/pjs Frank Meyer 1

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1 POLSKI PRZEGLĄD CHIRURGICZNY 2013, 85, 5, /pjs Gastric high-risk GIST and retroperitoneal liposarcoma a challenging combination of two mesenchymal tumor lesions with regard to diagnosis and treatment Jőrg Arend 1, Doerthe Kuester 2, Albert Roessner 2, Hans Lippert 1, Frank Meyer 1 Department of Surgery 1, and Institute of Pathology 2, Otto-von-Guericke University in Magdeburg, Germany Both gastrointestinal stromal tumors (GIST) and liposarcoma originate from mesenchymal tissue. Their coincidence requires a specific expertise in the diagnostic and therapeutic management. An unusual exemplary case is described representing a 47-year old female patient with a gastric GIST and a monstrous retroperitoneal liposarcoma with infiltration of the left kidney. The gastric tumor lesion was removed with a tangential resection of the gastric wall; the retroperitoneal tumor lesion was resected including the left kidney. Both tumors were resected with no macroscopic tumor residual. The technically difficult surgical intervention did not show any postoperative complication, and the postoperative course was also uneventful. The complete tumor resection is the treatment of choice in mesenchymal tumors (aim: R0). Depending on histologic tumor classification, resection status and tumor sensitivity, a subsequent radiation and/or chemotherapy is necessary, which allowed to achieve a postoperative tumor-free survival of 6 years including a good quality of life. Key words: GIST, liposarcoma, soft tissue tumor, radiatio-chemotherapy Gastrointestinal stromal tumors (GISTs) occur with a frequency of approximately 1,200 new cases per year in Germany (incidence 16/1,000,000; < 1% of all GI tumors) and a peak between the 55 th and 65 th year of life. Liposarcomas occur with an incidence of approximately 2-3/100,000, resulting in 0.1-1% of all malignant tumor lesions. Both GIST and liposarcoma originate from mesenchymal tissue (1, 2, 3). It is nowadays recognized that GIST s arise from multipotential mesenchymal stem cells (4). Using immunhistochemistry, it has become possible to differentiate the specific mesenchymal tumor lesions. GIST tumors have a mutation in the tyrosine kinase receptor c-kit (KIT, CD117) or PDGFRα (Platelet Derived Growth Factor Receptor Alpha) (5). Its diagnosis is usually based on the expression of the CD117 (90-95%), a membranebound receptor tyrosine kinase, and CD34 (70-80%). In 20-30% sm-actin and in 10% S-100 protein are positive, respectively. With 50-60% the majority of GIST are located in the stomach. Furthermore, GIST can be found in the small intestine (30-40%) (6) and in the colon-rectum (5-10%) as well as in the oesophagus (less than 5%) (7). Extragastrointestinal manifestation occurs rarely. Tumor localization and size, mitosis rate and resection status determine significantly the prognosis of GIST (2, 8-12). For instance, Jie et al. investigated 41 GIST cases and showed that tumor localization in the small intestine, tumor size > 5 cm in diameter, mitosis rate > 5/50 HPF and incomplete resection provide a much worse prognosis than GIST location in the stomach or colon, size < 5 cm, mitosis rate 5/50 HPF and complete resection (13). In addition, there is a high relapse rate after surgical resection and a poor response to radiation (14). GIST have been demonstrated to have an increased frequency of synchronous or metachronous occurrence of second tumor lesions (15, 16). Agaimy et al. (15) examined

2 285 GIST and retroperitoneal liposarcoma 97 cases of surgically resectable GIST, out of whom 18 patients (18.6%) demonstrated this one or two additional tumors: 9 cases with other gastrointestinal tumor lesions or pancreatic tumors, 3 gynecological tumors, each two cases with breast, lung and hematological neoplasia as well as one prostate and one renal carcinoma. Diagnostic differentiation was achieved using conventional pathohistologic investigation and immunhistochemistry. In addition, Ruka et al. found a second tumor lesion in 10% of 180 investigated patients (17). In the case reported here, the challenging combination of the simultaneous diagnosis of 2 mesenchymal tumors and their following therapeutic management is illustrated. After tumor resection and immunhistochemical investigations, the diagnosis of various tumor entities, GIST and liposarcoma, was found and metastatic tumor growth could be excluded. An additive radiochemotherapy after R1 resection of the retroperitoneal liposarcoma resulted in a tumor-free survival of 6 years as revealed by the follow-up investigation. Case report The 47-year old female patient reported weight loss of 8 kg in 6 weeks, but no further symptoms. The initial diagnostic revealed anemia in the profile of routine laboratory parameters and a palpable tumor mass in the left abdomen of 10 cm in diameter. The medical history was significant for arterial hypertension and arrhythmia. The contrast-enhanced multi-slice computed tomography demonstrated a localized subhepatic paragastric tumor mass of 5 x 5 cm in size (fig. 1A) and a further tumor lesion of 27 x 20 x 12 cm closed to spleen, pancreas and intestine but without signs of infiltrating tumor growth (fig. 1B, C, Fig. 1. Preoperative abdominal CT scans A GIST (G), B, C, D liposarcoma (L) with infiltration of the left kidney (N)

3 286 J. Arend et al. Fig. 2. Pathohistologic investigation of the gastric GIST GIST of 6.5 x 5 x 4.5 cm with localization between gastric mucosa (GaM) and muscularis of the gastric wall (GaW) (A,B). Histology revealed a spindle-cell type (C) with a mitotic rate of 6/50HPF (C, inlet). Typical immunohistochemical expression of CD117 (c-kit) (D) and negativity for sm-actin (E) were observed. Medium proliferation index was detected by Ki-67 antibody (F) D). Angiography revealed a displacement of branches of both the celiac trunk and mesenteric artery to the right as well as a mediocaudal displacement of the left kidney. There were numerous pathological, tumor-induced branches of the left renal artery. In addition, the blood supply of the tumor was also provided by lumbal vessels and branches of the left common iliac artery. The preoperative kidney function was characterized by 75% oft the right and 25% of the left kidney, respectively, participating in the clearance. The excretion phase of the left kidney showed a retention of urine. The surgical approach (in total, 150 min) comprised an explorative laparotomy, a tangential resection of the gastric wall and, after opening the left retroperitoneum, the monstrous tumor mass was circularly dissected including the adhesions to spleen and pancreas. Tumor infiltration of the left kidney was found; therefore, nephrectomy was required. Postoperatively, patient was transferred to the surgical intensive care unit for 4 days. There were no intra- and postoperative complications. Pathohistologic investigation revealed a gastric GIST measuring 6.5 x 5 x 4.5 cm (fig. 2A, B) and a retroperitoneal liposarcoma with a weight of 3,650 g and a size of 30 x 30 x 25 cm. Histologically, the gastric GIST was localized in the submucosa infiltrating mucosa and muscularis and demonstrated a spindle-cell pattern of the tumor cells (fig. 2C). Immunohistochemistry showed positive expression of CD117 and CD34 of the tumor cells and negativity for sm-actin as well as S-100 protein (fig. 2D, E, F). A mitotic rate of 6/50 HPF was counted, which resulted in the classification of this gastric GIST as a high risk GIST. Histology of the retroperitoneal tumor resection specimen presented a myofibroblastic dedifferentiated liposarcoma with mostly spindle-like cells with fine fibrillar eosinophilic cytoplasm and small lipoma-like areas (fig. 3A, B, C). There was no immunohistochemical expression of CD117, desmin or S-100 protein, whereas sm-actin protein was detectable (fig. 3D, E, F). Microscopically, there were several resection margins with detectable tumor cells

4 GIST and retroperitoneal liposarcoma 287 Fig. 3. Pathohistologic investigation of the retroperitoneal sarcoma Histology of the liposarcoma presented a dedifferentiated myofibroblastic type (A) with small lipoma-like areas (B,+) and typical lipoblasts (B, inlet). Gross parts of the tumor showed myofibroblastic dedifferentiation of medium malignancy (C) with typical immunohistochemical expression of sm-actin (D), whereas S-100 (E) or desmin (F) protein could not be detected and infiltration of the left kidney could be confirmed. The final tumor classification was pt2b G2 R1. The patient was discharged on the 11 th postoperative day with no further signs or problems. Because of microscopically detectable tumor cells at the resection margin, beginning in the third postoperative week, radiochemotherapy was initiated according to the VAIA protocol with Adriamycin, Ifosfamid, Vincristin (in total, 3 cycles) and radiation of the former tumor bed. It was targeted to the paraaortal region, stomach, left retroperitoneum, and the surrounding region of the left common iliac artery: Dosage in total, 46.6 Gy; single dose, 1.6 Gy. Radiation was followed by a second series of chemotherapy. The postoperative follow-up investigations of up to 6 years did not reveal any hint for tumor relapse. Discussion Both GIST and liposarcoma originate from mesenchymal tissue. Their coincidence requires a specific expertise in the diagnostic and therapeutic management (15, 16). For all mesenchymal tumors, a complete surgical resection is the treatment of choice (gold standard) (1, 2, 3, 18). The R0 resection is an important prognostic factor since soft tissue sarcomas show only a limited response to radiation and chemotherapy (19). Only the introduction of the tyrosine kinase inhibitor Imatinib made it possible to initiate a specific chemotherapy or targeted therapy providing a sufficient effect even against GIST. In studies, the use of Imatinib for a neoadjuvant and adjuvant treatment has been recently established. As recent studies showed, GIST occur synchronously with other tumor entities in up to 20% of cases (15, 16, 17). The misinterpretation as metastases can lead to disadvantageous treatment decisions. For this reason, an exact staging and pathohistologic diagnosis is urgently required (1, 3, 7, 20) as described in the case. Despite macroscopically tumor-free operative situs in the case reported here, the pathohistologic investigation revealed tumor cells at several resection margins according to an R1 resection status. Therefore, an additive ra-

5 288 J. Arend et al. diochemotherapy was required postoperatively and provided a tumor-free survival of 6 years. Further adequate follow-up investigation including CT scans also of the former gastric GIST manifestation (plus endoscopy of the upper GI tract and endoscopic ultrasonography for the former gastric tumor site) are recommendable (21, 22). references 1. Comandone A, Boglione A: Biology, diagnosis and therapeutic options in gastrointestinal stromal tumours. Minerva Chir 2005; 60(5): Fletcher CD, Bermann JJ, Corless C et al.: Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002; 33: Hohenberger P, Wardelmann E: Surgical conciderations for gastrointestinal stroma tumor. Chirurg 2006; 77: Stamatakos M, Douzinas E, Stefanaki C et al.: Gastrointestinal stromal tumor. WJSO 2009; 7: Schildhaus HU, Merkelbach-Bruse S, Büttner R, Wardelmann E: Pathology and molecular biology of gastrointestinal stromal tumors (GIST). Radiologe 2009; 49(12): Bai YK, Shao YF, Shi SS: Analysis of prognostic factors in gastrointestinal stromal tumours of the small intestine. Zhonghua WCWKZZ 2005; 8: Urbancyk K, Limon L, Korobowicz E: Gastrointestinal stromal tumors. A multicenter experience. Pol J Pathol 2005; 56(2): Blay JY, Bonvalot S, Casali P et al.: GIST consensus meeting panellists, Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of March 2004, under the auspices of ESMO. Ann Oncol 2005; 16(4): DeMatteo RP, Gold JS, Saran L et al.: Tumor mitotic rate, size and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer 2008; 112: Miettinen M, Lasota J: Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006; 23: Nakamura N, Yamamoto H, Yao T: Prognostic significance of expressions of cell-cycle proteins in gastrointestinal stromal tumor and relevance of the risk grade. Hum Pathol 2005; 36(7): Wilmans C, Eggstein S, Ruf G: Score Prediction of Metastatic Risk in Gastrointestinal Stromal Tumours (GIST). Zentralbl Chir 2007; 132: Jie ZG, Xie XP, Qin KW et al.: Clinical analysis of prognostic factors for patients with gastrointestinal stromal tumors. Zhonghua WCWKZZ 2005; 8(3): Miettinen M, Sobin LH, Lasota J: Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow up. Am J Surg Pathol 2005; 29: Agaimy A, Wuensch PH: Gastrointestinal stromal tumours in patients with other-type cancer, a mere coincidence or an etiological association? A study of 97 GIST cases. Z Gastroenterol 2005; 43(9): Clary BM, Dematteo RP, Lewis JJ et al.: Gastrointestinal stromal tumors and leiomyosarcoma of the abdomen and retroperitoneum: a clinical comparison. Ann Surg Oncol 2001; 8(4): Ruka W, Rutkowski P, Nowecki Z, Nasierowska- Guttmejer A: Other malignant neoplasms in patients with gastrointestinal stromal tumors. Med Sci Monit 2004; 10(8): LE Benseler V, Obed A, Schubert T et al.: Case Report Surgical Therapy of a Retroperitoneal Liposarcoma Weighing 45 kg. Zentralbl Chir 2009; 134: Gockel I, Oberholzer K, Gönner U et al.: Retroperitoneal Sarcomas: Diagnostic and Therapy. Zentralbl Chir 2006; 131: Wente MN, Büchler MW, Weitz J: Gastrointestinale Stromatumoren (GIST). Chirurg 2008; 79: Nishida T, Hirota S: Biological and clinical review of stromal tumors in the gastrointestinal tract. Histol Histopathol 2000; 15: Reichardt P, Reichardt A: Gastrointestinaler Stromatumor (GIST): Aktueller Stand der multimodalen Therapie. Zentrabl Chir 2011; 136(04): Received: r. Adress correspondence: Leipziger Strasse 44, D Magdeburg, Niemcy joerg.arend@med.ovgu.de