a variant of the Carney triad or the paraganglioma-gastric stromal sarcoma syndrome, or be coincidental.


KIT-Negative Gastrointestinal Stromal Tumors: Proof of Concept and Therapeutic Implications.

Medeiros F, Corless CL, Duensing A, Hornick JL, Oliveira AM, Heinrich MC, Fletcher JA, Fletcher CD.

*Department of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, MA; Departments of daggerPathology and double daggerMedicine, Oregon Health & Science University Cancer Institute and Portland VA Medical Center, Portland, OR; and section signDepartments of Pediatric and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. Drs. Medeiros and Corless contributed equally to this publication.
Am J Surg Pathol. 2004 Jul;28(7):889-894. Abstract quote  

The diagnosis of gastrointestinal stromal tumor (GIST) is currently based on morphologic features and immunohistochemical demonstration of KIT (CD117). However, some tumors (in our estimation approximately 4%) have clinicopathologic features of GIST but do not express KIT.

To determine if these lesions are truly GISTs, we evaluated 25 tumors with clinical and histologic features typical of GIST, but with negative KIT immunohistochemistry, for KIT and PDGFRA mutations using DNA extracted from paraffin-embedded tissue. Most tumors originated in the stomach (N = 14) or omentum/mesentery (N = 5). The neoplasms were composed of epithelioid cells (13 cases), admixed epithelioid and spindle cells (8 cases), or spindle cells (4 cases). Absence of KIT expression was confirmed by immunoblotting in 5 cases. Tumor karyotypes performed in 4 cases were noncomplex with monosomy 14 or 14q deletion, typical of GIST. Mutational analysis revealed PDGFRA and KIT mutations in 18 and 4 tumors, respectively, whereas 3 tumors did not have apparent KIT or PDGFRA mutations. The PDGFRA mutations primarily involved exon 18 (N = 15) and included 11 tumors with missense mutation in codon 842 (PDGFRA D842V or D842Y).

In conclusion, a small subset of GISTs with otherwise typical clinicopathologic and cytogenetic features do not express detectable KIT protein. When compared with KIT-positive GISTs, these KIT-negative GISTs are more likely to have epithelioid cell morphology, contain PDGFRA oncogenic mutations, and arise in the omentum/peritoneal surface. Notably, some KIT-negative GISTs contain imatinib-sensitive KIT or PDGFRA mutations; therefore, patients with KIT-negative GISTs should not, a priori, be denied imatinib therapy.

c-kit and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue).

Yamamoto H, Oda Y, Kawaguchi K, Nakamura N, Takahira T, Tamiya S, Saito T, Oshiro Y, Ohta M, Yao T, Tsuneyoshi M.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Am J Surg Pathol. 2004 Apr;28(4):479-88. Abstract quote

Extragastrointestinal stromal tumor (EGIST) is a unique tumor that occurs outside the gastrointestinal tract. EGIST shows a c-kit expression and histologic appearance similar to those of gastrointestinal stromal tumor (GIST).

Most GISTs have gain-of-functional mutation of the c-kit gene, and some have mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. However, the frequency of mutation of those genes in EGISTs remains unclear.

We examined the clinicopathologic features, prognostic factors, and c-kit and PDGFRA mutation in 39 cases of EGIST. Tumors with high mitotic counts (>or=5/50 high power fields) or a high Ki-67 labeling index (>or=10%) were significantly correlated with worse prognoses. The c-kit mutation was found in the juxtamembrane domain (exon 11) and the extracellular domain (exon 9) in 12 of 29 cases (41.4%) and 2 of 29 cases (6.9%), respectively. The PDGFRA gene mutation was found at the juxtamembrane domain (exon 12) and the tyrosine kinase domain (exon 18) in one case each. The pattern of kit and PDGFRA mutation in EGIST was essentially similar to that in GIST.

Our results suggest that the c-kit and PDGFRA mutations play an important role in the tumorigenesis of EGIST. High mitotic counts and a high Ki-67 labeling index may be useful for predicting the aggressive biologic behavior in EGIST. Furthermore, STI-571, targeting c-kit and PDGFR tyrosine kinase, seems to be a possible therapeutic strategy for EGISTs, especially advanced cases.

KIT 1530ins6 mutation defines a subset of predominantly malignant gastrointestinal stromal tumors of intestinal origin.

Lasota J, Kopczynski J, Sarlomo-Rikala M, Schneider-Stock R, Stachura T, Kordek R, Michal M, Boltze C, Roessner A, Stachura J, Miettinen M.

Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Hum Pathol. 2003 Dec;34(12):1306-12. Abstract quote  

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and show gain-of-function KIT mutations. Most of these mutations affect the KIT juxtamembrane domain, but other KIT domains are mutated at a lower frequency.

In this study, frequency of GCC TAT insertion mutation (1530ins6) in KIT exon 9 (extracellular domain) and its possible clinicopathologic significance was investigated. Screening of 520 GISTs identified 26 cases with 1530ins6 KIT mutation and confirmed the previously reported low frequency of this type of KIT mutation among GISTs of different locations. Of the 26 tumors with 1530ins6 KIT mutation studied, 21 originated from the small intestine, 1 from the colon, and 3 from the rectum. In 1 case, primary small intestinal versus colonic localization could not be clearly established because of intra-abdominal dissemination. No distinctive morphological features were identified for the cohort of tumors defined by 1530ins6 KIT mutations.

Most of the tumors showed predominant spindle cell morphology, and a few cases had epithelioid or pleomorphic histological features. Following previously published criteria based on tumor size and mitotic rate, 22 of 26 (85%) tumors were classified as malignant or potentially malignant, and 4 (15%) were classified as probably benign. A malignant clinical course was documented in 18 of 19 tumors from the malignant category. The survival times of 11 patients who died of disseminated GISTs ranged from 1 month to 105 months (median survival time, 26 months).

In contrast, 2 of 4 GISTs assigned as probably benign tumors with follow-up information had long disease-free survival. GISTs carrying 1530ins6 occur exclusively in the intestinal location, and a great majority of these tumors follow a malignant course.

Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas.

Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M.

Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.

Am J Pathol 1999 Jan;154(1):53-60 Abstract quote

Gastrointestinal stromal tumors (GISTs) comprise the largest subset of mesenchymal tumors of the gastrointestinal tract. These neoplasms differ histologically and immunohistochemically from typical leiomyomas and leiomyosarcomas. Most GISTs express CD34 and CD117 (c-kit protein) but not desmin. Recently, gain-of-function mutations of c-kit proto-oncogene have been shown in five solitary GISTs and in tumors and leukocytes from a family with multiple GISTs. An in-frame deletion or a point mutation in exon 11 of c-kit was detected in these cases. Stable transfection of the mutant c-kit complementary DNA was also shown to induce malignant transformation of murine lymphoid cells, suggesting that the c-kit mutations contribute to tumor development.

In this study, we evaluated 43 GISTs and 14 smooth muscle tumors for mutations in the exon 11 of c-kit by a PCR-assay. Half of the malignant GISTs (12/24) and only one benign GIST (1/19) revealed mutant bands. No mutant bands were found in 3 leiomyomas and 11 leiomyosarcomas. Sequence analysis confirmed the presence of an in-frame deletion of 3-21 bp in all 13 GISTs with mutant bands. Wild-type bands from 8 malignant and 11 benign GISTs and 7 smooth muscle tumors without mutant bands were cloned and sequenced. Additional mutations were found in 3 malignant and 2 benign GISTs. There were no mutations in 3 leiomyomas and 4 leiomyosarcomas. The mutation status of exon 11 did not correlate with immunohistochemically detectable expression of the CD117, as virtually all GISTs with or without such mutations showed CD117 immunoreactivity.

The c-kit mutations occur preferentially in malignant GISTs and might be a clinically useful adjunct marker in the evaluation of GISTs. The conservation of the c-kit mutation pattern, observed in consecutive lesions from the same patients, suggests that these mutations might be useful tumor markers in monitoring recurrence or minimal residual disease.

Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations.

Heinrich MC, Rubin BP, Longley BJ, Fletcher JA.

Department of Medicine, Division of Hematology/Oncology, Oregon Health Sciences University and Portland VA Medical Center, USA.

Hum Pathol 2002 May;33(5):484-95 Abstract quote

Recent studies have done much to reveal the biological and genetic underpinnings of gastrointestinal stromal tumors (GISTs). Constitutive activation of the KIT receptor tyrosine kinase is a central pathogenetic event in most GISTs and generally results from oncogenic point mutations which can involve either extracellular or cytoplasmic domains of the receptor.

Oncogenic mutations enable the KIT receptor to phosphorylate various substrate proteins, leading to activation of signal transduction cascades which regulate cell proliferation, apoptosis, chemotaxis, and adhesion. KIT mutations can be broadly assigned to 2 groups, those that involve the "regulatory" regions responsible for modulating KIT enzymatic activity and those that involve the enzymatic region itself. In vitro studies suggest that GISTs with regulatory-region KIT mutations are more likely to respond to STI-571 than are GISTs with enzymatic-region mutations. A minority of GISTs lack demonstrable KIT mutations, but KIT is nonetheless strongly activated. Such GISTs might contain KIT mutations which are not readily detected by conventional screening methods, or alternately, KIT might be activated by nonmutational mechanisms.

Most GISTs have noncomplex cytogenetic profiles, often featuring deletions of chromosomes 14 and 22. Additional chromosomal aberrations are acquired as the GISTs progress to higher histologic grade. These cytogenetic aberrations are undoubtedly important in GIST pathogenesis, but currently they do not play a key role as diagnostic adjuncts.


Mod Pathol 1998;11:401A

Most tumors may originate from a mesenchymal stem cell that differentiates toward an interstitial cell of Cajal (ICC) phenotype

Cellular origin of gastrointestinal stromal tumors: a study of 27 cases.

Wang L, Vargas H, French SW.

Departments of Pathology, University of California at Los Angeles, Harbor Medical Center, Torrance, CA, USA.

Arch Pathol Lab Med 2000 Oct;124(10):1471-5 Abstract quote

CONTEXT: Interstitial cells of Cajal (ICCs), also known as pacemaker cells, are cells in the gastrointestinal tract that play a role in the control of gut motility. The ICCs express the c-kit proto-oncogene encoding a type III tyrosine kinase (KIT) receptor, a ligand that is known as stem cell factor (SCF). The maturation of ICCs is dependent on SCF-KIT interaction. The cellular origin, differentiation, nomenclature, and prognosis of gastrointestinal stromal tumors (GISTs) are controversial.

OBJECTIVE: To test the hypothesis that GISTs originate from CD34-positive stem cells and differentiate toward an ICC phenotype.

MATERIALS AND METHODS: We studied 27 cases of smooth muscle differentiated GISTs collected for 14 years (1985-1999), including 8 benign (leiomyoma), 15 malignant primary (leiomyosarcoma), and 4 metastatic to the liver. Immunohistochemical studies of selected lineage-directed monoclonal antibodies of c-kit (CD117), CD34, vimentin, desmin, alpha-actin, S100, and MIB-1 were performed on both normal and tumor tissues. RESULTS: Immunoperoxidase stains of normal gastrointestinal tract showed both c-kit and CD34-positive cells surrounding the Auerbach ganglia plexus in the gastrointestinal tract. Twenty-seven of 27 tumors strongly expressed c-kit. Fourteen of 27 tumors were positive for CD34. Of the malignant GISTs, 14 of 19 were positive for CD34; of the benign tumors, 0 of 8 were positive for CD34. Thus, CD34 was the best indicator of malignant phenotype.

CONCLUSION: This is the first description of benign smooth muscle GISTs negative for CD34. The results of this study suggest that GISTs originate from CD34-positive stem cells and differentiate toward pacemaker cell phenotype. The lack of expression of CD34 in the benign GIST may indicate that benign GISTs are composed of more mature ICCs, whereas malignant GISTs are composed of dedifferentiated ICCs that express CD34-positive stem cells.


Complex genetic alterations in gastrointestinal stromal tumors with autonomic nerve differentiation.

Debiec-Rychter M, Pauwels P, Lasota J, Franke S, De Vos R, De Wever I, Hagemeijer A, Sciot R.

Center for Human Genetics (MD-R, AH, SF), Laboratory for Morphology and Molecular Pathology (RDV, RS), and Department of Surgery (IdW), Katholieke Universiteit Leuven, Belgium.

Mod Pathol 2002 Jul;15(7):692-8 Abstract quote

Gastrointestinal stromal tumors (GISTs) with neurogenic differentiation, also referred to as "gastrointestinal autonomic nerve tumors (GANTs)," form an ultrastructurally distinctive subgroup of mesenchymal neoplasms of gastrointestinal tract. Cytogenetic and molecular data of these tumors are limited.

In the current study, c-KIT gene sequenc-ing analysis, comparative genomic hybridization (CGH), and interphase fluorescence in situ hybrid- ization (FISH) analysis, utilizing chromosome 14- and 22-specific probes, were performed on five primary ultrastructurally confirmed GANTs. FISH and CGH analysis revealed loss of a whole or part of chromosome 14q in two tumors and of chromo- some 22q, with the common overlapping area of loss at q13, in all five tumors evaluated. c-KIT mu- tations were found in all cases; three tumors carried point mutation and/or deletions of exon 11, and in two tumors, insertion in exon 9 was found.

These findings suggest that accumulated genetic changes contribute to the pathogenesis of GANTs and that 22q13 loss may be a characteristic feature of these tumors.


Cyclooxygenase-2 expression in stromal tumors of the gastrointestinal tract.

Sheehan KM, Sabah M, Cummins RJ, O'Grady A, Murray FE, Leader MB, Kay EW.

Department of Pathology, Beaumont Hospital, Dublin, Ireland.

Hum Pathol. 2003 Dec;34(12):1242-6. Abstract quote  

Cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostaglandins, prostacyclin, and thromboxane. COX-2 is expressed in many epithelial malignancies, particularly those of the gastrointestinal (GI) tract. COX-2 has been implicated in the pathogenesis of cancers and has a significant negative effect on survival. To date, little is known about the expression of COX-2 in nonepithelial tumors.

The objective of this study was to evaluate the expression of COX-2 in GI stromal tumors (GISTs). We evaluated 15 GISTs using tissue microarray. Tissue blocks were retrieved and stained with hematoxylin and eosin to evaluate the histological tumor type. In addition, immunohistochemistry was performed for COX-2, the macrophage marker, CD68 (KP-1), and KIT (CD117). Two pathologists then evaluated the tissues to determine the extent and intensity of COX-2 expression. The location of CD68-positive cells, and whether these cells were COX-2 positive, was also evaluated. The results showed that 80% (12 of 15) of the tumors expressed COX-2. Expression was noted in the cytoplasm of the tumor cells, with variable intensity of staining among the tumors. COX-2 was expressed in both epithelial cell and spindle cell tumors, but appeared stronger in epithelial lesions. In mixed lesions, COX-2 was expressed to a greater extent in epithelial areas. There was a greater extent of COX-2 expression in malignant tumors and tumors located within the stomach. Tumor-infiltrating macrophages (CD68-positive cells) were identified in all of the lesions; in 80% of cases, those macrophages also expressed COX-2.

This study is the first to demonstrate COX-2 expression in stromal lesions of the GI tract. The enzyme may play a role in the proliferation of these lesions, suggesting the potential use of nonsteroidal anti-inflammatory drugs in treatment.
EGFR and gastrointestinal stromal tumor: an immunohistochemical and FISH study of 82 cases.

1Consultoria em Patologia, Botucatu, Sao Paulo, Brazil.


Mod Pathol. 2007 Sep;20(9):990-4. Abstract quote

Gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract. Mutually exclusive KIT or platelet-derived growth factor receptor-alpha mutations are key events in gastrointestinal stromal tumor pathogenesis, and specific treatment targeting KIT/platelet-derived growth factor receptor-alpha activation is available. Epidermal growth factor receptor plays an important role in cancer biology and also constitutes a promising molecular target of therapy. Very few reports have been published in the literature about the relationship between gastrointestinal stromal tumor and epidermal growth factor receptor.

The aim of this study was to investigate epidermal growth factor receptor immunohistochemical expression and epidermal growth factor receptor gene amplification in 82 consecutive gastrointestinal stromal tumor cases using tissue microarray technique. Hematoxylin- and eosin-stained sections and clinical information were reviewed, and expression of CD117 (KIT), CD34 and epidermal growth factor receptor was investigated by immunohistochemistry. Epidermal growth factor receptor gene copy number was determined using fluorescence in situ hybridization. Immunohistochemistry revealed that CD117 and CD34 were expressed in 96 and 57% of tumors, respectively. Variable epidermal growth factor receptor protein immunohistochemical overexpression was detected in 96% of gastrointestinal stromal tumor cases, but none of the 75 cases with represented tumor tissue cores and countable fluorescence signals exhibited epidermal growth factor receptor gene amplification by fluorescence in situ hybridization.

These results show that there is no correlation between epidermal growth factor receptor protein overexpression by immunohistochemistry and epidermal growth factor receptor gene amplification by fluorescence in situ hybridization.

Considering that the mechanisms of epidermal growth factor receptor protein overexpression are not well understood and the possibility that anti-epidermal growth factor receptor therapy may be beneficial for patients with gastrointestinal stromal tumor that overexpresses epidermal growth factor receptor, additional studies are encouraged.

Detection of c-kit–Activating Mutations in Gastrointestinal Stromal Tumors by High-Resolution Amplicon Melting Analysis

Carlynn Willmore, MT(ASCP), Joseph A. Holden, MD, PhD, Luming Zhou, PhD, Sheryl Tripp, MT(ASCP), QIHC(ASCP), Carl T. Wittwer, MD, PhD, and Lester J. Layfield, MD
Am J Clin Pathol 2004;122:206-216 Abstract quote

High-resolution amplicon melting analysis was used to scan for c-kit–activating mutations in exons 9, 11, 13, and 17 in 29 neoplasms diagnosed as gastrointestinal stromal tumors (GISTs).

Immunohistochemically, 7 of 29 did not show strong CD117 positivity and might represent true smooth muscle tumors or c-kit–negative GISTs. No c-kit–activating mutations were detected in the 7 CD117– cases by high-resolution amplicon melting analysis or direct DNA sequencing. Alterations in the remaining 22 CD117+ cases included 13 (59%) in exon 11, 2 (9%) in exon 9, 1 (5%) in exon 13, and none in exon 17. The genetic alterations consisted of point mutations and in-frame insertions, duplications, and deletions. In exon 11, 7 (54%) of 13 alterations have not been described previously.

In 2 cases, the identical exon 11 mutation was observed in the primary tumor and a metastatic/recurrent lesion. In all cases, direct DNA sequencing confirmed that polymerase chain reaction products with an abnormal melting curve contained a mutation and products with a normal melting curve, a normal DNA sequence.

High-resolution melting analysis can be used to scan DNA for potential c-kit–activating mutations and can aid in the diagnosis of GISTs.




Diagnosis of gastrointestinal stromal tumors: A consensus approach.

Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115, USA.


Hum Pathol 2002 May;33(5):459-65 Abstract quote

As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GISTs), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and the development of novel and effective therapy for GISTs using the receptor tyrosine kinase inhibitor STI-571, these tumors have become the focus of considerable attention by pathologists, clinicians, and patients.

Stromal/mesenchymal tumors of the gastrointestinal tract have long been a source of confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication.

Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity in diagnosis and a proposed scheme for estimating metastatic risk in these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term "benign" for any GIST, at least at the present time.


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

Miettinen M, Kopczynski J, Makhlouf HR, Sarlomo-Rikala M, Gyorffy H, Burke A, Sobin LH, Lasota J.


Am J Surg Pathol 2003 May;27(5):625-41 Abstract quote

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 of the Jejunum and Ileum: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 906 Cases Before Imatinib With Long-term Follow-up.

Miettinen M, Makhlouf H, Sobin LH, Lasota J.

*Departments of Soft Tissue Pathology daggerHepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC.

Am J Surg Pathol. 2006 Apr;30(4):477-489. Abstract quote  

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 </=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 </=5/50 HPF and those </=5 cm with mitoses >5/50 HPF had a high metastatic rate (>50%); tumors >5 cm </=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.
67% (Most common site)

Gastric stromal tumors: a clinicopathologic study of 77 cases with correlation of features with nonaggressive and aggressive clinical behaviors.

Trupiano JK, Stewart RE, Misick C, Appelman HD, Goldblum JR.

Departments of Anatomic Pathology (J.K.T., J.R.G.).

Am J Surg Pathol 2002 Jun;26(6):705-14 Abstract quote

Gastrointestinal stromal tumors are a heterogeneous group of neoplasms that have clinical and histologic features that vary depending on their location within the gastrointestinal tract. Prediction of clinical behavior in this group of tumors is notoriously difficult, and the same criteria for malignancy do not necessarily apply to stromal tumors from different sites within the gastrointestinal tract.

Using known clinical behavior with long-term follow-up, we attempted to determine which features, if any, are associated with clinical behavior in stromal tumors arising in the stomach, the most common site for such tumors. Seventy-seven gastric stromal tumors were studied and classified as "adverse outcome (AO) tumors" (malignant) or "nonadverse outcome tumors" (benign) based on their known clinical outcome. AO was defined as metastasis and/or death due to tumor. Patients with a non-AO had at least 5 years of tumor/metastasis-free follow-up.

Thirty-seven patients had an AO (follow-up [metastasis at presentation] 0-73 months; median 6 months), and 40 patients had a non-AO (follow-up 60-264 months; median 84 months). All cases were reviewed by two authors (J.R.G., H.D.A.), who were blinded to clinical outcome and gross features, and classified as histologically benign or not benign using preset, defined histologic criteria based upon the authors' prior experience with a large number of these tumors. If the tumor did not fit with either the characteristic cellular spindle cell or benign epithelioid cell patterns, the tumor was classified as not benign.

Clinical outcome was then correlated with the histologic designation to determine if these preset criteria were valid. The authors were able to accurately classify the tumors as benign or not benign with a sensitivity of 100% and a specificity of 92%. In addition, for all cases individual morphologic and clinical features were examined. Features associated with an AO included tumor size >/=7 cm, high cellularity, mucosal invasion, high nuclear grade, mitotic counts >/=5/50 high power fields, mixed cell type, and the presence of a myxoid background and/or absence of stromal hyalinization.

By recognizing several well-defined patterns of benign gastric stromal tumors and the myriad of individual features shown to correlate with an AO, one can better predict the clinical behavior of gastric stromal tumors.

25% (1/3 of these arise in the duodenum)

Jejunal gastrointestinal stromal tumor: a cause of obscure gastrointestinal bleeding.

Sass DA, Chopra KB, Finkelstein SD, Schauer PR.

Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa, USA.
Arch Pathol Lab Med. 2004 Feb;128(2):214-7. Abstract quote  

In cases of obscure gastrointestinal bleeding, when a source for blood loss is not apparent from examination of the colon and upper gastrointestinal tract, the small bowel usually becomes the focus of investigation.

A tumor with interesting pathologic features was found in a patient who presented with recurrent episodes of massive obscure gastrointestinal hemorrhage.

This case highlights the importance of considering small intestinal tumors as the likely cause of obscure gastrointestinal hemorrhage in young patients and how a noninvasive test, eg, abdominal computed tomography scan, might obviate the need for more invasive testing.

Gastrointestinal Stromal Tumors in the Appendix A Clinicopathologic and Immunohistochemical Study of Four Cases

Markku Miettinen, M.D. ; Leslie H. Sobin, M.D.

From the Department of Soft Tissue Pathology (M.M.) and the Division of Gastrointestinal Pathology (L.H.S.), Armed Forces Institute of Pathology, Washington, DC, U.S.A.

Am J Surg Pathol 2001;25:1433-1437 Abstract quote

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 -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.


Stromal Tumor of the Gallbladder With Phenotype of Interstitial Cells of Cajal A Previously Unrecognized Neoplasm

Carlos Ortiz-Hidalgo, M.D.; Beatriz de Leon Bojorge, M.D.; Jorge Albores-Saavedra, M.D.

From the Department of Pathology (C.O.-H., B.d.L.-B.), The American British Cowdray Medical Centre, Mexico City, Mexico; and the Division of Anatomic Pathology, Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. (J.A.-S.).

Am J Surg Pathol 2000;24:1420-1423 Abstract quote

We report a small, well-demarcated stromal tumor of the gallbladder in a 69-year-old woman.

The tumor and associated cholelithiasis led to chronic cholecystitis symptoms. The wall of the gallbladder contained a 2.4-cm hypocellular nodule composed of bland spindle-shaped cells that were immunoreactive for vimentin, CD34, and CD117. With the latter antibody, which stains interstitial cells of Cajal (ICC), the neoplastic cells appear fusiform with elongated bipolar projections or dendritic-like cytoplasmic projections. The gallbladder wall adjacent to the tumor contained numerous CD117-positive cells in close contact with the normal smooth muscle cells, whereas two of 10 gallbladders with minimal chronic cholecystitis showed only a few CD117-positive cells. These findings provide evidence that this stromal tumor of the gallbladder shows ICC differentiation similar to some stromal tumors of the gut.

The presence of numerous ICC in the uninvolved gallbladder wall suggests that this tumor might have evolved through hyperplasia of ICC.

Multiple Gastrointestinal Stromal Tumors: Clinicopathologic and Genetic Analysis of 12 Patients.

daggerDepartment of Pathology, Samsung Medical Center, Sungkyunkwan University *Department of Pathology, Chungnam National University double daggerDepartment of Pathology, Korea University section signDepartment of Pathology, Soonchunhyang University parallelDepartment of Pathology, Inje University paragraph signDepartment of Pathology, Chunbuk National University musical sharpDepartment of Pathology, Wonkwang University **Department of Pathology, Asan Medical Center, Ulsan University daggerdaggerDepartment of Pathology, Pochon Cha University, School of Medicine, Korea.

Am J Surg Pathol. 2007 Feb;31(2):224-232. Abstract quote

Multiple gastrointestinal stromal tumors (GISTs) are extremely rare and usually associated with type 1 neurofibromatosis and familial GIST.

The aim of this study was to investigate the clinical, phenotypic, and genetic characteristics of multiple GISTs to gain insights into their underlying pathogenesis and clinical behavior. Forty-seven paraffin blocks of multiple GISTs from 12 patients were analyzed. Genomic DNA was extracted from the tumor and normal mucosa and mutations for 4 exons of KIT gene and 3 exons of PDGFRA gene were determined. Among 12 patients with multiple GISTs, 5 were sporadic, 2 were familial with germline mutations of KIT gene, and 5 were associated with type 1 neurofibromatosis. All but 1 sporadic and familial multiple GISTs showed mutations of KIT gene shared by the same mutation on each GIST mass within a patient. But in 1 sporadic case, different types of KIT mutations were observed. Two familial multiple GIST cases showed diffuse involvement of the gastrointestinal tract with diffuse hyperplasia of interstitial cell of Cajal. Multiple GISTs associated with type 1 neurofibromatosis were located in the jejunum and harbored no mutations of KIT or PDGFRA.

Different types of KIT gene mutation found in our case raise a possibility that recurrence of GISTs within a gastrointestinal tract may have a chance to be a rare occurrence of multiple primary GISTs instead of true recurrence.

Multiple GISTs show unique clinical, phenotypic, and genotypic characteristics that are dependent on the particular underlying mechanisms, but the overall prognosis is favorable regardless of the numbers or phenotype of GISTs.

Multiple gastrointestinal stromal tumors in type I neurofibromatosis: a pathologic and molecular study.

Yantiss RK, Rosenberg AE, Sarran L, Besmer P, Antonescu CR.

1Department of Pathology, UMass Memorial Health Care, Worcester, MA, USA.
Mod Pathol. 2005 Apr;18(4):475-84. Abstract quote  

Multiple gastrointestinal stromal tumors typically occur in familial form associated with KIT receptor tyrosine kinase or platelet-derived growth factor receptor-alpha (PDGFRA) germline mutations, but may also develop in the setting of type 1 neurofibromatosis. The molecular abnormalities of gastrointestinal stromal tumors arising in neurofibromatosis have not been extensively studied.

We identified three patients with type 1 neuro-fibromatosis and multiple small intestinal stromal tumors. Immunostains for CD117, CD34, desmin, actins, S-100 protein, and keratins were performed on all of the tumors. DNA was extracted from representative paraffin blocks from separate tumor nodules in each case and subjected to a nested polymerase chain reaction, using primers for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18, followed by direct sequencing. The mean patient age was 56 years (range: 37-86 years, male/female ratio: 2/1). One patient had three tumors, one had five, and one had greater than 10 tumor nodules, all of which demonstrated histologic features characteristic of gastrointestinal stromal tumors and stained strongly for CD117 and CD34. One patient died of disease at 35 months, one was disease free at 12 months and one was lost to follow-up. DNA extracts from 10 gastrointestinal stromal tumors (three from each of two patients and four from one patient) were subjected to polymerase chain reactions and assessed for mutations. All of the tumors were wild type for KIT exons 9, 13, and 17 and PDGFRA exons 12 and 18. Three tumors from one patient had identical point mutations in KIT exon 11, whereas the other tumors were wild type at this locus.

We conclude that, although most patients with type 1 neurofibromatosis and gastrointestinal stromal tumors do not have KIT or PDGFRA mutations, KIT germline mutations might be implicated in the pathogenesis of gastrointestinal stromal tumors in some patients.



Spindled cells with varying cellularity, either spindled or epithelioid
Arranged in whorled, fascicular, and palisaded patterns

Small intestinal tumors may have skenoid fibers (rounded accumulations of collagen)

Gastrointestinal Stromal Tumors, Intramural Leiomyomas, and Leiomyosarcomas in the Rectum and Anus A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 144 Cases

Markku Miettinen, M.D.; Mary Furlong, M.D.; Maarit Sarlomo-Rikala, M.D.; Allen Burke, M.D.; Leslie H. Sobin, M.D.; Jerzy Lasota, M.D.

From the Departments of Soft Tissue Pathology (M.M., M.F., J.L.), Cardiovascular Pathology (A.B.), and Gastrointestinal Pathology (L.H.S.), Armed Forces Institute of Pathology, Washington, DC, U.S.A.; and the Department of Pathology (M.S.-R.), Haartman Institute of the University of Helsinki, Helsinki, Finland.

Am J Surg Pathol 2001;25:1121-1133 Abstract quote

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.


Diagnosis of gastrointestinal stromal tumor by endoscopic ultrasound-guided fine needle aspiration biopsy-a potential pitfall.

Fu K, Eloubeidi MA, Jhala NC, Jhala D, Chhieng DC, Eltoum IE.

Departments of Pathology and Gastroenterology and Hepatology, The University of Alabama at Birmingham, AL.

Ann Diagn Pathol 2002 Oct;6(5):294-301 Abstract quote

Endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNA) is considered to be a reliable and accurate method for the evaluation of submucosal lesions in the gastrointestinal tract. Herein, we report our experience with the diagnosis of 10 cases of gastrointestinal stromal tumor (GIST) using EUS-FNA. The materials obtained from the EUS-FNA were stained with the rapid Romanowsky or the Papanicolaou method for cytologic examination. The subsequent surgical resection specimens were submitted for histopathologic examination.

Immunoperoxidase stains were performed on the cell blocks and/or representative histologic sections of the tumor using commercially available antibodies against c-kit (CD117), CD34, S-100, and smooth muscle actin. Of the 10 cases studied, there were five men and five women with an average age of 62 years (range, 38 to 87 years). Five tumors were located in the stomach, and five in the duodenum. Tumor size ranged from 3.5 to 16.2 cm. Immediate on-site evaluation and cytologic diagnoses were given in eight cases (80%) with an average of three passes. The diagnoses were confirmed by strong and diffuse tumor cell c-kit immunoreactivity in the cell blocks. However, the final diagnoses of two other cases (20%) were not established until surgical resections were obtained.

Retrospectively, reviews of cytologic smears of both cases demonstrated rare cohesive sheets or clusters of spindle cells with cigar-shaped nuclei. These observations were initially misinterpreted as benign fibrous tissue and/or fragments of smooth muscle of the gastrointestinal wall such as one might encounter in a routine transgastric or transduodenal EUS-FNA.

The current study showed that when combining cytologic and immunocytochemical studies, EUS-FNA is accurate and efficient in the diagnosis of GIST. It exemplified the importance of considering GIST in the differential diagnosis of gastrointestinal lesions and also demonstrated the potential pitfalls of EUS-FNA evaluation of submucosal lesions in the gastrointestinal tract.

Gastrointestinal autonomic nerve tumor (GANT)

Tumor shows ultrastructural differentiation toward myenteric nerve plexus elements

More common in males with mean age of 55 years

Most >10 cm

Spindle cell tumors with skenoid fibers and myxoid change

Majority are malignant with 85% of tumors that metastasized >10 cm and had >5 mitoses per 10 hpf


Malignant gastrointestinal leiomyosarcoma and gastrointestinal stromal tumor with prominent osteoclast-like giant cells.

Insabato L, Di Vizio D, Ciancia G, Pettinato G, Tornillo L, Terracciano L.

Dipartimento di Anatomia Patologica, Facolta di Medicina, Universita Federico II, Napoli, Italy.
Arch Pathol Lab Med. 2004 Apr;128(4):440-3. Abstract quote

CONTEXT: One case of leiomyosarcoma and one case of gastrointestinal stromal tumor with prominent osteoclast-like giant cells have so far been reported in the digestive tract.

OBJECTIVE: To ascertain the clinicopathologic features and biologic behavior of these tumors, we report 3 additional cases of leiomyosarcoma of the gastrointestinal tract and one malignant gastrointestinal stromal tumor.

DESIGN: Histologic and immunohistochemical examinations were performed. Clinical and follow-up data were recorded, and the literature was reviewed.

RESULTS: The age of the patients ranged from 50 to 68 years (mean, 62 years). One of the lesions arose in the stomach, one in the ileum, and 2 in the colon. Three tumors showed a strong positivity for muscle actin and desmin and were diagnosed as leiomyosarcomas, 2 of them showing spindle cells and 1 of them showing epithelioid cells. The fourth tumor reacted strongly positive for c-Kit (CD117) and vimentin, and it was diagnosed as an epithelioid malignant gastrointestinal stromal tumor. All tumors were characterized by numerous osteoclast-like giant cells that were unevenly distributed and that, using immunohistochemistry, reacted strongly with CD68.

CONCLUSIONS: Malignant stromal tumors with osteoclast-like giant cells of the gastrointestinal tract are rare entities, are more commonly of a myogenic origin such as leiomyosarcoma, and seem to have an aggressive behavior.

A Malignant Gastrointestinal Stromal Tumor With Osteoclast-like Giant Cells.

Leung KM, Wong S, Chow TC, Lee KC.

Department of Pathology, Princess Margaret Hospital, Kowloon, Hong Kong.

Arch Pathol Lab Med 2002 Aug;126(8):972-4 Abstract quote

Gastrointestinal stromal tumors (GISTs) are a heterogeneous group of mesenchymal tumors with a wide spectrum of histologic features and consistent expression of c-Kit.

We describe an 85-year-old woman who presented with left lower quadrant abdominal pain and was subsequently diagnosed as having a malignant GIST. The tumor was composed of short fascicles of spindle cells. In addition to the presence of tumor giant cells, the tumor also demonstrated many osteoclast-like giant cells, a feature that has not been previously described in the literature. These giant cells expressed histiocytic markers CD68 and alpha(1)-antitrypsin but not c-Kit, a marker for GISTs. Electron microscopy showed no features of smooth muscle differentiation in the giant cells.

The possible origin of the osteoclast-like giant cells is discussed in the context of immunohistochemical and ultrastructural characteristics.

Myxoid epithelioid gastrointestinal stromal tumor (GIST) with mast cell infiltrations: A subtype of GIST with mutations of platelet-derived growth factor receptor alpha gene.

Sakurai S, Hasegawa T, Sakuma Y, Takazawa Y, Motegi A, Nakajima T, Saito K, Fukayama M, Shimoda T.
Hum Pathol. 2004 Oct;35(10):1223-30 Abstract quote.  

We analyzed 30 gastrointestinal stromal tumors (GISTs) that were immunohistochemically weak or negative for KIT. Histologically, all 30 GISTs consisted of epithelioid tumor cells in at least a part of the tumor. The tumor cells showed different morphologies and arranged themselves in different histological patterns.

In 20 of the 30 GISTs, round or oval epithelioid tumor cells often showed a less cohesive pattern of growth and showed eosinophilic cytoplasm and peripherally placed nuclei with myxoid stroma, whereas in the remaining 10 cases, tumor cells were arranged in a more cohesive pattern without myxoid stroma. The former type of tumors is called myxoid epithelioid GISTs in this study. Subsequent mutational analyses showed that the platelet-derived growth factor receptor alpha (PDGFRA) gene mutations in exon 12 or exon 18 were identified in 20 (66.7%) of the 30 GISTs, and especially in 18 (90%) of the 20 myxoid epithelioid GISTs. Moreover, 17 (85%) of the 20 myxoid epithelioid GISTs were accompanied by mast cell infiltrations within the tumor nodules. In the remaining cases, 2 (6.7%) of the 30 GISTs had c-kit gene mutations in exon 11, and no mutation was found in 8 (26.7%) of 30 GISTs. None of the patients with myxoid epithelioid GISTs died of disease.

These results suggest that myxoid epithelioid GISTs are a distinct subtype of GISTs that are closely correlated with the PDGFRA gene mutation and that recognition of such histological characteristics should be helpful for molecular subclassification of GISTs that are important for molecular targeting therapy by imatinib mesylate (STI571).
Minute Gastric Sclerosing Stromal Tumors (GIST Tumorlets) Are Common in Adults and Frequently Show c-KIT Mutations.

*Institute of Pathology, Nuremberg, Germany daggerInstitute of Pathology, University of Regensburg, Germany double daggerDepartment of Pathology, University of Vermont College of Medicine, Burlington, VT 05405.


Am J Surg Pathol. 2007 Jan;31(1):113-120. Abstract quote

Multifocal hyperplasia of interstitial cells of Cajal (ICC hyperplasia) is a precursor of hereditary gastrointestinal stromal tumors (GISTs) in patients with germline mutations of c-KIT or PDGFRA, but precursor lesions of sporadic GISTs have not been defined yet.

Small hyalinizing stromal tumors of the proximal stomach (referred to in this study as GIST tumorlets) were collected prospectively from 98 consecutive autopsies and additional cases were retrieved from surgical pathology files (total n=57). GIST tumorlets were grossly detectable in 22.5% consecutive autopsies performed in individuals older than 50 years.

All lesions were located in the cardia, fundus, or proximal body, and ranged in size from 1 to 10 mm (4 mm). Similar lesions were not detected in the antrum, duodenum, and the remainder of the bowel. Histologically, the spindle cell subtype comprised all cases, with hyalinization and calcification in 57% of cases. The spindle cells were immunohistochemically positive for vimentin, CD117, and CD34. Twenty-four cases yielded sufficient DNA for subsequent molecular analysis, which showed c-KIT mutations in 11 cases (46%) and PDGFRA mutations in 1 case (4%). Sporadic GIST tumorlets of the proximal stomach are common in the general population over the age of 50 years and frequently show somatic c-KIT mutations. GIST tumorlets probably represent the grossly recognizable counterpart of sporadic ICC hyperplasia caused by somatic c-KIT or PDGFRA mutations. Early hyalinization and calcification seems to confer limited growth potential, and complete regression of such lesions is common.

GIST tumorlets likely represent preclinical (preneoplastic) lesions that need additional stimuli to evolve into clinical GISTs, raising the possibility of a hyperplasia-neoplasia sequence in the development of sporadic GISTs.



beta-Catenin Immunohistochemistry Separates Mesenteric Fibromatosis From Gastrointestinal Stromal Tumor and Sclerosing Mesenteritis.

Montgomery E, Torbenson MS, Kaushal M, Fisher C, Abraham SC.

Am J Surg Pathol 2002 Oct;26(10):1296-301 Abstract quote

Although separating gastrointestinal stromal tumor (GIST) from mesenteric fibromatosis and sclerosing mesenteritis is clinically important, this distinction sometimes poses problems for practicing pathologists. In the STI571 (Gleevec, Imatinib) era, the problem may be further compounded when protocol-driven staining for CD117 (c-kit) is performed on spindle cell proliferations presenting in the bowel wall and mesentery using an antibody known to react with the majority of mesenteric fibromatoses when other antibodies are more specific.

Because most mesenteric fibromatoses have mutations in the pathway and hence have abnormal nuclear accumulation of beta-catenin protein, we studied beta-catenin expression among a panel of other immunohistochemical stains to distinguish mesenteric fibromatosis, GIST, and sclerosing mesenteritis. Examples of gastrointestinal stromal tumors (GIST, 11), sclerosing mesenteritis (5), and mesenteric fibromatosis (10) were retrieved from the archives of our institutions.

Cases were studied with an immunohistochemical panel consisting of CD117, beta-catenin, CD34, smooth muscle actin, desmin, keratin, and S-100 protein. Cases were scored as "negative," "focally positive," or "diffusely positive." In evaluating beta-catenin, nuclear accumulation was required. GIST all had CD117 (11 of 11, diffuse) and CD34 (11 of 11, diffuse) with variable actin (5 of 11, focal) and negative desmin, keratin, S-100 protein. All GIST lacked beta-catenin (0 of 11). Mesenteric fibromatosis had CD117 (6 of 10, 3 focal, 3 diffuse), typically expressed more weakly than in GIST, actin (5 of 9, focal), and desmin (3 of 8, focal) in keeping with myofibroblastic differentiation but lacked CD34, S-100, and keratin. CD117 staining was not eliminated by use of a non-avidin-biotin technique. Nuclear beta-catenin was detected in 9 of 10 fibromatoses, including one case associated with familial adenomatous polyposis. Two of five sclerosing mesenteritis cases focally expressed CD117. None of the sclerosing mesenteritis cases had nuclear beta-catenin. Sclerosing mesenteritis cases were otherwise fibroblastic and myofibroblastic with focal actin in 5 of 5 and negative desmin, keratin, and S-100 protein but one had CD34 (1 of 5, focal).

With increasing protocol-driven interest in evaluating bowel wall and mesenteric spindle cell lesions using CD117 (c-kit) antibodies, it is important for practicing pathologists to be aware that lesions other than GISTs are likely to express this antigen using certain antibodies. beta-Catenin staining identifies lesions that are, instead, mesenteric fibromatoses.

CD117 (c-kit)

CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34.

Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M.

Department of Pathology, Haartman Institute, University of Helsinki, Finland.

Mod Pathol 1998 Aug;11(8):728-34 Abstract quote

Gastrointestinal stromal tumors (GISTs) represent a distinct and the most important subset of mesenchymal tumors of the GI tract. These tumors are both phenotypically and genotypically different from true leiomyomas and usually express CD34, a hematopoietic progenitor cell antigen. CD34, however, is also present in a wide variety of fibroblastic and endothelial cell tumors.

In this immunohistochemical study of CD117, we evaluated 85 cases of GIST and more than 150 other mesenchymal tumors, including leiomyomas and schwannomas. CD117, the c-kit proto-oncogene product, is expressed in subsets of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal of the GI tract. CD117 was almost always (85%) expressed in both benign and malignant GISTs. CD117 was observed both in the spindle cell and epithelioid subtypes of GISTs in all locations. In addition to reacting with the CD34-positive GISTs, CD117 was positive in some CD34-negative cases. Approximately one-third of GISTs coexpressed CD117 and smooth muscle actins.

In contrast, true leiomyomas (desmin and actin-positive) and schwannomas in both GI and peripheral locations were consistently negative for CD117. Solitary fibrous tumors and Kaposi's sarcomas, which are typically CD34 positive, were consistently CD117 negative. Among the CD34-positive tumors that showed occasional CD117 reactivity were dermatofibrosarcoma protuberans (1 of 7) and hemangiopericytoma (2 of 10). Other mesenchymal tumors that were variably CD 117 positive included clear cell sarcoma (7 of 15), metastatic melanoma (9 of 25), and malignant fibrous histiocytoma (1 of 20). These results indicate that CD117 is a specific marker for GIST among tumors that occur in the GI tract and adjacent regions. CD117 expression also separates GISTs from true leiomyomas and gastric schwannomas.


c-kit Mutations in Gastrointestinal Stromal Tumors Occur Preferentially in the Spindle Rather Than in the Epithelioid Cell Variant

Eva Wardelmann, M.D., Iris Neidt, Ph.D., Erhard Bierhoff, M.D., Nicola Speidel, M.D., Christoph Manegold, M.D., Hans-Peter Fischer, M.D., Ulrich Pfeifer, M.D. and Torsten Pietsch, M.D.

Department of Pathology (EW, H-PF, UP), Department of Neuropathology (IN, TP), and Department of Surgery (NS), University of Bonn Medical Center, Bonn, Germany; Institute of Pathology (EB), Essen, Germany; Bernhard Nocht Institute for Tropical Medicine (CM), Hamburg, Germany


Mod Pathol 2002;15:125-136 Abstract quote

Gastrointestinal stromal tumors (GISTs) coexpress CD34 and the Kit tyrosine-kinase receptor (CD117). A subset of GISTs carry gain-of-function mutations of the c-kit proto-oncogene in its juxtamembrane domain. The relationship between the mutational status and histological as well as immunohistochemical features has not been assessed in detail.

36 GISTs and 14 other gastrointestinal mesenchymal tumors were investigated for their morphology and immunophenotype as well as for the presence of c-kit mutations. DNA was extracted from formalin-fixed, paraffin-embedded tissue. Exons 9, 11, 13, and 17 of c-kit were analyzed by SSCP. Bands with altered mobility were excised, reamplified, and sequenced. C-kit mutations in Exon 11 encoding the juxtamembrane domain were identified in 19 cases (52.8%), with deletions in 12 cases, insertions in 3 cases (2 of these as duplications), and point mutations in 4 cases. The mutations clustered between Codons 553 and 561, pinpointing the critical region for deregulated Kit receptor activation. In both Exons 9 and 13, single mutations could be identified, whereas no mutations were found in Exon 17. There were c-kit mutations in 66.6% of benign GISTs (14/21), 83.3% of the malignant (5/6), and 40% of the cases of intermediate malignancy (2/5). A low frequency of mutations in benign GISTs, as reported previously by other researchers, could not be observed in our panel. Interestingly, all GISTs with c-kit mutations displayed a spindle cell phenotype, whereas mutations were absent in all 7 tumors with an epithelioid component (P = .03).

This finding suggests a relationship between c-kit mutation and histological subtype in GISTs.

Gastrointestinal stromal tumor: Consistent CD117 immunostaining for diagnosis, and prognostic classification based on tumor size and MIB-1 grade.

Hasegawa T, Matsuno Y, Shimoda T, Hirohashi S.

Pathology and Clinical Laboratory Divisions, National Cancer Center Research Institute and Hospital, Tokyo, Japan.

Hum Pathol 2002 Jun;33(6):669-76 Abstract quote

Gain-of-function c-kit gene mutations and immunoreactivity of the c-kit protein CD117 in many gastrointestinal stromal tumors (GISTs) seem to support the idea that GISTs form a biologically distinct entity.

In this study, the clinicopathologic features of 171 cases of GIST at a single institution were investigated for accurate diagnosis, and their relative risk for mortality was estimated by multivariate analysis. A GIST was defined diagnostically as a mesenchymal spindle or epithelioid cell lesion arising in the wall of the gastrointestinal tract with consistent immunoreactivity for CD117. The 171 patients with GISTs comprised 96 males (56.1%) and 75 females (43.9%), with a mean age of 59.4 years. One hundred and forty-five tumors (84.8%) occurred in the stomach, 18 (10.5%) in the small intestine, 6 (3.5%) in the rectum, and 2 (1.2%) in the esophagus. The median tumor size was 4.5 cm (range, 1.2 to 38 cm). Spindle-cell GISTs were present in 132 cases (77.2%); mixed GISTs, in 25 cases (14.6%); and epithelioid GISTs, in 14 cases (8.2%). Ten cases (55.6%) of spindled small intestine GIST contained eosinophilic skeinoid fibers.

Immunoreactivity for CD34, h-caldesmon, alpha-smooth-muscle actin (SMA), desmin, and S-100 was observed in 156 (91.2%), 131 (76.6%), 46 (26.9%), 7 (4.1%), and 14 (8.2%) tumors, respectively. The percentage of CD34 positivity (38.8%) was low, in contrast with the high percentage of reactivity for SMA (77.8%) and S-100 (44.4%) in small intestine GISTs. By our histologic grading system using tumor differentiation, MIB-1 score, and necrosis, 129 tumors (75.4%) were classified as low grade and 42 tumors (24.6%) were classified as high grade. With a median follow-up period of 83.5 months for 122 living patients, the 5-year and 10-year survival rates were 81.7% and 67.4%, respectively. Multivariate analysis showed that both tumor size >10 cm and high grade were significantly associated with a poor outcome. As a result, GISTs >10 cm or high grade, 5 to 10 cm and low grade, and </=5 cm and low grade were regarded as high risk, intermediate risk, and low risk for mortality, respectively.

In conclusion, it is important to recognize GISTs that have a specific molecular pathogenesis and to separate them from other mesenchymal tumors with optimal immunostaining for CD117 when making a diagnosis and prognostic classification based on tumor size and MIB-1 grade.

Immunohistochemical comparison of gastrointestinal stromal tumor and solitary fibrous tumor.

Shidham VB, Chivukula M, Gupta D, Rao RN, Komorowski R.

Department of Pathology, Medical College of Wisconsin, Milwaukee (Drs Shidham, Chivukula, Rao, and Komorowski) and the University of Pittsburgh-Shadyside Hospital, Pittsburgh, Pa (Dr Gupta).

Arch Pathol Lab Med 2002 Oct;126(10):1189-92 Abstract quote

Context.-The differential diagnosis of gastrointestinal stromal tumors (GIST) and solitary fibrous tumors (SFT) may be a diagnostic challenging because of overlapping clinicopathologic features. Many studies have shown consistent immunoreactivity for CD117 (c-Kit) in GIST. However, only a few studies have evaluated CD117 expression in SFT, and these studies have used an antibody from Santa Cruz Biotechnology. In non-GIST lesions, reactivity with this antibody has been shown to differ from that with a CD117 antibody from Dako Corporation. The immunoreactivity of SFT with the Dako CD117 antibody has not been reported. Conversely, CD99 is a marker for SFT, and its expression in GIST has not been evaluated.

Objective.-To study the immunohistochemical profiles of GIST and SFT to evaluate their diagnostic overlap.

Design.-We studied the immunoreactivity of 27 unequivocal GIST and 19 unequivocal extra-abdominal SFT for CD117, CD34, CD99, alpha-smooth muscle actin, vimentin, CD31, S100 protein, and muscle-specific actin. All antibodies, including CD117, were from Dako Corporation.

Results.-We found positive immunoreactivity for CD117 in 100% of GIST and none of SFT; for CD34 in 89% of GIST, and 100% of SFT; for CD99 in 89% of GIST and 100% of SFT; for alpha-smooth muscle actin in 48% of GIST and 31% of SFT; for vimentin in 89% of GIST and 90% of SFT; and for muscle-specific actin in 22% of GIST and none of SFT. None of the GIST or SFT showed immunoreactivity for CD31 and S100 protein.

Conclusions.-The major difference between GIST and SFT was strong CD117 immunoexpression in all GIST and an absence of this expression in all SFT. With the exception of muscle-specific actin, the prevalence of immunoreactivity for the markers studied did not differ substantially between these 2 tumors. We conclude that GIST and SFT show distinctly divergent immunoprofiles with respect to CD117 and muscle-specific actin.

Positive, but may be negative in benign tumors

Gastrointestinal stromal tumors--value of CD34 antigen in their identification and separation from true leiomyomas and schwannomas.

Miettinen M, Virolainen M, Maarit-Sarlomo-Rikala.

Department of Pathology and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.

Am J Surg Pathol 1995 Feb;19(2):207-16 Abstract quote

The term "gastrointestinal stromal tumor" (GIST) has been applied to mesenchymal tumors that represent neither typical leiomyomas nor schwannomas.

In this study we analyzed immunohistochemically 67 histologically benign [< 2 mitoses/10 high-power field (HPF)], six borderline (3-5 mitoses/10 HPF), and 23 malignant GIST (> 5 mitoses/10 HPF) and compared them with 10 typical leiomyomas and 5 schwannomas of the gastrointestinal tract.

The benign GISTs with spindle cell pattern (67 cases) were typically negative for muscle cell markers (only 3% positive for desmin and 25% for alpha-smooth muscle actin) and S100 protein, but 70% of the cases were positive for CD34, the myeloid progenitor cell antigen also present in endothelial cells and some fibroblasts. However, none of the cases was positive for CD31 (PECAM-1), a more endothelial cell-specific antigen. The absence of CD31 in GIST separates it from Kaposi's sarcoma, a tumor known to be positive for both CD34 and CD31. Fourteen cases of benign GIST of epithelioid cell type showed an immunophenotypic profile similar to the spindle cell tumors. The small intestinal tumors were more commonly actin positive and less commonly CD34 positive than were the gastric tumors.

The malignant spindle and epithelioid GIST showed features essentially similar to those in corresponding benign tumors. In contrast, all typical leiomyomas were positive for muscle cell markers and were negative for CD34 and S100 protein. Gastrointestinal schwannomas were S100-protein positive, and negative for muscle markers and CD34.

Our results show that gastrointestinal mesenchymal tumors can be immunophenotypically divided in categories that correlate with light microscopically defined diagnostic entities, namely typical leiomyomas, schwannomas, and GIST, most cases of the latter representing tumors of primitive mesenchymal cells that are CD34 positive.

L1 (CD171) is highly expressed in gastrointestinal stromal tumors.

Kaifi JT, Strelow A, Schurr PG, Reichelt U, Yekebas EF, Wachowiak R, Quaas A, Strate T, Schaefer H, Sauter G, Schachner M, Izbicki JR.

1Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Mod Pathol. 2006 Mar;19(3):399-406. Abstract quote  

The treatment strategy for mesenchymal tumors of the gastrointestinal tract is based upon typing of the tumor. Especially differential diagnosis of gastrointestinal stromal tumors (GISTs) to leiomyomas is crucial for determining radicality of surgery. L1 cell adhesion molecule (CD171) plays an essential role in tumor progression.

The aim of this study was to determine expression of L1 in GISTs, smooth muscle tumors, desmoid-type fibromatosis and peripheral nerve sheath tumors (PNSTs). We retrospectively analyzed a total of 129 surgically resected primary tumors or metastases of 72 GISTs, 29 smooth muscle tumors, seven PNSTs and 21 desmoid-type fibromatosis by immunohistochemistry for c-kit, CD34, smooth muscle actin, desmin, vimentin, S-100 and L1 expression. L1 expression was detected in 53 (74%) of 72 GISTs but in none of 29 smooth muscle tumors or 21 desmoid-type fibromatosis (P<0.01 by Fisher's test). In all, four (57%) of seven peripheral nerve sheath tumors were L1-positive. Survival analysis of 55 surgically completely resected GISTs presenting without metastasis at initial diagnosis revealed no tumor-specific death among L1-negative patients (P=0.13 by log-rank test; median follow-up time 41 months) and one recurrence was observed (P=0.12). Interestingly high levels of L1 were seen in tumor vascular endothelial cells of smooth muscle tumors and PNSTs, but not in GISTs.

Our data show that L1 is highly expressed in GISTs but not in smooth muscle tumors and desmoid-type fibromatosis being important differential diagnoses. The trend towards a reduced survival of L1-positive patients in this study has to be further evaluated in future trials with higher patient numbers.

Role of PTEN in gastrointestinal stromal tumor progression.

Ricci R, Maggiano N, Castri F, Rinelli A, Murazio M, Pacelli F, Potenza AE, Vecchio FM, Larocca LM.

Department of Pathology, Universita Cattolica del Sacro Cuore, Universita Cattolica, Rome, Italy.
Arch Pathol Lab Med. 2004 Apr;128(4):421-5. Abstract quote

CONTEXT: Gastrointestinal stromal tumors (GISTs) are Kit/CD117-expressing mesenchymal neoplasms of uncertain malignant potential. The lack of a reliable method of prognostication hampers the selection of patients eligible for STI571 therapy. 10q22-q23 is a region involved in chromosomal losses found in a fraction of malignant primary and metastatic GISTs harboring PTEN (phosphatase and tensin homologue deleted on chromosome 10), a tumor suppressor gene often altered in human neoplasms.

OBJECTIVE: To investigate the role of PTEN in GISTs, an issue that to our knowledge has not been addressed previously.

DESIGN: PTEN status was determined in a series of 21 GISTs, with follow-up ranging between 6 and 198 months, using immunohistochemistry correlated with clinical data.

RESULTS: A greater than 25% fraction of cells with low or absent PTEN immunostaining was detected in 9 GISTs, including all those showing malignancy. By the log-rank test, a fraction of PTEN-deficient cells greater than 25% was associated with malignancy (P <.001). Percentage of cells underexpressing PTEN, size, cellularity, MIB-1 immunoreactivity, and coagulative necrosis proved to be associated with malignancy by Cox proportional hazards univariate analysis; low or absent expression of PTEN was the only factor selected by multivariate analysis (P =.03).

CONCLUSIONS: PTEN downregulation is implied in GIST progression. The immunohistochemical assessment of PTEN status appears to be a promising method of GIST prognostication.

Expression of microtubule-associated protein tau by gastrointestinal stromal tumors

Marie-Laure Chambonnière, MD
Michèle Mosnier-Damet, MD
Jean-François Mosnier, MD, PhD

Hum Pathol 2001;32:1166-1173. Abstract quote

The purpose of this work was to study the expression in gastrointestinal stromal tumors (GISTs) of various antigens, including the protein tau associated with enteric neuronal differentiation; to compare their expression with that of c-kit, known to be associated with interstitial cell of Cajal differentiation; and to correlate their expression with the observation of ultrastructural features of gastrointestinal autonomic nerve tumors.

Twenty-six GISTs of the stomach and 16 GISTs of the small bowel were included in the study group. Thirty-five tumors served as controls. Tissue sections were immunostained with vimentin, CD34, desmin, specific smooth muscle actin, S100 protein, neuron-specific enolase, PGP9.5, neurofilament, bcl-2 oncoprotein, synaptophysin, chromogranin A, c-kit, and tau. Twenty-one of these tumors were also analyzed ultrastructurally. Of the 42 GISTs, 28 were predominantly spindled, 7 were predominantly epithelioid, and 7 were a mixture of epithelioid and spindle cells. Ten primary GISTs were classified as benign, 9 as borderline, and 23 as malignant. Metastatic dissemination was present at primary surgery in 1 case and eventually developed in 6 patients. Six disease-related deaths were counted. In normal submucous and myenteric plexuses of stomach and small bowel, ganglion cell bodies and nerve fibers strongly expressed tau.

Twenty (76.9%) GISTs of the stomach and 12 (75%) of the small bowel expressed tau. Tau often showed intense, diffuse staining patterns in both spindled and epithelioid tumors. Ten (100%) of the 10 benign GISTs, 7 (77.8%) of the borderline GISTs, and 15 (65.2%) of the 23 frankly malignant GISTs expressed tau. Thirty-six GISTs expressed at least 2 different neuronal markers. A coexpression of the neuronal markers and c-kit was observed in 90% of GISTs. The expression of tau was observed in 12 of the 15 GISTs with dense core granules, considered as the definitive finding for a diagnosis of gastrointestinal autonomic nerve tumors. Ten of these also expressed c-kit; 9 were malignant. Tau also immunostained other intra-abdominal tumors, including neuroendocrine carcinomas, paragangliomas and desmoplastic round cell tumors.

This immunohistochemical study shows that GISTs are specific tumors of the digestive tract and are nearly always characterized by simultaneous neuronal and interstitial cell of Cajal differentiation. Although the loss of tau expression is observed only in borderline and malignant tumors, its prognostic value is not clear cut.


Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117).

Pauser U, da Silva MT, Placke J, Klimstra DS, Kloppel G.

1Department of Pathology, University of Kiel, Germany.
Mod Pathol. 2005 Sep;18(9):1211-6. Abstract quote  

Solid tumors of the pancreas are usually neoplastic. We report on two adult patients, each with a solid tumor of the pancreas that presented with an unusual histology and seemed to follow a benign course.

The tumors, one located in the body and one in the tail, were well demarcated and composed of irregularly arranged but well-differentiated acini and small intralobular and interlobular ducts embedded in predominantly hypocellular fibrotic tissue that contained fascicles of cytologically bland spindle cells. Islets were lacking, but immunohistochemical staining for chromogranin A and insulin revealed individual scattered insulin-producing cells distributed between acinar and ductal cells. The spindle cell component tissue showed coexpression of CD34, c-kit (CD117) and bcl-2. The follow-up (2 and 4 years) of the patients was uneventful.

We propose to designate the tumors as 'cellular hamartoma resembling gastrointestinal stromal tumor.'

Gastrointestinal Stromal Tumor Versus Intra-abdominal Fibromatosis of the Bowel Wall A Clinically Important Differential Diagnosis

Rhonda K. Yantiss, M.D.; Ira J. Spiro, M.D.; Carolyn C. Compton, M.D.; Andrew E. Rosenberg, M.D.

From the Department of Pathology, Harvard Medical School; and the James Homer-Wright Pathology Laboratories and the Department of Radiation Oncology of Massachusetts General Hospital, Boston, Massachusetts, U.S.A.

Am J Surg Pathol 2000;24:947-957 Abstract quote

Intra-abdominal fibromatosis (IAF) is an uncommon benign neoplasm that usually occurs in the mesentery or retroperitoneum and may, on occasion, mimic a gastrointestinal stromal tumor (GIST). Differentiating between these two entities is important clinically because IAF is a benign tumor whereas GISTs frequently have malignant potential.

In this study, the authors identified 13 cases of IAF with prominent involvement of the bowel wall as well as 35 GISTs of the small intestine, colon, or mesentery and analyzed their clinical, gross, histologic, immunophenotypic, and ultrastructural characteristics to identify important distinguishing features. Patients with IAF were younger (mean, 34 yrs) than patients with GIST (mean, 54 yrs). Both types of tumors tended to be large, but GISTs were soft and lobulated with hemorrhage, necrosis, or cystification whereas IAFs were firm, tan, and homogeneous.

Histologic features characteristic of GIST included the presence of spindle or epithelioid cells with variable architecture, mitotic activity (range, <1–95 mitoses/50 high-power fields [hpf]; mean, 15 mitoses/50 hpf), nuclear atypia, and myxoid or hyalinized stroma. Necrosis and hemorrhage were seen in 16 and 25 tumors, respectively.

In contrast, IAFs were composed of broad, sweeping fascicles of monotonous spindle cells with mitotic activity (range, <3–11 mitoses/50 hpf; mean, 4 mitoses/50 hpf), bland nuclear features, and finely collagenous stroma. Necrosis, hemorrhage, and myxoid degeneration were not seen.

Immunohistochemical studies performed on a limited number of GISTs and IAFs demonstrated that cells expressed vimentin (100% GIST and IAF), CD117 (88% GIST and 75% IAF), CD34 (42% GIST and 0% IAF), smooth muscle actin (63% GIST and 75% IAF), muscle actin (75% GIST and 75% IAF), desmin (8% GIST and 50% IAF), and S-100 protein (16% GIST and 0% IAF). Ultrastructural analysis of 21 GISTs revealed incomplete smooth muscle differentiation in some tumors whereas IAFs were shown to have complete myofibroblastic/fibroblastic differentiation.

Information regarding clinical outcome was available on 29 patients and revealed that three patients with histologically benign GISTs were alive with no evidence of disease at 5 months to 6 years (mean, 3.5 yrs) and one patient with a histologically benign tumor died of disease after 7 years. Of patients with histologically malignant GIST, one died of surgical complications, 10 were alive without disease at 1 to 13 years (mean, 5.4 yrs), four were alive with disease at 4 months to 15 years (mean, 3.8 yrs), three had disseminated disease at operation, and seven were dead of disease at 10 months to 3 years (mean, 2.2 yrs). Follow up of eight patients with IAF demonstrated that five were alive without disease at 4 months to 15 years (mean, 5.3 yrs) and three had recurrences at 1 (two patients) and 2 years (one patient).

In summary, IAFs can have many features (large size, infiltration of adjacent structures, mitotic activity) that can cause diagnostic confusion with GISTs and, importantly, the degree of mitotic activity present in IAFs may overlap that seen in malignant GISTs. These entities can be distinguished primarily by their light microscopic and ultrastructural features but there is a notable overlap in their immunohistochemical profiles. The distinction between these neoplasms is important because there are important clinical implications for the patient.

Endoscopic Ultrasound–Guided Fine-Needle Aspiration Findings of Gastrointestinal Leiomyomas and Gastrointestinal Stromal Tumors

Edward B. Stelow, MD,1 Michael W. Stanley, MD,1 Shawn Mallery, MD,2 Rebecca Lai, MD,2 Bradley M. Linzie, MD,1 and Ricardo H. Bardales, MD

Am J Clin Pathol 2003;119:703-708 Abstract quote

True leiomyomas of the gastrointestinal system are rare but remain the most common mesenchymal tumors of the esophagus. It has become important to distinguish these tumors from gastrointestinal stromal tumors (GISTs) because the neoplasms have different prognoses and treatment options.

We describe and compare clinical findings and the following fine-needle aspiration (FNA) features of 9 gastrointestinal leiomyomas and 19 GISTs sampled with endoscopic ultrasound: overall cellularity, cell group features, cell shape and cytoplasmic features, nuclear characteristics, background, cell block features, and immunohistochemical results.

Gastrointestinal leiomyomas and GISTs have different clinical and cytologic features that help pathologists distinguish these tumors, and the immunohistochemical findings that help define these lesions can be derived readily from cell block material obtained by endoscopic ultrasound–guided FNA.

Mesenchymal Tumors of Muscularis Mucosae of Colon and Rectum are Benign Leiomyomas that Should be Separated from Gastrointestinal Stromal Tumors—A Clinicopathologic and Immunohistochemical Study of Eighty-Eight Cases

Markku Miettinen, M.D., Maarit Sarlomo-Rikala, M.D. and Leslie H. Sobin, M.D.

Department of Soft Tissue Pathology (MM)Armed Forces Institute of Pathology, Washington, DC; Department of Pathology (MSR), Haartman Institute of the University of Helsinki, Helsinki, Finland; and Division of Gastrointestinal Pathology (LS), Armed Forces Institute of Pathology, Washington, DC

Mod Pathol 2001;14:950-956 Abstract quotes

Most mesenchymal tumors of the gastrointestinal tract are currently classified as specific gastrointestinal stromal tumors. However, true leiomyomas are more common in the esophagus, and they have been occasionally noted in the colon and rectum, but the small number of reported cases does not allow for clinicopathologic profiling.

This study was undertaken to characterize 88 tumors of the muscularis mucosae of the colon and rectum.

Seventy tumors were obtained form the files of AFIP and 18 cases from the Department of Pathology of the Haartman Institute of the University of Helsinki. The lesions, except one, were removed by snare polypectomy as incidental lesions at cancer or polyp surveillance; one small tumor was an incidental finding in the rectal resection specimen. The tumors had a significant male predominance in both institutions (overall 2.4:1). They occurred in age range of 38 to 85 years (median 62 years). The lesions were typically small (range 1 to 22 mM, median 4 mM) and located predominantly in the rectum and sigmoid (72%). All tumors were composed of well-differentiated, eosinophilic smooth muscle cells that were seen immediately beneath the mucosa obliterating the muscularis mucosae layer and merging with it. Two tumors had significant atypia ("symplastic leiomyoma"); mitotic activity was seen in one of these tumors, but not in others. The lesional cells were uniformly positive for smooth muscle actin and desmin and negative for CD34, CD117 and S100-protein, based on immunohistochemical studies on 20 to 24 cases with each marker. No gastrointestinal stromal tumors were identified among the tumors of muscularis mucosae, and no CD117-positive cells, except mast cells, were seen in the muscularis mucosae layer. None of the patients had morbidity related to the tumor.

Based on follow-up data on 29 patients, leiomyomas of muscularis mucosae are benign. They should be separated from gastrointestinal stromal tumors that have a clinicopathologic spectrum including frequent disease-related mortality. Snare polypectomy is an adequate treatment, but ensuring the complete removal and follow-up are necessary precautions for tumors with any atypia or mitotic activity.


Gastrointestinal Stromal Tumors and Leiomyosarcomas in the Colon A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 44 Cases

Markku Miettinen, M.D.; Maarit Sarlomo-Rikala, M.D.; Leslie H. Sobin, M.D.; Jerzy Lasota, M.D.

From the Department of Soft Tissue Pathology and Division of Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC, U.S.A.; and the Department of Pathology, Haartman Institute of the University of Helsinki, Helsinki, Finland.

Am J Surg Pathol 2000;24:1339-1352 Abstract quote

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 (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 -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.


Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery: a clinicopathologic study of five cases.

Yantiss RK, Nielsen GP, Lauwers GY, Rosenberg AE.


Am J Surg Pathol 2003 Apr;27(4):532-40 Abstract quote

Although the majority of mesenchymal lesions of the gastrointestinal tract are neoplastic in nature, nonneoplastic reactive processes may involve the gastrointestinal tract and mesentery, causing diagnostic confusion with more aggressive neoplasms, such as fibromatosis or gastrointestinal stromal tumors.

In this study, we report a series of fibroinflammatory lesions of the gastrointestinal tract that we think represent a relatively cohesive group of tumors and describe the clinical and pathologic features of this entity, which we have termed "reactive nodular fibrous pseudotumor." The tumors affected five patients (four male and one female patient) who ranged in age from 48 to 71 years (mean 56 years). Two patients presented with acute abdominal pain without a significant past medical history, two had incidental lesions discovered during evaluation for other medical conditions, and one was found to have an abdominal mass. Three patients had a history of abdominal surgery. The tumors were multiple in three patients and solitary in two patients. In four cases, at least one of the tumors involved the small intestine or colon, and the lesion was confined to the peripancreatic soft tissue in one case.

The tumors were firm, tan-white, ranged in size from 4.3 to 6.5 cm in greatest dimension, and were grossly well circumscribed. All of the lesions were of low to moderate cellularity and composed of stellate or spindled fibroblasts arranged haphazardly or in intersecting fascicles. Three cases had microscopically infiltrative borders. The stroma was rich in collagen, which was wire-like, keloidal, or hyalinized. Intralesional mononuclear cells were sparse but were more numerous peripherally and frequently arranged in lymphoid aggregates. Immunohistochemical stains demonstrated that all of the tumors stained for vimentin, 80% stained for CD117 or muscle specific actin, 60% stained for smooth muscle actin or desmin, and none of the tumors stained for CD34, S-100 protein, or anaplastic lymphoma kinase-1.

Follow-up information was available in all cases: four patients had no residual disease following surgical resection (mean follow-up 16.3 months) and one patient who had an incomplete surgical resection had stable disease at 26 months. In summary, we report a series of distinct intraabdominal fibroinflammatory pseudotumors that we have collectively termed "reactive nodular fibrous pseudotumors."

These lesions are uncommon and may infiltrate the bowel wall, thereby mimicking primary bowel neoplasms or intraabdominal fibromatosis. Recognition of these nonneoplastic lesions is important, as they pursue a benign clinical course, but may be confused with other mesenchymal neoplasms that require more aggressive treatment.



In general, tumors invading the mucosa, tumor size, and mitotic rate are most useful prognostic indicators

However, there is considerable variation and tumors arising in different sites of the GI tract may behave differently despite similar histologies

It may be that gastric and duodenal tumors ranging from 2-4 cm may have marked ability to recur and metastasize. This is in contrast to other tumors which are usually >5 cm before there is a marked propensity to metastasize

Factors associated with disease progression in patients with gastrointestinal stromal tumors in the pre-imatinib era.

Iesalnieks I, Rummele P, Dietmaier W, Jantsch T, Zulke C, Schlitt HJ, Hofstadter F, Anthuber M.

Department of Surgery, University of Regensburg, Regensburg, Germany.

Am J Clin Pathol. 2005 Nov;124(5):740-8. Abstract quote  

The aim of this study was to determine the predictors of survival in 38 patients with curatively resected gastrointestinal stromal tumors (GISTs). The tumor was located in the stomach in 23 cases, the small bowel in 13, and the colon in 2. In 23 patients (61%), a mutation in exon 11 of the kit gene was detected.

In 7 cases, all small gastric tumors, a mutation in the platelet-derived growth factor receptor a (PDGFRA) gene was detected. The overall 5-year survival rate was 70%. In 9 patients, GISTs relapsed, leading to an actuarial 5-year disease-free survival of 78%. By multivariate analysis, the presence of distant metastases, the proliferative (MIB-1) index, and deletional mutation in codons 557 and/or 558 of kit exon 11 correlated significantly with poor outcome. None of the PDGFRA mutant GISTs relapsed.

These findings suggest a strong relationship between various tyrosine kinase receptor mutations and survival outcome in patients with GISTs.
Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade.

Nakamura N, Yamamoto H, Yao T, Oda Y, Nishiyama K, Imamura M, Yamada T, Nawata H, Tsuneyoshi M.

Department of Anatomic Pathology, Graduate School of Medical Sciences of Kyushu University, Fukuoka 812-8582, Japan; Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences of Kyushu University, Fukuoka 812-8582, Japan.
Hum Pathol. 2005 Jul;36(7):828-37. Abstract quote  

Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators.

The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (>/=5 cm), mitotic counts (>/=5/50 high-power fields), Ki-67 LI (>/=4.92%), cyclin A LI (>/=1.61%), and cdc2 LI (>/=1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs.

Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.
Gastrointestinal Stromal Tumors of the Stomach: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 1765 Cases With Long-term Follow-up.

Miettinen M, Sobin LH, Lasota J.

From the Departments of *Soft Tissue Pathology and daggerHepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC.
Am J Surg Pathol. 2005 Jan;29(1):52-68. Abstract quote  

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.

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

Miettinen M, El-Rifai W, H L Sobin L, Lasota J.

Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.

Hum Pathol 2002 May;33(5):478-83 Abstract quote

This paper reviews data on the prognosis of gastrointestinal stromal tumors (GISTs). These tumors are specific KIT-expressing and KIT-signaling-driven mesenchymal tumors, many of which have KIT-activating mutations. GISTs occur in the entire gastrointestinal (GI) tract and may also arise from the omentum, mesenteries, and retroperitoneum. They range from small benign tumors to sarcomas at all sites of occurrence. A KIT tyrosine kinase inhibitor, STI-571 (imatinib [Gleevec]; Novartis, Basel, Switzerland), has recently shown promise in the treatment of metastatic GISTs.

Understanding the natural history of GIST before introduction of STI-571 will help assess the impact and position of this new treatment. The frequency of benign versus malignant GISTs varies between sites. Benign GISTs outnumber malignant GISTs in the stomach, whereas malignant GISTs are more common in the intestines. Tumors that have metastasized at presentation have a very poor prognosis. Traditionally, the 3 key prognostic factors have been mitotic rate, tumor size, and site. Tumors that are small (< or =2 cm) and show mitotic activity not exceeding 5 mitoses per 50 high-power fields (HPFs) have an excellent prognosis, probably independent of site, although this has not been shown specifically for all sites. In the stomach, most epithelioid GISTs are benign, provided that mitotic counts do not exceed 5/50 HPFs. However, a small proportion of tumors apparently lacking mitotic activity do metastasize. Tumors with a mitotic rate >5/50 HPFs usually have a malignant behavior.

The Ki67 index may help identify tumors with malignant potential, but large site-specific series are not yet available. Genetic markers, including DNA-copy number changes, telomerase activity, and KIT mutation status, may be useful in more accurately identifying tumors with malignant potential.


Am J Surg Pathol 1999;23:82-87

Esophagus and stomach
Small intestine
Colon and rectum
CD 44 LOSS  

CD44 Loss in Gastric Stromal Tumors as a Prognostic Marker

Montgomery, Elizabeth MD*; Abraham, Susan C MD*; Fisher, Cyril MD, DSC†; Deasel, Mari Robinette BS*; Amr, S S MD‡; Sheikh, Salwa S MD‡; House, Michael MD*; Lilliemoe, Keith MD*; Choti, Michael MD*; Brock, Malcolm MD*; Ephron, David T MD*; Zahuruk, Mariana MD*; Chadburn, Amy MD§

From the *Johns Hopkins Medical Institutions, Baltimore, MD; †Royal Marsden Hospital, London, UK; ‡Dhahran Health Center, Dhahran, Saudi Arabia; and §Cornell Medical Center, New York, NY. Dr. Abraham is currently at Mayo Clinic, Rochester, MN.


The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 168-177 Abstract quote

Background: The adhesion molecule CD44 (CD44s; CD44H) and its isoforms (CD44v3-6 and v9) are preferentially expressed by different cell types. These transmembrane glycoproteins are involved in cell-cell and cell-matrix interactions and in cell trafficking and, thus, may play a role in tumor metastasis and/or local invasion. The expression pattern of CD44s and variant isoforms, particularly CD44v6 and CD44v9, of some neoplasms, including soft tissue tumors, correlates with clinical course and outcome. The clinical behavior of gastrointestinal stromal tumors (GIST) is site specific; however, other reliable predictors of clinical outcome have not been identified. Thus, the prognostic value of CD44s and isoform expression in GIST were evaluated by immunohistochemistry of tissue microarrays.

Design: Paraffin-embedded formalin-fixed tissue cores (129: 103 GIST and 26 normal stomach smooth muscle) from 33 patients with clinical outcome data were collected and used for the construction of the tissue microarrays. One to five tissue cores from each patient specimen were evaluated (mean = 3 tissue cores/patient). Array slides were stained with anti-CD44s (CD44H) and with antibodies to v3, v4, v5, v6, and v9 isomers. CD44s and isoform expression and staining intensity were scored semiquantitatively without knowledge of patient identity or outcome: 0 = no; 1 = weak; 2 = moderate; 3 = moderate to strong; 4 = strong. The scores of multiple cores from the same GIST were averaged; the nonneoplastic smooth muscle was similarly graded. CD44s and isoform expression and intensity were compared with outcome.

Results: The 33 patients with gastric GIST, 0.8 to 30 cm in size, were followed for 1 to 111 months with a median follow-up of 7 months (mean 17.5 months). The overall median survival was 25 months. Nine of the 33 (27%) patients had metastases, 9 (27%) had recurrent disease, and 9 (27%) died of disease (9-111 months; mean 39 months; median 23 months). All 18 patients with GIST CD44s expression >2+ were alive at last follow-up (1-62 months; median 3.5 months; mean 11 months). More than half (53%) of patients with GIST CD44s expression =2+ died (9-111months; median 23 months; mean 38 months); the median follow-up of the surviving patients with CD44 expression =2 was 5 months (2-22 months; mean 6.5 months; log rank P = 0.07). The majority of tumors were variably positive CD44v3 and CD44v4, but there was minimal staining (number of cases and/or expression level) with antibodies directed against the v5, v6, and v9 isomers.

Conclusion: These preliminary results suggest that although gastric GISTs variably express CD44s and variants, only the expression of CD44s correlates with clinical outcome with loss of CD44s positivity correlating with poor clinical outcome.

Loss of heterozygosity of chromosome 9p and loss of p16(INK4A) expression are associated with malignant gastrointestinal stromal tumors.

Sabah M, Cummins R, Leader M, Kay E.

1Department of Histopathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland.
Mod Pathol. 2004 Nov;17(11):1364-71. Abstract quote

Gastrointestinal stromal tumors GISTs are distinctive KIT-positive mesenchymal neoplasms. The genetic alterations leading to the malignant behavior of these tumors are not well characterized.

In this study, 21 cases of GISTs (eight low malignant potential, nine primary malignant and four intra-abdominal recurrences) were characterized by immunohistochemistry and evaluated for loss of heterozygosity of the short arm of chromosome 9, using six microsatellite markers. Loss of heterozygosity with at least one microsatellite marker at 9p region was a common finding in high-risk GISTs (malignant and recurrent group) but was absent in the low malignant potential group. Recurrent GISTs showed more frequent deletions than their primary tumors. All cases with loss of heterozygosity showed deletions at 9p21. Similarly, all low malignant potential GISTs were immunoreactive for p16, whereas malignant tumors were negative for p16.

These results suggest that loss of p16(INK4A) gene on 9p may contribute to the progression and/or malignant transformation of GISTs.

Gastrointestinal stromal tumors with internal tandem duplications in 3' end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course.

Lasota J, Dansonka-Mieszkowska A, Stachura T, Schneider-Stock R, Kallajoki M, Steigen SE, Sarlomo-Rikala M, Boltze C, Kordek R, Roessner A, Stachura J, Miettinen M.

Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Mod Pathol. 2003 Dec;16(12):1257-64 Abstract quote.  

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and have KIT mutations. Majority of these mutations cluster in the 5' end of the KIT juxtamembrane domain. Little is known about the clinicopathological profile of GIST carrying internal tandem duplications in the 3' end of KIT juxtamembrane domain (ITDs in the 3' KIT-JM).

In this study, 500 immunohistochemically KIT-positive GISTs were screened for this type of mutation, and 18 cases were identified (3.6%). The majority of the ITDs consisted of 1 to 18 codon duplications, with Tyr(578), Asp(579), and Leu(576) being the most commonly duplicated codons. There were 14 gastric (78%), 2 small intestinal (11%), and 2 anal (11%) primary tumors diagnosed in 12 females and 6 males with median age of 71 years. The frequency of IDTs in gastric GISTs was 6.5% and was only 0.5% in intestinal GISTs. There was a strong female predominance (79%) among the patients with gastric tumors. Histologically, 16 GISTs were spindle cell, and 2 had epithelioid morphology. The sizes of primary tumors varied from 1 to >20 cm.

Based on the combination of tumor size and mitotic activity, six tumors were classified as benign or probably benign, eight as having uncertain malignant potential, and only four as malignant. Follow-up data available in 17 patients confirmed the malignant course of disease in 3 cases. Only one of the tumors classified as potentially malignant metastasized, although the follow-up was limited in some cases.

In summary, the great majority of GISTs with ITDs in the 3' KIT-JM were mitotically inactive tumors occurring predominantly in the stomach and that seemed to have a favorable course. This suggests that presence of these IDTs may define a clinicopathologically favorable subset of GISTs. The consequence of these mutations to KIT signaling should be investigated.

Biological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors.

Gunawan B, Bergmann F, Hoer J, Langer C, Schumpelick V, Becker H, Fuzesi L.

Institute of Pathology, Georg-August-University Gottingen; Department of Surgery, RWTH Aachen; and Department of Surgery, Georg-August-University Gottingen, Germany.

Hum Pathol 2002 Mar;33(3):316-21 Abstract quote

We report cytogenetic findings in 19 c-Kit-positive gastrointestinal stromal tumors (GISTs) that represent a heterogenous group of mesenchymal neoplasms with respect to site, histology, and biologic behavior.

All of the GISTs (5 low-risk, 11 high-risk, 3 recurrences) displayed clonal chromosomal aberrations; 15 were hypo- to near-diploid, and 4 were near-triploid and hypotetraploid. The most common abnormalities were loss of chromosomes 14 and/or 22, demonstrated in 14 GISTs irrespective of site or predominant phenotype.

Ten cases (2 low-risk, 5 high-risk, 3 recurrences) were characterized by loss of both chromosomes 14 and 22, 2 cases (1 low-risk, 1 high- risk), by loss of chromosome 14; and 2 high-risk cases, by loss of chromosome 22. Additional chromosomal aberrations occurred preferentially in high-risk and recurrent GISTs, including loss of 9p and 1p in 8 cases each, loss of 15 in 6 cases, loss of 3p in 5 cases, loss of 13q and 10q in 4 cases each, loss of 19 in 3 cases, and complete or partial gains of chromosomes 5 and 4 in 2 cases each. More significantly, 5 of 6 patients with clinically aggressive GISTs, including 2 recurrences and 3 metastasing GISTs, were additionally characterized by loss of 9p; four of these had additional loss of chromosomes 1p and 15.

The presented results herein indicate that loss of chromosome 14 and/or 22 is an early change in GIST tumorigenesis irrespective of site or differentiation, whereas malignant transformation and progression of GISTs appear to be associated with an increasing incidence of additional secondary aberrations.

Am J Clin Pathol 1995;103:41-47
Size >/= 5 cm AND mitotic rate >/= 2/10 hpf
Size >/= 5cm OR mitotic rate >/= 2/10 HPF
PCNA index >10%
Size <5 cm AND mitotic rate <2/10 hpf
Size >/= 5 cm OR mitotic rate >/= 2/10 hpf AND
PCNA index </=10%

Using the above cited criteria:

86% (18/21) at high risk showed aggressive behavior
8% (1/12) at low risk showed aggressive behavior

CONSENSUS APPROACH Hum Pathol 2002;33:459-465
Size< 2cm
MF <5/50 hpf
2-5 cm
MF<5/50 hpf
<5 cm and 6-10 MF/50 hpf
5-10 cm and MF <5/50 hpf
>5 cm and >5/50 hpf
Any size and >10/50 hpf
Role of p16/INK4a in Gastrointestinal Stromal Tumor Progression

Riccardo Ricci, MD, PhD, Vincenzo Arena, MD, etal.
Am J Clin Pathol 2004;122:35-43 Abstract quote

Because the p16 locus is involved consistently in chromosomal losses found in malignant gastrointestinal stromal tumors (GISTs), we studied p16 in a series of 21 GISTs with complete follow-up using immunohistochemical analysis, semiquantitative reverse transcriptase–polymerase chain reaction (RT-PCR) and methylation-specific PCR (MSP).

A fraction of cells of more than 20% with low or absent p16 immunostaining was detected in 12 GISTs, including all showing malignancy. RT-PCR revealed decreased p16 transcription in all except 2 p16 protein–deficient GISTs. By MSP, 7 cases showed p16 promoter methylation (all hypoexpressing p16; 6 malignant). A fraction of p16-deficient cells of more than 20% was associated with clinical malignancy (P = .003; log-rank test). The percentage of cells underexpressing p16, size, cellularity, mitotic count, and coagulative necrosis were associated with malignancy by Cox proportional hazards univariate analysis; only the former factor was selected by multivariate analysis (P = .039).

Thus, p16 down-regulation, partly due to p16 promoter methylation, is implied in GIST progression. Furthermore, p16 immunohistochemical assessment seems a promising method for GIST prognostication.
Expression of human telomerase reverse transcriptase in gastrointestinal stromal tumors occurs preferentially in malignant neoplasms.

Sabah M, Cummins R, Leader M, Kay E.

Hum Pathol. 2004 Oct;35(10):1231-5. Abstract quote  

Telomerase is expressed in many human cancers and cell lines and is thought to contribute to their immortality. To date, little is known about the expression of telomerase in nonepithelial tumors.

The objective of this study was to evaluate the expression of human telomerase reverse transcriptase (hTERT) in gastrointestinal stromal tumors (GISTs). Twenty-three GISTs (9 low malignant potential, 10 primary malignant, and 4 intra-abdominal recurrences) were evaluated for hTERT expression by using immunohistochemistry on tissue microarray. Tissue blocks were retrieved, and hematoxylin and eosin stains were performed to evaluate the histological tumor type. All cases were strongly positive for KIT (CD117). Immunohistochemistry for hTERT was performed. Eight of 9 cases of the low malignant potential group were negative for hTERT immunoexpression, whereas all malignant GISTs showed positive staining that varied from weak to strong immunoreactivity. Six of 10 cases of the primary malignant GISTs were strongly positive for hTERT. The remaining cases (4/10) showed weak staining. All recurrent GISTs (4/4) showed strong positive immunostaining for hTERT. One malignant case was weakly positive for hTERT, but its recurrence was strongly positive.

These results suggest that hTERT expression occurs preferentially in malignant tumors and that telomerase activity may occur during the progression of GISTs. Immunohistochemical staining for hTERT may be a useful marker for the prognostication of GISTs.

Perspectives in Pathology Gastrointestinal stromal tumor workshop

Jules Berman, MD, PhD and Timothy J. O'Leary, MD, PhD

Hum Pathol 2001;32:578-582 Abstract quote

Gastrointestinal stromal tumor (GIST) has emerged in the past year as a prototypical neoplasm that responds to therapy directed against a single target molecule—the KIT receptor tyrosine kinase protein.

Although GIST seldom responds to conventional chemotherapeutic agents, early experience with the tyrosine kinase inhibitor, STI-571 (Gleevec; Novartis, Basel, Switzerland), has been extremely encouraging. Early results have appeared in a recent case report in the New England Journal of Medicine (April 5, 2001),1 and in early clinical trials from the United States and Europe that were reported at the plenary session of the American Society of Clinical Oncology in San Francisco on May 14, 2001. STI-571 is one of the earliest examples of a nontoxic chemotherapeutic agent (an agent whose anti-cancer activity is not predicated on a cytotoxic mechanism). STI-571 has already shown clinical value in BCR-ABL-positive leukemias. Early clinical results in GIST are so encouraging that oncologists may soon be wrestling with the opportunity of referring every patient with malignant GIST into clinical trials with STI-571.

To ensure appropriate treatment, pathologists need to understand the biology and treatment of this tumor and to have standard methods and criteria for providing diagnosis (GIST or not GIST) and consistent prognostic classification (high risk of metastasis or low risk of metastasis).

STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications.

Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD, Fletcher JA, Demetri GD.

MIT Cancer Center and Department of Biology, Cambridge, MA 02139, USA.

Oncogene 2001 Aug 16;20(36):5054-8 Abstract quote

Mutations in the c-KIT receptor occur somatically in many sporadic Gastrointestinal Stromal Tumors (GIST), and similar mutations have been identified at the germline level in kindreds with multiple GISTs. These mutations activate the tyrosine kinase activity of c-KIT and induce constitutive signaling.

To investigate the function of activated c-KIT in GIST, we established a human GIST cell line, GIST882, which expresses an activating KIT mutation (K642E) in the first part of the cytoplasmic split tyrosine kinase domain. Notably, the K642E substitution is encoded by a homozygous exon 13 missense mutation, and, therefore, GIST882 cells do not express native KIT. GIST882 c-KIT protein is constitutively tyrosine phosphorylated, but tyrosine phosphorylation was rapidly and completely abolished after incubating the cells with the selective tyrosine kinase inhibitor STI571. Furthermore, GIST882 cells evidenced decreased proliferation and the onset of apoptotic cell death after prolonged incubation with STI571. Similar results were obtained after administering STI571 to a primary GIST cell culture that expressed a c-KIT exon 11 juxtamembrane mutation (K558NP).

These cell-culture-based studies support an important role for c-KIT signaling in GIST and suggest therapeutic potential for STI571 in patients afflicted by this chemoresistant tumor.

Clinical management of gastrointestinal stromal tumors: before and after STI-571.

Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G.

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Hum Pathol 2002 May;33(5):466-77 Abstract quote

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Until recently, surgery has been the only effective therapy for GIST. However, even after complete resection of tumor, many patients still eventually die of disease recurrence. Conventional chemotherapy and radiation therapy have been of limited value. Within the last few years, it was discovered that most GISTs have a gain-of-function mutation in the c-kit proto-oncogene. This results in ligand-independent activation of the KIT receptor tyrosine kinase and an unopposed stimulus for cell growth. STI-571 is a small molecule that selectively inhibits the enzymatic activity of the ABL, platelet-derived growth factor receptor, and KIT tyrosine kinases and the BCR-ABL fusion protein and is a landmark development in cancer therapy.

Its clinical development marks a new era of rational and targeted molecular inhibition of cancer that emanates from direct collaborations between scientists and clinicians. It provides proof of the principle that a specific molecular inhibitor can drastically and selectively alter the survival of a neoplastic cell with a particular genetic aberration.

The advent of STI-571 has markedly altered the clinical approach to GIST. It has proven to be effective in metastatic GIST and is also under investigation as a neoadjuvant and adjuvant therapy.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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