Case 32-2004 — A 68-Year-Old Man with a Large Retroperitoneal Mass
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《新英格兰医药杂志》
George D. Demetri, M.D., Ross L. Titton, M.D., David P. Ryan, M.D., and Christopher D.M. Fletcher, M.D.
Presentation of Case
Dr. David P. Ryan: A 68-year-old man was admitted to the hospital because of a large retroperitoneal tumor.
The patient had been in excellent health. A few days before admission, a routine physical examination by his primary physician had revealed a large abdominal mass. He was admitted to the hospital.
The man was married and had retired from a sedentary occupation. He ran 5 to 10 miles weekly and remarked that, but for the mass, he would not know that he had cancer. There was a three-year history of hypertension, and he had been given a diagnosis of anxiety disorder. He did not smoke, and he used alcohol moderately. His medications were amlodipine, citalopram, and temazepam, which he took at bedtime, and lorazepam, which he took when he was feeling tense. He was allergic to penicillin. His father had died of multiple myeloma at 63 years of age and a brother had died of throat cancer at 57 years of age.
On admission, the temperature was 37.3°C, the heart rate 88 beats per minute, and the blood pressure 170/90 mm Hg. The weight was 75 kg. The patient looked well. There was no icterus or lymphadenopathy. The lungs and heart appeared normal. A hard, nontender mass occupied the entire left upper abdominal quadrant. There was + peripheral edema, but it had not been noticed by the patient. The results of a neurologic examination were unremarkable.
Laboratory tests were performed. The hematocrit was 35.1 percent, the white-cell count 9400, the platelet count 347,000, and the mean corpuscular volume 89 μm3; the prothrombin and partial-thromboplastin times were normal. The aspartate aminotransferase level was 50 U per liter. Normal results were obtained for the measurements of urea nitrogen, creatinine, glucose, conjugated and total bilirubin, calcium, total protein, albumin, globulin, electrolytes, alanine aminotransferase, alkaline phosphatase, prostate-specific antigen, carcinoembryonic antigen, and CA 19-9. May we see the imaging studies?
Dr. Ross L. Titton: An ultrasonographic study of the abdomen showed a large heterogeneous mass in the upper abdomen that was contiguous with the pancreas; an isoechoic mass, measuring 3 to 4 cm in diameter, was evident in the right hepatic lobe. The patient's physician was called, and a decision was made to perform a biopsy; however, gas from a loop of bowel partially obscured the mass and made the location unsuitable for an ultrasound-guided biopsy. A nonenhanced computed tomographic (CT) scan of the abdomen (Figure 1A), obtained 20 minutes after the ultrasonographic study, confirmed that there was a heterogeneous mass, 13 cm by 10 cm, that originated in the left upper retroperitoneum. The mass is contiguous with the posterior wall of the stomach anteriorly and with the pancreas posteriorly; several masses are evident in the right and left hepatic lobes (Figure 1B); the spleen, left kidney, and left adrenal gland are unremarkable; and there is no lymphadenopathy or ascites.
Figure 1. CT Scans of the Abdomen.
A nonenhanced CT scan of the abdomen (Panel A) shows a heterogeneous mass, 13 cm by 10 cm, that originated in the left upper retroperitoneum (arrows); the mass is contiguous with the posterior wall of the stomach anteriorly and with the pancreas and spleen posteriorly. In another view, a mass is visible in the left hepatic lobe, which is not well seen in this nonenhanced study (Panel B, arrows). Four months later, repeated scans, obtained after the administration of oral and intravenous contrast material (Panel C), show an increase in the size of the retroperitoneal mass from 13 cm by 10 cm to 17 cm by 13 cm (arrows), as well as an increase in the number and size of the hepatic metastases (Panel D, arrows).
Under CT guidance, multiple fine-needle aspirates and 18-gauge core-biopsy specimens were obtained from the main mass by an anterior subcostal approach; then, with the use of a right lateral transpleural approach, multiple fine-needle aspirates and 18-gauge core-biopsy specimens of the largest mass in the right hepatic lobe were obtained, without complications.
Dr. Nancy Lee Harris (Pathology): Dr. Fletcher, will you show us the findings on fine-needle aspiration?
Pathological Discussion
Dr. Christopher D.M. Fletcher: The biopsy of both the retroperitoneal and liver masses revealed a cytologically uniform, eosinophilic spindle-cell neoplasm with fascicular architecture and minimal nuclear atypia (Figure 2A and Figure 2B). The differential diagnosis includes a smooth-muscle neoplasm, a gastrointestinal stromal tumor, and a nerve-sheath neoplasm. Immunohistochemical staining revealed striking cytoplasmic positivity for KIT (CD117) (Figure 2C) and CD34 with scattered cells positive for actin, whereas the cells were negative for desmin and S-100 protein, confirming the diagnosis of gastrointestinal stromal tumor. Despite the lack of nuclear atypia and the very low mitotic rate, the size of the primary tumor and the presence of hepatic metastases left no doubt that this lesion was malignant (gastrointestinal stromal sarcoma).
Figure 2. Needle-Biopsy Specimens of the Retroperitoneal Mass and the Liver.
On cytologic examination of the biopsy specimen of the retroperitoneal mass, a cytologically uniform spindle-cell neoplasm with bland nuclear morphologic features is evident (Panel A; Papanicolaou stain). The needle-biopsy specimen of the liver (Panel B; hematoxylin and eosin) contains spindle cells with eosinophilic cytoplasm and a fascicular architecture. Immunohistochemical staining reveals striking cytoplasmic positivity for KIT (CD117) (Panel C; immunoperoxidase stain), confirming the diagnosis of gastrointestinal stromal tumor.
This case raises the issue of the diagnosis and classification of spindle-cell tumors of the gastrointestinal tract, a discussion that has evolved dramatically in the past four to five years.1,2 For many years, most of these lesions were regarded as smooth-muscle neoplasms (leiomyoma or leiomyosarcoma), with either spindle-cell or epithelioid cytomorphology. The introduction of electron microscopy and, subsequently, immunohistochemical study revealed that there was considerable phenotypic heterogeneity, which included lesions with smooth-muscle, neural, autonomic, and biphenotypic features, or even no evident differentiation. This heterogeneity led, in the early 1980s, to the introduction of the generic (and at that time less specific) term gastrointestinal stromal tumor. By the early 1990s, CD34 was regarded as a frequently expressed and diagnostically useful marker in this context — although this has subsequently been disproved, since CD34 positivity is practically ubiquitous among spindle-cell tumors (Table 1). Until recently, it was believed that there was phenotypic variation among gastrointestinal stromal tumors that arose in different parts of the gastrointestinal tract, with smooth-muscle lesions predominating in the esophagus and large bowel and neural lesions predominating in the small bowel. However, this perception has been at least partially overturned by insights into the biology of these lesions.
Table 1. Immunohistochemical Classification of Spindle-Cell Tumors in the Gastrointestinal Tract.
Within the past decade, several groups of investigators recognized that interstitial cells of Cajal — cells normally present in the myenteric plexus that coordinate peristalsis by linking the autonomic innervation to the smooth muscle of the bowel wall — showed immunohistochemical positivity for KIT; subsequently, investigators showed that many gastrointestinal stromal tumors had similar KIT positivity.3,4 Ultrastructurally, interstitial cells of Cajal share features of both myogenic and neural differentiation,4 which in part helps to explain the immunohistochemical heterogeneity of the tumors. Hirota et al.3 in Japan, in drawing parallels with previous studies in mast-cell neoplasms, demonstrated activating KIT mutations in five of six gastrointestinal stromal tumors, as well as the ability of the mutant KIT cDNA to induce malignant transformation in a lymphoid cell line.
KIT is a transmembrane tyrosine kinase receptor; normally, the ligand for this is stem-cell factor (Figure 3). KIT is expressed by (and required for the normal development of) mast cells, germ cells, melanocytes, erythroid stem cells, and interstitial cells of Cajal. Normally, binding of stem-cell factor to KIT causes dimerization and cross-phosphorylation, triggering signal transduction through the KIT receptor and inducing proliferation and inhibiting apoptosis. The mutations in KIT found in gastrointestinal stromal tumors allow the molecule to dimerize in the absence of ligand, resulting in constitutive activation and phosphorylation, thereby activating downstream signaling pathways, which exert a proliferative and antiapoptotic effect (Figure 3).
Figure 3. Normal and Mutated KIT and the Action of Imatinib.
KIT is a transmembrane tyrosine kinase receptor. Binding of its ligand, stem-cell factor, causes dimerization and cross-phosphorylation of KIT, triggering signal transduction through the KIT receptor, inducing proliferation and inhibiting apoptosis. The mutations in the KIT gene found in gastrointestinal stromal tumors allow the molecule to dimerize in the absence of ligand, resulting in constitutive activation and phosphorylation and activating downstream signaling pathways, which stimulate cell proliferation and inhibit apoptosis. Imatinib binds to the ATP-binding site and inhibits the phosphorylation of KIT.
Since the initial recognition that KIT mutations are present in gastrointestinal stromal tumors, it has been demonstrated in larger series that more than 90 percent of spindle-cell and epithelioid mesenchymal neoplasms in the gastrointestinal tract (including those previously classified as gastrointestinal autonomic-nerve tumors) had KIT-activating mutations. In the majority of cases, these mutations — irrespective of size, site, or histotype5,6 — were associated with immunohistochemically detectable expression of KIT protein. True smooth-muscle neoplasms and schwannomas lack KIT positivity — a fact that makes it possible to distinguish them from gastrointestinal stromal tumors (Table 1). Approximately 60 to 70 percent of KIT mutations occur in the juxtamembrane region (exon 11) of the receptor, with an additional 10 to 15 percent in the extracellular domain (exon 9), and roughly 5 to 7 percent in the split kinase domain. Patients with familial gastrointestinal stromal tumors have germ-line KIT mutations, often also associated with systemic mast-cell disease, pigmentation disorders, or both, underscoring the central pathogenetic role of KIT in this context.
It was initially believed that the type of KIT mutation correlated with the pathobiologic nature of a given gastrointestinal stromal tumor (i.e., whether the lesion would behave ultimately as a benign neoplasm or as an aggressive cancer), but this theory has not been borne out by subsequent studies. After a workshop at the National Institutes of Health in 2001, consensus guidelines for the diagnosis of gastrointestinal stromal tumor were developed,1 and this diagnosis now relies heavily on the demonstration of KIT immunopositivity. Such positivity is not shared by most other types of sarcoma,7 and hence, it is critical that staining to determine the KIT status is performed consistently and reliably in pathology laboratories.8,9 Approximately 4 percent of otherwise morphologically typical gastrointestinal stromal tumors are KIT-immunonegative; most of these tumors harbor PDGFRA mutations.10
Defined in this way, gastrointestinal stromal tumor is the most common mesenchymal tumor of the gastrointestinal tract; it affects mainly middle-aged adults, with a slight predominance in women, and arises most often in the stomach or small bowel and less often in the mesentery, large bowel, esophagus, and retroperitoneum. These tumors typically spread, at least initially, around the peritoneal cavity and to the liver, and the overall survival rate among patients who present with clinical symptoms is approximately 40 to 50 percent at 5 years and 15 to 25 percent at 10 years. Prediction of the prognosis in patients with gastrointestinal stromal tumors is difficult, because about 10 percent of lesions that are less than 5 cm in diameter and lesions with minimal proliferative activity or atypia may give rise to metastases in a seemingly unpredictable fashion. This difficulty has led to the consensus,1 based on extensive cumulative experience, that no gastrointestinal stromal tumor can be definitively labeled as benign and that, instead, the risk of metastasis should be assessed on the basis of size and mitotic rate (Table 2).
Table 2. Proposed Guidelines for Defining the Risk of Aggressive Behavior in Gastrointestinal Stromal Tumors.
Dr. Ryan: Because the patient was asymptomatic, and because there was no available chemotherapeutic agent for the treatment of gastrointestinal stromal tumor at the time of his diagnosis, he was advised to continue his customary activities. Four months later, another abdominal–pelvic CT scan was obtained.
Dr. Titton: This CT scan (Figure 1C) shows an increase in the size of the retroperitoneal mass from 13 cm by 10 cm to 17 cm by 13 cm, as well as an increase in the number and size of the hepatic metastases (Figure 1D). A positron-emission tomographic (PET) scan (Figure 4A) reveals a mass with intense peripheral fludeoxyglucose F 18 uptake and central photopenia that occupies nearly the entire left side of the abdomen and extends to the left side of the pelvis; multiple foci of increased uptake are seen within both hepatic lobes, consistent with hepatic metastases.
Figure 4. Positron-Emission Tomography (PET) with the Use of Fludeoxyglucose F 18.
A PET scan with the use of the tracer fludeoxyglucose F 18 (Panel A) at the time of the diagnosis reveals a mass with peripheral intense uptake and central photopenia throughout nearly the entire left side of the abdomen, extending to the left side of the pelvis (arrows). Multiple foci of increased uptake are seen within both hepatic lobes, consistent with hepatic metastases (arrows). A repeated scan (Panel B), obtained two months after the beginning of treatment with imatinib, shows a marked decrease in the size of the mass (arrows) and a slight decrease in the hepatic metastases.
Discussion of Management
Dr. George D. Demetri: This middle-aged man had a very large abdominal tumor that had metastasized to his liver. Despite the advanced stage of disease, he was asymptomatic, and his organ function and the results of laboratory tests were normal. This discordance between the extent of the disease and the relatively subtle clinical presentation is not uncommon for patients with gastrointestinal stromal tumors.
The first step in the management of advanced gastrointestinal stromal tumor is to confirm the diagnosis and to discuss with the pathologist whether the tissue provided was adequate for a definitive diagnosis. The diagnostic criteria for gastrointestinal stromal tumor have evolved, and this evolution has critical therapeutic implications. No conventional cytotoxic chemotherapy, either alone or in combination, is useful in the management of metastatic gastrointestinal stromal tumors. In contrast, other soft-tissue tumors, such as leiomyosarcomas of the abdomen or the retroperitoneum, desmoid tumors, or liposarcomas, may respond to such therapy. Thus, each of these possible tumors must be differentiated from a gastrointestinal stromal tumor because each would be managed quite differently. The slides should be reviewed by a pathologist with experience in the field of soft-tissue tumors. If there is any question about the adequacy of the tissue, a repeated biopsy should be performed.
The initial therapeutic step for this patient, who presented just before molecularly targeted therapy specific for gastrointestinal stromal tumors became available, would have been either participation in a clinical research study or simply management of symptoms with the best supportive care. It is admirable that the oncologist refrained from giving ineffective, though toxic, chemotherapy. Four months after the diagnosis was made, follow-up evaluation documented progression of the disease, with a 70 percent increase in the size of the mass, enlargement of the existing liver metastases, and development of new liver lesions. This rapid progression despite the low-grade histologic appearance demonstrates that standard histopathological features do not accurately predict the clinical behavior of some gastrointestinal stromal tumors. Despite the massive tumor burden, this patient was still asymptomatic, with good performance status and laboratory values within the normal ranges.
At this point in the case, a new therapeutic approach became available as part of a clinical trial: imatinib mesylate, formerly known by the code name of signal transduction inhibitor 571, or STI571.11 This agent selectively inhibits the KIT tyrosine kinase receptor, including the activated mutant forms of KIT that characterize most cases of gastrointestinal stromal tumors12 (Figure 3). Imatinib binds to the ATP binding site of the intracellular portion of the KIT kinase, preventing ATP from binding and eliminating autophosphorylation and, thus, the induction of downstream signaling pathways.
After preclinical laboratory studies in a gastrointestinal stromal tumor cell line13 showed that inhibition of KIT activity by imatinib led to the arrest of proliferation and the induction of apoptosis, a patient with a gastrointestinal stromal tumor was treated with imatinib and had a rapid response.14 Clinical trials have demonstrated that more than 60 percent of patients with metastatic gastrointestinal stromal tumors who have been treated with imatinib have major durable responses (often resulting in the elimination of more than 70 to 90 percent of the disease bulk).15 Within 24 hours after a single dose of imatinib, decreased tumor glycolytic activity may be seen with the use of PET imaging with fludeoxyglucose F 18. In addition, approximately 15 to 20 percent of patients have disease that remains stable during treatment. The median time necessary for patients to achieve an objective response is approximately three months, but it can range to more than one year after the initiation of imatinib therapy.
Imatinib has relatively few serious side effects. The most dangerous is hemorrhage in the gastrointestinal tract or within the tumor, which occurred in approximately 5 percent of patients in the initial clinical studies of imatinib in gastrointestinal stromal tumors.14,15,16 Other adverse effects include edema and fluid retention, which can be severe in about 5 percent of patients. Rash has also been a problem in a very small percentage of patients. The efficacy of imatinib and, in turn, the duration of disease control with this agent appear to correlate with the specific type of KIT mutation present in a given patient's gastrointestinal stromal tumor.17,18 Eighty percent of tumors with an exon 11 mutation have clinically important responses to imatinib. Only 50 percent with an exon 9 mutation respond, and 20 percent of tumors with no mutation have a partial response. Approximately 4 percent of gastrointestinal stromal tumors harbor activating mutations of another tyrosine kinase receptor, PDGFRA, which provides an alternative oncogenetic pathway independent of KIT.18,19 Some of the tumors with PDGFRA mutations are also responsive to imatinib.18
For this patient, I would recommend immediate treatment with imatinib. Preliminary reports of results have not noted any difference in survival between patients who received 400 mg per day and those who received 800 mg per day of imatinib. When treating patients with very large, bulky tumors, my colleagues and I have generally prescribed the lower starting dose of 400 mg orally once daily, with the potential to increase the dose if the drug is well tolerated. We follow the patients closely for signs of intratumoral bleeding or other treatment-associated toxic effects. We repeat the CT scanning in approximately three months to assess the status of the disease. Once a maximal response has been achieved, we recommend surgical resection of residual disease, if that is feasible without undue risk; imatinib treatment is maintained as long as it continues to be well tolerated. Patients who stop the drug may have progression of their disease within weeks to months, so we recommend lifetime administration of the drug. This opinion is supported by a panel of experts who have developed evidence-based clinical practice guidelines for the management of gastrointestinal stromal tumors.20
Dr. Ryan: Ten days after the patient's second abdominal–pelvic CT scan was obtained, chemotherapy was started with imatinib mesylate, 400 mg orally each day. The medication caused diarrhea that responded to treatment with loperamide.
Dr. Titton: Whole-body PET imaging with fludeoxyglucose F 18 performed two months after the start of imatinib therapy showed a marked improvement in tracer activity in the left upper abdominal mass and in the multiple liver metastases, with some residual tracer uptake (Figure 4B).
Dr. Ryan: After two months of treatment, a diffuse desquamative rash appeared over the patient's neck, chest, arms, and legs. Chemotherapy was withheld for three days, with transient improvement, and was then restarted. The rash worsened and the patient was readmitted to the hospital three weeks later. A skin-biopsy specimen showed signs of a hypersensitivity reaction; no fungal organisms were identified. Chemotherapy was discontinued. The rash improved, and the patient was discharged on the third hospital day with instructions to continue using topical fluocinolone ointment, petrolatum, and mupirocin. Four months later, the abdominal mass was resected, and a biopsy specimen of the liver lesion was obtained; however, the specimen yielded no cells.
Dr. Fletcher: The resected mass was 20 cm in diameter and was approximately 50 percent necrotic when examined grossly. Histologic examination revealed extensive hemorrhagic necrosis (Figure 5). Areas of residual viable tumor showed spindle cells with hyperchromatic, somewhat pyknotic nuclei, and virtually no detectable mitotic activity (Figure 5, inset). The results of immunostaining were the same as on the initial biopsy specimen.
Figure 5. A Specimen of the Resected Tumor (Hematoxylin and Eosin).
Extensive hemorrhagic necrosis is evident. Areas of residual viable tumor are characterized by spindle cells with hyperchromatic, pyknotic nuclei (inset) and virtually no detectable mitotic activity.
Dr. Ryan: The patient continued to do well after the operation, running two to three miles each day. Six months after the operation, a follow-up CT scan showed an increase in the size of the liver lesions; a PET scan obtained one month later showed new, intense tracer uptake in the liver lesions, indicating active disease.
Dr. Harris: Dr. Demetri, what additional treatment would you recommend at this point?
Dr. Demetri: The management of metastatic gastrointestinal stromal tumors in patients who have refractory disease or who are intolerant of imatinib continues to be a problem. As was done in this patient's case, surgical resection or other local ablation options should be considered. However, the benefits of local therapies are quite transient unless an effective and selective inhibition of the relevant kinases can be maintained.
There is a pressing need to evaluate the functional kinase activity of the lesions from gastrointestinal stromal tumors that have become resistant to imatinib, in order to learn more about the mechanisms of resistance.21 Selective tyrosine kinase inhibitors with various profiles of target-enzyme inhibition — from the highly selective, such as imatinib, to other agents that inhibit multiple signaling pathways — are being developed. A new kinase inhibitor, known as SU11248, which my colleagues and I are testing, has a broader spectrum of activity, inhibiting KIT and PDGFRA, as well as the vascular endothelial growth factor receptor, so that it is also a powerful antiangiogenic agent. This agent has rapidly moved forward from phase 1 to phase 3 in clinical trials. For patients with a metastatic gastrointestinal stromal tumor who have a life-threatening intolerance of imatinib or whose tumors have a documented resistance to imatinib, it is most appropriate to seek another clinical research study.
This patient was offered participation in the clinical trial of SU11248, and he accepted with enthusiasm. Ten months after the resection of the mass, he began taking SU11248 at 50 mg per day in cycles consisting of two weeks of therapy followed by two weeks of no therapy. The abnormally high glycolytic activity of the liver metastases, as imaged by PET scanning with fludeoxyglucose F 18, disappeared within one month after the initiation of therapy with SU11248. The liver lesions decreased slightly in size over six months and became cystic; they have not enlarged. The patient has had no toxic reactions and, in particular, has had no rash. He remains physically active, running one to two miles each morning. Two years after beginning treatment with SU11248, he continues to take the drug and there is no evidence of disease progression.
Dr. Robert B. Colvin (Pathology): Is the drug actually cytotoxic or does it just slow cell proliferation? If the former, are there other drugs that could be used synergistically with imatinib?
Dr. Demetri: Laboratory studies show that the cells go into cell-cycle arrest, followed by apoptosis. However, in vivo, not all the cells die, and we have seen no patients who would be considered to have had a complete response. We need to search for other pathways in order to develop a useful combination therapy.
Dr. Harris: This patient's initial biopsy was a fine-needle aspiration, which left barely enough tissue for the CD117 staining and certainly none for molecular studies. Would you advocate that patients who participate in clinical trials have repeated biopsies to obtain tissue for analysis of KIT mutations?
Dr. Demetri: We are advocating that biopsy specimens for mutational analysis be obtained from these patients whenever possible.
Dr. Fletcher: If we want to have molecularly targeted therapies and if we want to understand the biology of the disease, we will need adequate tissue for these studies. Minimally invasive techniques such as fine-needle aspiration may not provide sufficient tissue on a consistent basis and, at least in sarcoma centers, there is an increasing trend to return to the convention of open biopsies.22
Anatomical Diagnosis
Gastrointestinal stromal tumor.
Dr. Demetri reports having received research support from Novartis, Pfizer, Bristol-Myers Squibb, and Johnson & Johnson and having served as a consultant to these companies.
Source Information
From the Center for Sarcoma and Bone Oncology, Dana–Farber Cancer Institute (G.D.D.); the Departments of Radiology (R.L.T.) and Hematology/Oncology (D.P.R.), Massachusetts General Hospital; the Department of Pathology, Brigham and Women's Hospital (C.D.M.F.); and the Departments of Medicine (G.D.D., D.P.R.), Radiology (R.L.T.), and Pathology (C.D.M.F.), Harvard Medical School — all in Boston.
References
Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002;33:459-465.
Miettinen M, Lasota J. Gastrointestinal stromal tumors -- definition, clinical, histological, immunohistochemical and molecular genetic features and differential diagnosis. Virchows Arch 2001;438:1-12.
Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577-580.
Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998;152:1259-1269.
Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 2001;61:8118-8121.
Corless CL, McGreevey L, Haley A, Town A, Heinrich MC. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 2002;160:1567-1572.
Hornick JL, Fletcher CDM. Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin Pathol 2002;117:188-193.
Fletcher CDM, Fletcher JA. Testing for KIT (CD117) in gastrointestinal stromal tumors: another HercepTest? Am J Clin Pathol 2002;118:163-164.
Hornick JL, Fletcher CDM. Validating immunohistochemical staining for KIT (CD117). Am J Clin Pathol 2003;119:325-327.
Medeiros F, Corless CL, Duensing A, et al. KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol 2004;28:889-894.
Savage DG, Antman KH. Imatinib mesylate -- a new oral targeted therapy. N Engl J Med 2002;346:683-693.
Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000;96:925-932.
Tuveson DA, Willis NA, Jacks T, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 2001;20:5054-5058.
Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052-1056.
Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-480.
van Oosterom A, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358:1421-1423.
Singer S, Rubin BP, Lux ML, et al. Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in gastrointestinal stromal tumors. J Clin Oncol 2002;20:3898-3905.
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342-4349.
Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708-710.
Demetri GD, Benjamin R, Blanke C, et al. Optimal management of patients with gastrointestinal stromal tumors (GIST): expansion and update of the NCCN clinical practice guidelines. J Natl Compr Cancer Net 2004;2:1-68.
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Presentation of Case
Dr. David P. Ryan: A 68-year-old man was admitted to the hospital because of a large retroperitoneal tumor.
The patient had been in excellent health. A few days before admission, a routine physical examination by his primary physician had revealed a large abdominal mass. He was admitted to the hospital.
The man was married and had retired from a sedentary occupation. He ran 5 to 10 miles weekly and remarked that, but for the mass, he would not know that he had cancer. There was a three-year history of hypertension, and he had been given a diagnosis of anxiety disorder. He did not smoke, and he used alcohol moderately. His medications were amlodipine, citalopram, and temazepam, which he took at bedtime, and lorazepam, which he took when he was feeling tense. He was allergic to penicillin. His father had died of multiple myeloma at 63 years of age and a brother had died of throat cancer at 57 years of age.
On admission, the temperature was 37.3°C, the heart rate 88 beats per minute, and the blood pressure 170/90 mm Hg. The weight was 75 kg. The patient looked well. There was no icterus or lymphadenopathy. The lungs and heart appeared normal. A hard, nontender mass occupied the entire left upper abdominal quadrant. There was + peripheral edema, but it had not been noticed by the patient. The results of a neurologic examination were unremarkable.
Laboratory tests were performed. The hematocrit was 35.1 percent, the white-cell count 9400, the platelet count 347,000, and the mean corpuscular volume 89 μm3; the prothrombin and partial-thromboplastin times were normal. The aspartate aminotransferase level was 50 U per liter. Normal results were obtained for the measurements of urea nitrogen, creatinine, glucose, conjugated and total bilirubin, calcium, total protein, albumin, globulin, electrolytes, alanine aminotransferase, alkaline phosphatase, prostate-specific antigen, carcinoembryonic antigen, and CA 19-9. May we see the imaging studies?
Dr. Ross L. Titton: An ultrasonographic study of the abdomen showed a large heterogeneous mass in the upper abdomen that was contiguous with the pancreas; an isoechoic mass, measuring 3 to 4 cm in diameter, was evident in the right hepatic lobe. The patient's physician was called, and a decision was made to perform a biopsy; however, gas from a loop of bowel partially obscured the mass and made the location unsuitable for an ultrasound-guided biopsy. A nonenhanced computed tomographic (CT) scan of the abdomen (Figure 1A), obtained 20 minutes after the ultrasonographic study, confirmed that there was a heterogeneous mass, 13 cm by 10 cm, that originated in the left upper retroperitoneum. The mass is contiguous with the posterior wall of the stomach anteriorly and with the pancreas posteriorly; several masses are evident in the right and left hepatic lobes (Figure 1B); the spleen, left kidney, and left adrenal gland are unremarkable; and there is no lymphadenopathy or ascites.
Figure 1. CT Scans of the Abdomen.
A nonenhanced CT scan of the abdomen (Panel A) shows a heterogeneous mass, 13 cm by 10 cm, that originated in the left upper retroperitoneum (arrows); the mass is contiguous with the posterior wall of the stomach anteriorly and with the pancreas and spleen posteriorly. In another view, a mass is visible in the left hepatic lobe, which is not well seen in this nonenhanced study (Panel B, arrows). Four months later, repeated scans, obtained after the administration of oral and intravenous contrast material (Panel C), show an increase in the size of the retroperitoneal mass from 13 cm by 10 cm to 17 cm by 13 cm (arrows), as well as an increase in the number and size of the hepatic metastases (Panel D, arrows).
Under CT guidance, multiple fine-needle aspirates and 18-gauge core-biopsy specimens were obtained from the main mass by an anterior subcostal approach; then, with the use of a right lateral transpleural approach, multiple fine-needle aspirates and 18-gauge core-biopsy specimens of the largest mass in the right hepatic lobe were obtained, without complications.
Dr. Nancy Lee Harris (Pathology): Dr. Fletcher, will you show us the findings on fine-needle aspiration?
Pathological Discussion
Dr. Christopher D.M. Fletcher: The biopsy of both the retroperitoneal and liver masses revealed a cytologically uniform, eosinophilic spindle-cell neoplasm with fascicular architecture and minimal nuclear atypia (Figure 2A and Figure 2B). The differential diagnosis includes a smooth-muscle neoplasm, a gastrointestinal stromal tumor, and a nerve-sheath neoplasm. Immunohistochemical staining revealed striking cytoplasmic positivity for KIT (CD117) (Figure 2C) and CD34 with scattered cells positive for actin, whereas the cells were negative for desmin and S-100 protein, confirming the diagnosis of gastrointestinal stromal tumor. Despite the lack of nuclear atypia and the very low mitotic rate, the size of the primary tumor and the presence of hepatic metastases left no doubt that this lesion was malignant (gastrointestinal stromal sarcoma).
Figure 2. Needle-Biopsy Specimens of the Retroperitoneal Mass and the Liver.
On cytologic examination of the biopsy specimen of the retroperitoneal mass, a cytologically uniform spindle-cell neoplasm with bland nuclear morphologic features is evident (Panel A; Papanicolaou stain). The needle-biopsy specimen of the liver (Panel B; hematoxylin and eosin) contains spindle cells with eosinophilic cytoplasm and a fascicular architecture. Immunohistochemical staining reveals striking cytoplasmic positivity for KIT (CD117) (Panel C; immunoperoxidase stain), confirming the diagnosis of gastrointestinal stromal tumor.
This case raises the issue of the diagnosis and classification of spindle-cell tumors of the gastrointestinal tract, a discussion that has evolved dramatically in the past four to five years.1,2 For many years, most of these lesions were regarded as smooth-muscle neoplasms (leiomyoma or leiomyosarcoma), with either spindle-cell or epithelioid cytomorphology. The introduction of electron microscopy and, subsequently, immunohistochemical study revealed that there was considerable phenotypic heterogeneity, which included lesions with smooth-muscle, neural, autonomic, and biphenotypic features, or even no evident differentiation. This heterogeneity led, in the early 1980s, to the introduction of the generic (and at that time less specific) term gastrointestinal stromal tumor. By the early 1990s, CD34 was regarded as a frequently expressed and diagnostically useful marker in this context — although this has subsequently been disproved, since CD34 positivity is practically ubiquitous among spindle-cell tumors (Table 1). Until recently, it was believed that there was phenotypic variation among gastrointestinal stromal tumors that arose in different parts of the gastrointestinal tract, with smooth-muscle lesions predominating in the esophagus and large bowel and neural lesions predominating in the small bowel. However, this perception has been at least partially overturned by insights into the biology of these lesions.
Table 1. Immunohistochemical Classification of Spindle-Cell Tumors in the Gastrointestinal Tract.
Within the past decade, several groups of investigators recognized that interstitial cells of Cajal — cells normally present in the myenteric plexus that coordinate peristalsis by linking the autonomic innervation to the smooth muscle of the bowel wall — showed immunohistochemical positivity for KIT; subsequently, investigators showed that many gastrointestinal stromal tumors had similar KIT positivity.3,4 Ultrastructurally, interstitial cells of Cajal share features of both myogenic and neural differentiation,4 which in part helps to explain the immunohistochemical heterogeneity of the tumors. Hirota et al.3 in Japan, in drawing parallels with previous studies in mast-cell neoplasms, demonstrated activating KIT mutations in five of six gastrointestinal stromal tumors, as well as the ability of the mutant KIT cDNA to induce malignant transformation in a lymphoid cell line.
KIT is a transmembrane tyrosine kinase receptor; normally, the ligand for this is stem-cell factor (Figure 3). KIT is expressed by (and required for the normal development of) mast cells, germ cells, melanocytes, erythroid stem cells, and interstitial cells of Cajal. Normally, binding of stem-cell factor to KIT causes dimerization and cross-phosphorylation, triggering signal transduction through the KIT receptor and inducing proliferation and inhibiting apoptosis. The mutations in KIT found in gastrointestinal stromal tumors allow the molecule to dimerize in the absence of ligand, resulting in constitutive activation and phosphorylation, thereby activating downstream signaling pathways, which exert a proliferative and antiapoptotic effect (Figure 3).
Figure 3. Normal and Mutated KIT and the Action of Imatinib.
KIT is a transmembrane tyrosine kinase receptor. Binding of its ligand, stem-cell factor, causes dimerization and cross-phosphorylation of KIT, triggering signal transduction through the KIT receptor, inducing proliferation and inhibiting apoptosis. The mutations in the KIT gene found in gastrointestinal stromal tumors allow the molecule to dimerize in the absence of ligand, resulting in constitutive activation and phosphorylation and activating downstream signaling pathways, which stimulate cell proliferation and inhibit apoptosis. Imatinib binds to the ATP-binding site and inhibits the phosphorylation of KIT.
Since the initial recognition that KIT mutations are present in gastrointestinal stromal tumors, it has been demonstrated in larger series that more than 90 percent of spindle-cell and epithelioid mesenchymal neoplasms in the gastrointestinal tract (including those previously classified as gastrointestinal autonomic-nerve tumors) had KIT-activating mutations. In the majority of cases, these mutations — irrespective of size, site, or histotype5,6 — were associated with immunohistochemically detectable expression of KIT protein. True smooth-muscle neoplasms and schwannomas lack KIT positivity — a fact that makes it possible to distinguish them from gastrointestinal stromal tumors (Table 1). Approximately 60 to 70 percent of KIT mutations occur in the juxtamembrane region (exon 11) of the receptor, with an additional 10 to 15 percent in the extracellular domain (exon 9), and roughly 5 to 7 percent in the split kinase domain. Patients with familial gastrointestinal stromal tumors have germ-line KIT mutations, often also associated with systemic mast-cell disease, pigmentation disorders, or both, underscoring the central pathogenetic role of KIT in this context.
It was initially believed that the type of KIT mutation correlated with the pathobiologic nature of a given gastrointestinal stromal tumor (i.e., whether the lesion would behave ultimately as a benign neoplasm or as an aggressive cancer), but this theory has not been borne out by subsequent studies. After a workshop at the National Institutes of Health in 2001, consensus guidelines for the diagnosis of gastrointestinal stromal tumor were developed,1 and this diagnosis now relies heavily on the demonstration of KIT immunopositivity. Such positivity is not shared by most other types of sarcoma,7 and hence, it is critical that staining to determine the KIT status is performed consistently and reliably in pathology laboratories.8,9 Approximately 4 percent of otherwise morphologically typical gastrointestinal stromal tumors are KIT-immunonegative; most of these tumors harbor PDGFRA mutations.10
Defined in this way, gastrointestinal stromal tumor is the most common mesenchymal tumor of the gastrointestinal tract; it affects mainly middle-aged adults, with a slight predominance in women, and arises most often in the stomach or small bowel and less often in the mesentery, large bowel, esophagus, and retroperitoneum. These tumors typically spread, at least initially, around the peritoneal cavity and to the liver, and the overall survival rate among patients who present with clinical symptoms is approximately 40 to 50 percent at 5 years and 15 to 25 percent at 10 years. Prediction of the prognosis in patients with gastrointestinal stromal tumors is difficult, because about 10 percent of lesions that are less than 5 cm in diameter and lesions with minimal proliferative activity or atypia may give rise to metastases in a seemingly unpredictable fashion. This difficulty has led to the consensus,1 based on extensive cumulative experience, that no gastrointestinal stromal tumor can be definitively labeled as benign and that, instead, the risk of metastasis should be assessed on the basis of size and mitotic rate (Table 2).
Table 2. Proposed Guidelines for Defining the Risk of Aggressive Behavior in Gastrointestinal Stromal Tumors.
Dr. Ryan: Because the patient was asymptomatic, and because there was no available chemotherapeutic agent for the treatment of gastrointestinal stromal tumor at the time of his diagnosis, he was advised to continue his customary activities. Four months later, another abdominal–pelvic CT scan was obtained.
Dr. Titton: This CT scan (Figure 1C) shows an increase in the size of the retroperitoneal mass from 13 cm by 10 cm to 17 cm by 13 cm, as well as an increase in the number and size of the hepatic metastases (Figure 1D). A positron-emission tomographic (PET) scan (Figure 4A) reveals a mass with intense peripheral fludeoxyglucose F 18 uptake and central photopenia that occupies nearly the entire left side of the abdomen and extends to the left side of the pelvis; multiple foci of increased uptake are seen within both hepatic lobes, consistent with hepatic metastases.
Figure 4. Positron-Emission Tomography (PET) with the Use of Fludeoxyglucose F 18.
A PET scan with the use of the tracer fludeoxyglucose F 18 (Panel A) at the time of the diagnosis reveals a mass with peripheral intense uptake and central photopenia throughout nearly the entire left side of the abdomen, extending to the left side of the pelvis (arrows). Multiple foci of increased uptake are seen within both hepatic lobes, consistent with hepatic metastases (arrows). A repeated scan (Panel B), obtained two months after the beginning of treatment with imatinib, shows a marked decrease in the size of the mass (arrows) and a slight decrease in the hepatic metastases.
Discussion of Management
Dr. George D. Demetri: This middle-aged man had a very large abdominal tumor that had metastasized to his liver. Despite the advanced stage of disease, he was asymptomatic, and his organ function and the results of laboratory tests were normal. This discordance between the extent of the disease and the relatively subtle clinical presentation is not uncommon for patients with gastrointestinal stromal tumors.
The first step in the management of advanced gastrointestinal stromal tumor is to confirm the diagnosis and to discuss with the pathologist whether the tissue provided was adequate for a definitive diagnosis. The diagnostic criteria for gastrointestinal stromal tumor have evolved, and this evolution has critical therapeutic implications. No conventional cytotoxic chemotherapy, either alone or in combination, is useful in the management of metastatic gastrointestinal stromal tumors. In contrast, other soft-tissue tumors, such as leiomyosarcomas of the abdomen or the retroperitoneum, desmoid tumors, or liposarcomas, may respond to such therapy. Thus, each of these possible tumors must be differentiated from a gastrointestinal stromal tumor because each would be managed quite differently. The slides should be reviewed by a pathologist with experience in the field of soft-tissue tumors. If there is any question about the adequacy of the tissue, a repeated biopsy should be performed.
The initial therapeutic step for this patient, who presented just before molecularly targeted therapy specific for gastrointestinal stromal tumors became available, would have been either participation in a clinical research study or simply management of symptoms with the best supportive care. It is admirable that the oncologist refrained from giving ineffective, though toxic, chemotherapy. Four months after the diagnosis was made, follow-up evaluation documented progression of the disease, with a 70 percent increase in the size of the mass, enlargement of the existing liver metastases, and development of new liver lesions. This rapid progression despite the low-grade histologic appearance demonstrates that standard histopathological features do not accurately predict the clinical behavior of some gastrointestinal stromal tumors. Despite the massive tumor burden, this patient was still asymptomatic, with good performance status and laboratory values within the normal ranges.
At this point in the case, a new therapeutic approach became available as part of a clinical trial: imatinib mesylate, formerly known by the code name of signal transduction inhibitor 571, or STI571.11 This agent selectively inhibits the KIT tyrosine kinase receptor, including the activated mutant forms of KIT that characterize most cases of gastrointestinal stromal tumors12 (Figure 3). Imatinib binds to the ATP binding site of the intracellular portion of the KIT kinase, preventing ATP from binding and eliminating autophosphorylation and, thus, the induction of downstream signaling pathways.
After preclinical laboratory studies in a gastrointestinal stromal tumor cell line13 showed that inhibition of KIT activity by imatinib led to the arrest of proliferation and the induction of apoptosis, a patient with a gastrointestinal stromal tumor was treated with imatinib and had a rapid response.14 Clinical trials have demonstrated that more than 60 percent of patients with metastatic gastrointestinal stromal tumors who have been treated with imatinib have major durable responses (often resulting in the elimination of more than 70 to 90 percent of the disease bulk).15 Within 24 hours after a single dose of imatinib, decreased tumor glycolytic activity may be seen with the use of PET imaging with fludeoxyglucose F 18. In addition, approximately 15 to 20 percent of patients have disease that remains stable during treatment. The median time necessary for patients to achieve an objective response is approximately three months, but it can range to more than one year after the initiation of imatinib therapy.
Imatinib has relatively few serious side effects. The most dangerous is hemorrhage in the gastrointestinal tract or within the tumor, which occurred in approximately 5 percent of patients in the initial clinical studies of imatinib in gastrointestinal stromal tumors.14,15,16 Other adverse effects include edema and fluid retention, which can be severe in about 5 percent of patients. Rash has also been a problem in a very small percentage of patients. The efficacy of imatinib and, in turn, the duration of disease control with this agent appear to correlate with the specific type of KIT mutation present in a given patient's gastrointestinal stromal tumor.17,18 Eighty percent of tumors with an exon 11 mutation have clinically important responses to imatinib. Only 50 percent with an exon 9 mutation respond, and 20 percent of tumors with no mutation have a partial response. Approximately 4 percent of gastrointestinal stromal tumors harbor activating mutations of another tyrosine kinase receptor, PDGFRA, which provides an alternative oncogenetic pathway independent of KIT.18,19 Some of the tumors with PDGFRA mutations are also responsive to imatinib.18
For this patient, I would recommend immediate treatment with imatinib. Preliminary reports of results have not noted any difference in survival between patients who received 400 mg per day and those who received 800 mg per day of imatinib. When treating patients with very large, bulky tumors, my colleagues and I have generally prescribed the lower starting dose of 400 mg orally once daily, with the potential to increase the dose if the drug is well tolerated. We follow the patients closely for signs of intratumoral bleeding or other treatment-associated toxic effects. We repeat the CT scanning in approximately three months to assess the status of the disease. Once a maximal response has been achieved, we recommend surgical resection of residual disease, if that is feasible without undue risk; imatinib treatment is maintained as long as it continues to be well tolerated. Patients who stop the drug may have progression of their disease within weeks to months, so we recommend lifetime administration of the drug. This opinion is supported by a panel of experts who have developed evidence-based clinical practice guidelines for the management of gastrointestinal stromal tumors.20
Dr. Ryan: Ten days after the patient's second abdominal–pelvic CT scan was obtained, chemotherapy was started with imatinib mesylate, 400 mg orally each day. The medication caused diarrhea that responded to treatment with loperamide.
Dr. Titton: Whole-body PET imaging with fludeoxyglucose F 18 performed two months after the start of imatinib therapy showed a marked improvement in tracer activity in the left upper abdominal mass and in the multiple liver metastases, with some residual tracer uptake (Figure 4B).
Dr. Ryan: After two months of treatment, a diffuse desquamative rash appeared over the patient's neck, chest, arms, and legs. Chemotherapy was withheld for three days, with transient improvement, and was then restarted. The rash worsened and the patient was readmitted to the hospital three weeks later. A skin-biopsy specimen showed signs of a hypersensitivity reaction; no fungal organisms were identified. Chemotherapy was discontinued. The rash improved, and the patient was discharged on the third hospital day with instructions to continue using topical fluocinolone ointment, petrolatum, and mupirocin. Four months later, the abdominal mass was resected, and a biopsy specimen of the liver lesion was obtained; however, the specimen yielded no cells.
Dr. Fletcher: The resected mass was 20 cm in diameter and was approximately 50 percent necrotic when examined grossly. Histologic examination revealed extensive hemorrhagic necrosis (Figure 5). Areas of residual viable tumor showed spindle cells with hyperchromatic, somewhat pyknotic nuclei, and virtually no detectable mitotic activity (Figure 5, inset). The results of immunostaining were the same as on the initial biopsy specimen.
Figure 5. A Specimen of the Resected Tumor (Hematoxylin and Eosin).
Extensive hemorrhagic necrosis is evident. Areas of residual viable tumor are characterized by spindle cells with hyperchromatic, pyknotic nuclei (inset) and virtually no detectable mitotic activity.
Dr. Ryan: The patient continued to do well after the operation, running two to three miles each day. Six months after the operation, a follow-up CT scan showed an increase in the size of the liver lesions; a PET scan obtained one month later showed new, intense tracer uptake in the liver lesions, indicating active disease.
Dr. Harris: Dr. Demetri, what additional treatment would you recommend at this point?
Dr. Demetri: The management of metastatic gastrointestinal stromal tumors in patients who have refractory disease or who are intolerant of imatinib continues to be a problem. As was done in this patient's case, surgical resection or other local ablation options should be considered. However, the benefits of local therapies are quite transient unless an effective and selective inhibition of the relevant kinases can be maintained.
There is a pressing need to evaluate the functional kinase activity of the lesions from gastrointestinal stromal tumors that have become resistant to imatinib, in order to learn more about the mechanisms of resistance.21 Selective tyrosine kinase inhibitors with various profiles of target-enzyme inhibition — from the highly selective, such as imatinib, to other agents that inhibit multiple signaling pathways — are being developed. A new kinase inhibitor, known as SU11248, which my colleagues and I are testing, has a broader spectrum of activity, inhibiting KIT and PDGFRA, as well as the vascular endothelial growth factor receptor, so that it is also a powerful antiangiogenic agent. This agent has rapidly moved forward from phase 1 to phase 3 in clinical trials. For patients with a metastatic gastrointestinal stromal tumor who have a life-threatening intolerance of imatinib or whose tumors have a documented resistance to imatinib, it is most appropriate to seek another clinical research study.
This patient was offered participation in the clinical trial of SU11248, and he accepted with enthusiasm. Ten months after the resection of the mass, he began taking SU11248 at 50 mg per day in cycles consisting of two weeks of therapy followed by two weeks of no therapy. The abnormally high glycolytic activity of the liver metastases, as imaged by PET scanning with fludeoxyglucose F 18, disappeared within one month after the initiation of therapy with SU11248. The liver lesions decreased slightly in size over six months and became cystic; they have not enlarged. The patient has had no toxic reactions and, in particular, has had no rash. He remains physically active, running one to two miles each morning. Two years after beginning treatment with SU11248, he continues to take the drug and there is no evidence of disease progression.
Dr. Robert B. Colvin (Pathology): Is the drug actually cytotoxic or does it just slow cell proliferation? If the former, are there other drugs that could be used synergistically with imatinib?
Dr. Demetri: Laboratory studies show that the cells go into cell-cycle arrest, followed by apoptosis. However, in vivo, not all the cells die, and we have seen no patients who would be considered to have had a complete response. We need to search for other pathways in order to develop a useful combination therapy.
Dr. Harris: This patient's initial biopsy was a fine-needle aspiration, which left barely enough tissue for the CD117 staining and certainly none for molecular studies. Would you advocate that patients who participate in clinical trials have repeated biopsies to obtain tissue for analysis of KIT mutations?
Dr. Demetri: We are advocating that biopsy specimens for mutational analysis be obtained from these patients whenever possible.
Dr. Fletcher: If we want to have molecularly targeted therapies and if we want to understand the biology of the disease, we will need adequate tissue for these studies. Minimally invasive techniques such as fine-needle aspiration may not provide sufficient tissue on a consistent basis and, at least in sarcoma centers, there is an increasing trend to return to the convention of open biopsies.22
Anatomical Diagnosis
Gastrointestinal stromal tumor.
Dr. Demetri reports having received research support from Novartis, Pfizer, Bristol-Myers Squibb, and Johnson & Johnson and having served as a consultant to these companies.
Source Information
From the Center for Sarcoma and Bone Oncology, Dana–Farber Cancer Institute (G.D.D.); the Departments of Radiology (R.L.T.) and Hematology/Oncology (D.P.R.), Massachusetts General Hospital; the Department of Pathology, Brigham and Women's Hospital (C.D.M.F.); and the Departments of Medicine (G.D.D., D.P.R.), Radiology (R.L.T.), and Pathology (C.D.M.F.), Harvard Medical School — all in Boston.
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