|Year : 2014 | Volume
| Issue : 3 | Page : 763-766
Imatinib-induced pathologic changes including bile duct dilatation in hepatic metastases of gastrointestinal stromal tumor: Case report and review of literature
Young Sub Lee, Sung Hak Lee, Yeong Jin Choi, Eun Sun Jung
Department of Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
|Date of Web Publication||14-Oct-2014|
Dr. Eun Sun Jung
Department of Hospital Pathology, Main Building, Seoul St. Mary's Hospital, 505 Banpo-dong, Seocho-gu, Seoul 137-040
Source of Support: None, Conflict of Interest: None
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs), such as imatinibmesylate, have been used for the adjuvant treatment of KIT-positive GISTs. Several pathologic changes after imatinib treatment of metastatic GIST including tumor necrosis, myxohyaline or sclerohyalinestroma, proliferative index decline, a varying degree of hemorrhage, edema, and cystic change have been reported in previous studies. More specifically, cystic changes after imatinib treatment were mainly induced by necrosis, hemorrhage, and degeneration. Until now, there have been no reports of cystic changes due to a dilated bile duct entrapped by a totally regressed tumor. We report a case of a 61-year-old man who was diagnosed with high-risk GIST of the stomach complicated by hepatic metastasis and who had such a unique pathologic changes with imatinib treatment.
Keywords: Bile duct dilatation, gastrointestinal stromal tumors, imatinib, liver metastasis
|How to cite this article:|
Lee YS, Lee SH, Choi YJ, Jung ES. Imatinib-induced pathologic changes including bile duct dilatation in hepatic metastases of gastrointestinal stromal tumor: Case report and review of literature. J Can Res Ther 2014;10:763-6
|How to cite this URL:|
Lee YS, Lee SH, Choi YJ, Jung ES. Imatinib-induced pathologic changes including bile duct dilatation in hepatic metastases of gastrointestinal stromal tumor: Case report and review of literature. J Can Res Ther [serial online] 2014 [cited 2020 Jul 13];10:763-6. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/763/136030
| > Introduction|| |
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, many of which have KIT or PDGFA gene mutations. Metastases from GISTs are often found in the liver and peritoneum. Tyrosine kinase inhibitors (TKIs), such as imatinibmesylate (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), inhibit KIT and PDGFA receptor tyrosine kinases and were FDA approved in 2008 for the adjuvant treatment of KIT-positive GISTs.  Although imatinib has improved survival in advanced GIST, complete response is rare. 
Pathologic changes associated with imatinib treatment in patients with metastatic GIST have been investigated in eight studies. Several pathologic changes including cystic change, tumor necrosis, a varying degree of hemorrhage, edema, myxohyaline or sclerohyalinestroma, a decline in proliferative index, loss of KIT expression, and rare dedifferentiation and/or trans-differentiation into another phenotype such as rhabdomyosarcoma were observed in these studies. ,,,,,,, In these studies, it was reported that cystic change of metastatic GIST after imatinib treatment was mainly induced by tumor necrosis, hemorrhage, and degeneration. We report a unique case of metastatic GIST to the liver with imatinib-induced pathologic change, which shows cystic dilatation of the bile duct entrapped in a totally regressed tumor. Such cystic changes due to dilatation of the bile duct entrapped in a regressed tumor have not yet been documented.
| > Case Reports|| |
The patient is a 61-year-old Asian male who two years prior to presentation underwent a proximal gastrectomy at an outside hospital for a high-risk GIST. Seven months post-gastrectomy, the patient presented to an oncologist at Seoul St. Mary's Hospital complaining of left upper quadrant (LUQ) abdominal pain and weight loss. An abdominopelvic CT was performed, which revealed a 16-cm mass in the left upper quadrant (LUQ) region located in the gastrosplenic ligament, as well as two nodules on liver segments 6 and 8 (4.6 cm and 1.2 cm in diameter, respectively), suggestive of metastatic GISTs. Imatinib was administered subsequently (400 mg daily). On follow up CT after four weeks of imatinib treatment, the masses decreased in size and were interpreted as having necrotic changes [Figure 1]a and b. After 23 months of further imatinib treatment, suspicious tumor recurrences in the necrotic nodules in liver segments 6 and 8 were found on follow up CT [Figure 1]c and d. The patient underwent laparoscopic wedge resections of liver segments 6 and 8 for both diagnosis and treatment. The mass in the gastrosplenic ligament was not resected.
|Figure 1: (a-b) CT with contrast after 4 weeks of imatinib showing tumors in left upper quadrant, and segments 8 and 6 of the liver. (c-d) CT with contrast after 23 months of imatinib treatment showing septal-like enhancement in the mass on segment 8 and a new enhancing nodule in the mass on segment 6 of the liver|
Click here to view
Two wedge-shaped liver fragments were submitted for pathologic examination. On segment 6, there was a well-demarcated hemorrhagic cyst, 1.2 cm in diameter, containing a round solid mass, 0.7 cm in diameter, grossly [Figure 2]a. The round solid mass was composed of two areas: The inner whitish solid area and the outer grayish soft area. Microscopically, the inner area showed a relatively dense spindle tumor cells with a palisading pattern and bizarre nuclei, while the outer area showed marked myxoid degeneration with hemorrhage and a few remaining tumor cells [Figure 2]b. Mitosis and inflammatory cell infiltration were not found. Immunohistochemistry was positive for KIT [Figure 2]c, DOG-1, CD34, and Ki-67 (labeling 20%), but negative for actin, desmin, and S-100. Mutation analysis of C-KIT gene (exons 9, 11, 13, and 17) showed c. 1669_1674del (p.Trp557_Lys558del) in exon 11.
|Figure 2: a) Sections of liver segment 6 showing a hemorrhagic cyst with a mass in it, composed of two areas (* and #). b) Microscopic view of the mass showing the inner area (*) of atypical spindle cells, and the outer area (#) of myxoid degeneration. c) KIT expression in a few viable tumor cells. (B: H and E ×100, C: Immunoperoxidase, KIT ×400)|
Click here to view
On segment 8, there was a well-defined ovoid mass, 3.5 cm in diameter, with cystic changes, 2.2 cm in diameter, on one side, grossly. The ovoid mass had a yellowish myxoid soft cut surface and an adjacent cystic lesion with a smooth thin-walled inner surface containing clear fluid [Figure 3]a. Microscopically, the nodule showed diffuse myxohyaline degeneration without viable tumor cell component, and a cystic lesion entrapped in it was lined by simple columnar epithelium with mucin production [Figure 3]b. Immunohistochemically, the myxohyaline nodule was negative for KIT and CD34, and the epithelial cells of the cyst were positive for CK7 [Figure 3]c and CK19, indicative of a bile duct epithelium phenotype.
|Figure 3: (a) Sections of liver segment 8 showing a mass composed of a myxoid nodule (**) and an adjacent thin-walled cyst (arrows). (b) Microscopic examination showing myxohyaline degeneration (**) and a dilated cyst lined by simple columnar epithelium (arrows). (c) CK7 expression in epithelial cells of the cyst. (B: H and E ×100, C: Immunoperoxidase, KIT ×400)|
Click here to view
| > Discussion|| |
Imatinib-induced pathologic changes in GIST with hepatic metastases have been studied by several researchers [Table 1]. For the first time, Jonesuu et al. reported a case of liver biopsy of metastatic GIST after one and two months of imatinib treatment, which showed a marked decrease in tumor cell density, myxoid degeneration, and scarring. There were no signs of an inflammatory reaction or necrosis.A few remaining cells were positive for CD117 (KIT) and negative for CD45 and Ki-67.  Abdulkader et al. reported similar findings to those reported by Jonesuu. 
|Table 1: Clinico-pathologic Findings of Imatinib-induced change in GIST with Hepatic Metastasis|
Click here to view
Only two studies have described complete histological remission of metastatic GIST. Högenauer et al. reported a case of multiple metastatic GISTs involving the liver, peritoneum, mesentery, and pelvis. Biopsy after 5 months of imatinib treatment demonstrated areas of myxoid degeneration with few macrophages and stromal elements, but no viable tumor cells.  Agaram et al. studied 28 patients with imatinib-stable or imatinib-responsive GISTs including 18 patients with liver and/or peritoneum metastases, and found a few cases of dense hyalinization with a complete loss of tumor cells. Other cases showed heterogeneous histological responses such as remaining viable solid areas, gross tumor necrosis with central areas of cystic change, and hemorrhage.  Bümming et al. also noted cystic changes in metastatic GIST after imatinib treatment in tumor tissue from two patients with liver metastases. One case showed extensive hyalinization with scattered residual tumor cells, necrosis, cystic change, and areas of viable tumor in which the Ki-67 index was virtually zero, whereas no histological changes were seen in the other case. In all cases of these two studies, cystic change was induced by degeneration and was not a true cyst with epithelial lining. 
Three studies have described various phenotypic changes in imatinib-resistant GISTs after imatinib treatment. Pauwels et al. comparedhistopathologic and genetic findings of two clinically progressive and one clinically stable GIST with liver metastasis before and after imatinib treatment. All three primary GISTs from these patients were classical spindle-cell type tumors, whereas metastatic masses after imatinib treatment revealed a diffuse epithelioid or pseudopapillaryepithelioid growth pattern.A complete loss of KIT expression without new genotypic modifications was also noted.  Bickenbach et al. reported a case of rapidly progressing recurrent GIST after two years of imatinib treatment, showing a mildly cellular spindle cell tumor with extensive bone and cartilage formation, as well as focal epithelioid differentiation. All cell types in the tumor were immunohistochemically negative for KIT and CD34, and genetically similar with one another by c-kit mutational analysis.  Liegl et al. reported five cases of progressing metastatic GIST after imatinib treatment, including three liver metastases with heterologous rhabdomyoblastic differentiation in all cases. In these studies, cystic change was not noted. 
In the present case, two liver masses showed different histopathologic features after imatinib treatment for 24 months. One mass on segment 6 of the liver showed a hemorrhagic cyst containing a recurrent tumor nodule characterized by pleomorphism, decreased cellularity, partial change of myxoid degeneration, and persistent KIT expression without inflammatory reaction [Figure 2]a-c. These findings are consistent with metastatic GIST and are congruent with previous studies. In contrast, the other mass on segment 8 of the liver showed a complete tumor regression replaced by a myxohyalinestroma [Figure 3]a-c. Furthermore, there was a dilated cyst lined by columnar epithelium partially entrapped in a nodule. The epithelial cells were immunohistochemically positive for both CK7 and CK19, suggesting an epithelium of bile duct origin. Thus, it is thought that the septal-like enhancement of the liver mass on segment 6 seen on CT with contrast [Figure 1]c was a wall of the dilated bile duct. The bile duct might have been dilated due to continuous secretion from bile epithelium, in addition to an obstruction via compression by the myxohyaline nodule. In previous reports, all cystic changes found in hepatic metastases of GISTs post-imatinib treatment were mainly induced by hemorrhage and myxoid degeneration of stroma. , The present case, however, is the first case in the literature of distinct cystic changes induced by dilatation of the bile duct, which was partially entrapped by the tumor. Moreover, it is clinically important that such a lesion of cystic dilatation of the bile duct can mimic tumor recurrence on CT findings.
We report a case of a unique pathologic change of cystic dilatation of the bile duct entrapped in hepatic metastatic GIST in a 61-year-old man with high-risk GIST of the stomach status post-imatinib treatment.
| > References|| |
Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al
. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004;364:1127-34.
Cohen MH, Cortazar P, Justice R, Pazdur R. Approval summary: Imatinibmesylate in the adjuvant treatment of malignant gastrointestinal stromal tumors. Oncologist 2010;15:300-7.
Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, et al
. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052-6.
Abdulkader I, Cameselle-Teijeiro J, Forteza J. Pathological changes related to Imatinib treatment in a patient with a metastatic gastrointestinal stromal tumour. Histopathology 2005;46:470-2.
Högenauer C, Langner C, Lipp RW, Höfler G, Krejs GJ, Hinterleitner TA. Complete remission of a metastatic gastrointestinal stromal tumour with the tyrosine kinase inhibitor imatinib (STI 571): Effect of low dosage in an advanced tumour with exon 11 mutation. Eur J Gastroenterol Hepatol 2003;15:323-7.
Agaram NP, Besmer P, Wong GC, Guo T, Socci ND, Maki RG, et al
. Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res 2007;13:170-81.
Bümming P, Andersson J, Meis-Kindblom JM, Klingenstierna H, Engström K, Stierner U, et al
. Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib: A centre-based study of 17 patients. Br J Cancer 2003;89:460-4.
Pauwels P, Debiec-Rychter M, Stul M, De Wever I, Van Oosterom AT, Sciot R. Changing phenotype of gastrointestinal stromal tumours under imatinibmesylate treatment: A potential diagnostic pitfall. Histopathology 2005;47:41-7.
Bickenbach K, Wilcox R, Veerapong J, Kindler HL, Posner MC, Noffsinger A, et al
.A review of resistance patterns and phenotypic changes in gastrointestinal stromal tumors following imatinibmesylate therapy. J Gastrointest Surg 2007;11:758-66.
Liegl B, Hornick JL, Antonescu CR, Corless CL, Fletcher CD.Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: A novel form of tumor progression. Am J Surg Pathol 2009;33:218-26.
[Figure 1], [Figure 2], [Figure 3]