J Med Ultrasonics DOI 10.1007/s10396-014-0566-4
CASE REPORT
Inflammatory myofibroblastic tumor of the gallbladder: imaging aspects Radu Badea • Antonia Alexandra Veres • Vasile Andreica • Cosmin Caraiani • Nadim Al-Hajjar • Roxana Sechel • Liliana Chiorean
Received: 2 May 2014 / Accepted: 1 July 2014 Ó The Japan Society of Ultrasonics in Medicine 2014
Abstract Inflammatory myofibroblastic tumors (IMT) are rare benign lesions that may often be mistaken for malignancies due to their imaging resemblance. There are a limited number of case reports in the literature on the location at the level of the gallbladder. We present a case of IMT of the gallbladder that emphasizes the importance of conventional ultrasound as the primary method of detection, as well as the role of contrast-enhanced ultrasound and strain elastography in describing the lesion, thus contributing to the differential diagnosis. Keywords Inflammatory myofibroblastic tumor Contrast-enhanced ultrasound Elastography Gangrenous cholecystitis Gallbladder tumor R. Badea L. Chiorean (&) Ultrasonography Department, ‘‘Octavian Fodor’’ Institute of Gastroenterology and Hepatology, ‘‘Iuliu Hatieganu’’ University of Medicine and Pharmacy, 21 Croitorilor str., 400 162 Cluj-Napoca, Romania e-mail: [email protected] A. A. Veres V. Andreica Gastroenterology Department, ‘‘Octavian Fodor’’ Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania C. Caraiani Radiology and Computed Tomography Department, ‘‘Octavian Fodor’’, Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania N. Al-Hajjar General Surgery Department, ‘‘Octavian Fodor’’ Institute of Gastroenterology and Hepatology, ‘‘Iuliu Hatieganu’’ University of Medicine and Pharmacy, Cluj-Napoca, Romania R. Sechel Morphopathology Department, ‘‘Octavian Fodor’’ Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
Abbreviations IMT Inflammatory myofibroblastic tumor US Ultrasound CEUS Contrast-enhanced ultrasound CT Computed tomography
Introduction Inflammatory myofibroblastic tumors (IMT) (also known as inflammatory pseudotumors—IPT) are very rare benign lesions. Brunn first described them in 1939 [1]. IMT may occur in almost any organ, such as the lungs, liver, orbit, mediastinum, bronchus, small intestine, mesentery, kidney, spleen, stomach, meninges, spine, thyroid gland, and urinary bladder [2]. The location at the level of the gallbladder is extremely rare [3]. Even if the pathogenesis has not yet been established, possible risk factors are reported in the literature, such as infections (including hepatitis B and C) and vascular or autoimmune diseases [4–6]. Their origin has been widely debated concerning the neoplastic or post-inflammatory nature, consequently being regarded as ‘‘intermediate malignancy’’ [7]. Due to the fact that it has no specific clinical or radiological features, when located in the liver, this lesion can often be mistaken as a malignant tumor, the differential diagnosis being difficult in most of the cases. It includes a variety of neoplastic and reactive lesions [7] such as: hepatocellular carcinoma (especially in patients with chronic viral B or C infection), cholangiocarcinoma, metastatic tumor or inflammatory lesions, for instance liver abscesses [5, 8–11]. The diagnosis management involves multimodality imaging, and is finally based on histopathological examination [2, 5, 7, 12].
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Fig. 1 Ultrasound examination. a Gray-scale: a structural change encompassing the gallbladder and affecting also the 4th and 5th segments of the liver. The gallbladder wall is uniformly thickened (up
to 6 mm), with a discontinuity on the superior wall; b strain elastography: high rigidity of the described structure
We present the case of an IMT of the gallbladder that raised problems of differential diagnosis, the final diagnosis being established by histopathology.
examination evidenced the presence of blood vessels inside the previously described zone. Manual compression strain elastography was performed with a GE Logiq E9 ultrasound system, using the 1.0–5.0 MHz transducer. The elastographic image was displayed in real time as color images (red, green, and blue) in a region-of-interest box (ROI) that was superimposed over the conventional grayscale B-mode US image. The ROI was sufficiently large to contain the area to be evaluated (the previously described structural change within the liver, encompassing the gallbladder) and enough surrounding ‘‘normal’’ liver parenchyma for comparison. The qualitative color map showed the analyzed structure color-coded in blue, representing a harder consistency than the surrounding liver parenchyma (Fig. 1b). Contrast-enhanced ultrasound (CEUS) centered at the level of the described structural change was performed using a high-frequency transducer, the i.v. contrast agent SonoVue (Bracco), and tissue harmonic imaging in the presence of a low mechanical index (MI). After injection of the contrast agent in the peripheral vein (1.6 ml, followed by 10 ml of saline solution), enhancement of the followed structural change started in approximately 14 s, and proceeded up to 28 s, when the peak intensity was reached. The entire zone presenting the described structural changes was uniformly enhanced (Fig. 2a—imaging at 28 s shown). In the venous phase, the contrast agent concentration decreased faster at the level of the followed structural change compared to the surrounding liver parenchyma (Fig. 2b—imaging at 51 s shown). During the late venous phase, the liver parenchyma was evaluated, without evidence of other hypo-enhanced lesions. A tumoral mass of the gallbladder, most probably malignant due to the hepatic invasion, was highly suspected, without the total exclusion of an inflammatory process, especially considering the stone depicted at the level of the main bile duct.
Case report A 65-year-old woman with known ischemic heart disease, aortic stenosis, obesity, and type II diabetes was referred to our Institute for evaluation of a gallbladder mass, initially detected on the occasion of an abdominal ultrasound performed at another medical institution. There she had been diagnosed with endocarditis, for which she received antibiotic treatment (penicillin G, 12 million U/d i.v. in 6 equally divided doses for a 4-week period). Her complaints occurred 2 months previously, with mild abdominal pain (rather a discomfort), asthenia, and moderate body weight loss (5 kg during the last month). On physical examination, she had tenderness in the right flank. Laboratory tests revealed mild anemia (hemoglobin level of 10.8 g/dl), unspecific inflammatory syndrome [the erythrocyte sedimentation rate (ESR) was elevated to 80 mm/h; normal range 0–11 mm/h], and important cholestasis (alkaline phosphatase 1025 IU/l; normal range 100–256 IU/l). Tests for serum alpha-fetoprotein (aFP), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 were between normal ranges. Serology for virus infection B or C was negative. Abdominal ultrasound (US) revealed a structural change encompassing the gallbladder and affecting also the 4th and 5th segments of the liver. The gallbladder wall was uniformly thickened (up to 6 mm), with a discontinuity on the superior wall (Fig. 1a). No stones were detected inside the gallbladder, but a stone inside the retro pancreatic segment of the main biliary duct was detected, causing upstream expansion of the biliary ducts. Doppler
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J Med Ultrasonics Fig. 2 Contrast-enhanced ultrasound. a The structural change encompassing the gallbladder and the 4th and 5th liver segments shows uniform arterial enhancement, with the peak intensity reached at 28 s after contrast agent injection; b in the venous phase, the contrast agent concentration decreased faster at the level of the followed structural change compared to the surrounding liver parenchyma (imaging at 51 s shown)
Computed tomography (CT) revealed a zone of hypodense hepatic parenchyma close to the gallbladder (Fig. 3a), with a maximum width of 25 mm, and a continuity solution at the level of the gallbladder wall (dimensions of B2 mm) (Fig. 3b). The wall of the gallbladder was circumferentially thickened (up to 13 mm) (Fig. 3a, b), and thin septa inside the gallbladder could be seen. Intrahepatic bile ducts were dilated at the level of both hepatic lobes (Fig. 3b). Also, the main bile duct was dilated, with a diameter of 15 mm, and could be followed till close to the ampulla of Vater, where a stone could be seen on the native examination (Fig. 3a). Multiple lymph nodes at the level of the hepatic hilum were present, having an inflammatory aspect. A diagnosis of gangrenous cholecystitis was taken into consideration, but a gallbladder tumor could not be ruled out. At this point, since the existence of a malignant proliferative process could not be totally excluded, the patient underwent surgery. Laparoscopy revealed intense adhesions between the gallbladder, omentum, and liver, and required conversion to classical surgery. After the gallbladder was freed from its adhesions, the hepatic parenchyma infiltration could be seen, and also the enlarged cystic and main bile ducts (Fig. 4a). Resection of the 4th
and 5th liver segments in block with cholecystectomy (Fig. 4b) and lymphadenectomy of the hepatic hilum lymph nodes were performed. The cut section of the surgical specimen showed an eccentrically tumoral mass of 6.5 9 5.2 9 4 cm with a light grayish color, bulging from the fundus of the gallbladder (Fig. 5a). The tumor infiltrated the surrounding liver parenchyma to a depth of 4 cm. The walls of the cholecyst were thickened and indurated with a tan-yellowish discoloration. Microscopic examination of the gallbladder revealed a heavily fibrosed wall with a mucosa presenting extensive areas of ulceration and a rich subjacent inflammatory infiltrate, composed of lymphocytes, plasma cells, and numerous foamy macrophages. The eccentrically located tumor consisted of a spindleshaped cell proliferation mainly represented by myofibroblasts and fibroblasts, alongside with inflammatory cells (Fig. 5b). No cholesterol clefts, hemosiderin deposits, or giant cells were seen. The lack of significant nuclear atypia, the absence of abnormal mitotic figures, and the reactive changes in the lymph nodes were indicators of a benign lesion. Immunohistochemical (IHC) staining detected a strong and
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Fig. 3 Computed tomography. a Native examination: axial section at the level of the gallbladder showing a zone of hypo-dense hepatic parenchyma close to the gallbladder and a stone at the level of the main biliary duct, close to the Vater papilla; b contrast-enhanced examination: portal phase, coronal reconstruction showing the hypo-
enhanced structural change, affecting the liver at the level of the 4th and the 5th segments with maximum width of 25 mm; the gallbladder walls are circumferentially thickened (up till 13 mm), and a continuity solution at the level of gallbladder wall, with dimensions of B2 mm can be visualized; the left intrahepatic duct is dilated
Fig. 4 Intraoperatory findings: a enlarged cystic and main biliary ducts; b the hepatic parenchyma infiltration can be seen. Resection of the 4th and 5th liver segments en bloc with cholecystectomy was performed
uniform reactivity to the smooth muscle actin (SMA) (Fig. 5c) of the spindle-cell component of the tumor, while staining for anaplastic lymphoma kinase (ALK) was equivocal. A diagnosis of IMT was proposed. In this case, the alternate hypothesis of xanthogranulomatous cholecystitis was ruled out based on the macroscopic presentation (unique eccentric mass) and on the histology appearance (dense myofibroblastic proliferation with strong reactivity to SMA and significantly lighter inflammatory infiltrate in the tumor compared to the gallbladder wall itself).
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Discussion Conventional ultrasound is widely used in the diagnosis of gallbladder diseases. More recently developed techniques such as CEUS and elastography have improved the chances of a more accurate diagnosis, allowing at the same time an earlier detection and a better characterization of gallbladder tumors [13, 14]. IMT has been known under different names: inflammatory granuloma, inflammatory histiocytoma, plasmocytoma, plasma cell granuloma, pseudolymphoma and fibroxanthoma [15, 16]. Umiker et al. named it
J Med Ultrasonics
Fig. 5 Histopathological findings: a the tumoral mass (6.5 9 5.2 9 4 cm) of a light grayish color, infiltrating the surrounding liver parenchyma; b H&E 9200: fibroblast and myofibroblast cells alongside mild inflammatory infiltrate; c immunohistochemical staining with SMA
‘inflammatory pseudotumor’ in 1954 [3, 17], but when the cell origin was established as a myofibroblast by immunohistochemical markers and electron microscopic studies, this designation has been replaced with the current ‘inflammatory myofibroblastic tumor’ [18]. Histologically, IMT represents a combination of myofibroblasts, fibroblasts, lymphocytes, and plasma cells in varying proportions [9]. In the recent literature, IMTs are classified by the World Health Organization as tumors of intermediate biological potential due to a tendency for local recurrence and its small risk for distant metastasis [19]. Primary IMTs of the gallbladder are rather infrequent; therefore, present knowledge is based on case reports [20]. The first case of an IPT affecting both the gallbladder and the bile duct was cited in the literature by Ikeda et al. [21]. A 43-year-old man with obstructive jaundice had thickened walls of the gallbladder and common bile duct due to diffuse granulomatous lesions composed mainly of plasma cells, lymphocytes, and fibroblasts identical with IPT. The same histological findings also were observed in the lung and lymph nodes. All clinical and laboratory abnormalities subsided after high-dose prednisolone therapy [21]. In 1995, Coffin published a clinicopathological and immunohistochemical study of 84 cases of IMT occurring in the soft tissues and viscera of 48 female patients and 36 male patients between the ages of 3 months and 46 years. Sites of involvement included the abdomen, retroperitoneum, or pelvis (61 cases); head and neck, including the upper respiratory tract (12 cases); trunk (8 cases); and extremities (3 cases) [22]. The same year, a case of chronic cholecystitis with features of xanthogranulomatous inflammation due to the presence of a prominent inflammatory infiltrate composed of plasma cells, lymphocytes, macrophages, foamy histiocytes, and huge fibroblastic and myofibroblastic proliferation was described by Corsi and
Bosman [23]. Ten years later, Behranwala et al. [24] reported the case of a 51-year-old female who underwent excision of a gallbladder tumor in which histopathology showed it to be IMT of the gallbladder. Muduly et al. [3] also reported a case of IMT of the gallbladder in a patient with suspected cancer of the gallbladder who underwent radical cholecystectomy for a gallbladder mass lesion. In ¨ zsan et al. [20] published in the Balkan Medical 2013, O Journal a case report of a 66-year-old male patient with a mass almost completely filling the gallbladder detected by imaging studies, which subsequent to the histopathological examination of the surgical specimen revealed an IMT. Vasiliadis presented the case of a 71-year-old female patient who underwent an extra-hepatic bile duct resection en-bloc with the gallbladder and regional lymph nodes for an obstructing intraluminal growing tumor of the mid common bile duct. Histologically, the tumor proved to be an IMT arising from the bile duct epithelium, composed of inflammatory cells and reactive mesenchymal tissues [25]. Cases of liver and gallbladder IMT reported in the literature involve a reactive inflammatory process that develops in response to a previous cause such as: biliary disease, tropical parasites, gastrointestinal infection, ulcerating gastric carcinoma [10], chronic cholangitis and primary sclerosing cholangitis [8]. There are no specific symptoms for IMT [26]. Abdominal pain (mostly in the right upper quadrant), weight loss, malaise, general weakness, jaundice, and fever may be present [2, 7, 8, 11, 12, 27]. Laboratory findings also lack specificity. However, elevation of C-reactive protein (CRP) and ESR and/or increase in white blood cell count have been observed [7]. Diabetic patients require special attention since their susceptibility to infections is well known, with very poor clinical outcomes [28]. Our patient had type II diabetes and had been treated with penicillin for endocarditis for a month. This might explain the lack of
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symptoms such as fever and intense abdominal pain and the absence of leukocytosis in this case. Imaging features of IMT are not specific and they mimic other pathologies, especially malignant tumors, and often do not provide a definitive diagnosis [3–5, 8, 27, 29]. In our case, abdominal US and CEUS raised the suspicion of a gallbladder malignant tumor due to the thickness of the wall and signs of invasion into the 4th and 5th hepatic segments, and also due to hyper-enhancement and washout at CEUS. The term ‘‘invasion’’ should be considered with caution in this case because it relies on the delineation of the tumor in relation to the surrounding liver parenchyma. The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) has recently published Guidelines and Recommendations on the clinical use of ultrasound elastography [30, 31]. It is a newly developed technique that has already proved its added value as a complementary, noninvasive imaging method, helpful to better characterize and differentiate between benign and malignant masses, by assessing their stiffness [32]. Malignant tissue exhibits increased stiffness compared to benign or normal tissue, and thus deforms to a lesser degree in response to compression [33, 34]. The suspicion of malignancy was supported by elastography in our case since it revealed a stiffer area inside the liver as compared to the surrounding normal liver parenchyma. Differential diagnosis of IMT with other malignant entities is important because surgical resection is not always mandatory [9], although it is considered to be the therapeutic gold standard [7, 35]. In most of the cases, the final diagnosis is based on histopathological and immunohistochemical studies [7, 26, 36]. Also, the histological examination excludes another possible diagnosis (a benign one): xanthogranulomatous cholecystitis. This entity represents a chronic inflammatory disease of the gallbladder consisting of multiple yellow–brown intramural nodules that are composed of extensive fibrosis and foam cells. Like IMT, it is a rare condition with unclear origin. The differential diagnosis between the two conditions depends exclusively on the pathological examination. In our case, the patient was also diagnosed with choledochal lithiasis. Although cholestasis and chronic inflammation are considered responsible factors for eventually developing IMT, in our patient the tumor was located at the fundus of the gallbladder and no vesicular stones were found. Therefore, we could not establish a connection between the gallbladder IMT and the choledochal stone. Some cases of spontaneous remission have been reported in the literature [2, 29]. Extremely rare malignant transformations of IMT have been encountered [3, 37]. Conservative treatment with antibiotics [2, 8, 29] and steroidal or non-steroidal anti-inflammatory drugs [2, 3, 35]
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has been proposed [2, 5, 9, 12, 29, 35, 38, 39] in cases of IMT at other locations (liver, lung, pancreas, spleen). Chemotherapy and radiation therapy have also been tried but proved to be useful only in cases of incomplete resection [26]. However, there are no case reports of gallbladder IMT being treated by conservative methods [3]. Complete surgical excision of the tumor and long-term multidisciplinary follow-up is the safer approach [2, 3, 7, 26]. Our patient underwent complete surgical resection of the tumor, and 3-month follow-up did not indicate recurrence or metastatic disease.
Conclusion IMT of the gallbladder is an extremely rare entity, and should be considered in the differential diagnosis of a gallbladder mass. Our case was a rare example of a complex pathology: main bile duct lithiasis, diabetes, endocarditis, and IMT. Despite the fact that imaging features of IMT are heterogeneous, conventional US and CEUS are useful tools in the diagnostic process (primary detection, characterization) and in the long-term follow-up of the patient. Acknowledgments The authors thank Mrs. Szasz Zsoka for the implication in follow-up of the patient. Conflict of interest There are no financial or other relations that could lead to a conflict of interest. Consent Written informed consent was obtained from the patient for the publication of this manuscript and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal. Human rights statements and informed consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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J Med Ultrasonics 6. Schneider G, Fries P, Samaras P, et al. Inflammatory pseudotumor of the liver in a patient with congenital granulocytopenia and HCV infection. Eur J Radiol. 2003;48:293–8. 7. Kosma L, Khaldi L, Galani P, et al. A rare case of an inflammatory myofibroblastic tumor in a middle-aged female. Case Rep Oncol Med. 2012;2012:148053. 8. Masaya S, Yasushi S, Yoshihiko Y, et al. Sonazoid-enhanced ultrasonography and Ga-EOB-DTPA-enhanced MRI of hepatic inflammatory pseudotumor: a case report. Intern Med. 2012;51:723–6. 9. Seong WH, Woo YL, Yeo GC, et al. Inflammatory myofibroblastic tumor mimicking hepatocellular carcinoma with dense lipiodol uptake. J Korean Surg Soc. 2013;85:89–92. 10. Pack GT, Baker HW. Total right hepatic lobectomy: report of a case. Ann Surg. 1953;138:253–8. 11. Kruth J, Michaely H, Trunk M, et al. A rare case of fever of unknown origin: inflammatory myofibroblastic tumor of the liver. Case report and review of the literature. Acta Gastroenterol Belg. 2012;75:448–53. 12. Rosa B, Moutinho-Ribeiro P, Pereira JM, et al. Ghost tumor: an inflammatory pseudotumor of the liver. Gastroenterol Hepatol (N Y). 2012;8:630–3. 13. Tang S, Wang Y, Wang Y. Contrast-enhanced ultrasonography to diagnose gallbladder perforation. Am J Emerg Med. 2013;31:1240–3. 14. Adamietz B, Wenkel E, Uder M, et al. Contrast enhanced sonography of the gallbladder: a tool in the diagnosis of cholecystitis? Eur J Radiol. 2007;61:262–6. 15. Hagenstad CT, Kilpatrick SE, Pettenati MJ, et al. Inflammatory myofibroblastic tumor with bone marrow involvement. A case report and review of the literature. Arch Pathol Lab Med. 2003;127:865–7. 16. Shek TW, Ng IO, Chan KW. Inflammatory pseudotumor of the liver. Report of four cases and review of literature. Am J Surg Pathol. 1993;17:231–8. 17. Umiker WO, Iverson L. Postinflammatory tumors of the lung; report of four cases simulating xanthoma, fibroma, or plasma cell tumor. J Thorac Surg. 1954;28:55–63. 18. Coffin CM, Humphrey PA, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor: a clinical and pathological survey. Semin Diagn Pathol. 1998;15:85–101. 19. Gleason BC, Hornick JL. Inflammatory myofibroblastic tumours: where are we now? J Clin Pathol. 2008;61:428–37. ¨ zsan I, O ¨ zsoy M, S¸ ahin E, et al. Inflammatory myofibroblastic 20. O tumor of the gallbladder. Balkan Med J. 2013;30:323–6. 21. Ikeda H, Oka T, Imafuku I, et al. A case of inflammatory pseudotumor of the gallbladder and bile duct. Am J Gastroenterol. 1990;85:203–6. 22. Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor): a clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol. 1995;19:859–72.
23. Corsi A, Bosman C. Chronic cholecystitis with features of diffuse inflammatory pseudotumour: a clinico-pathological case study and review of the literature. Ital J Gastroenterol. 1995;27:252–5. 24. Behranwala KA, Straker P, Wan A, Fisher C, Thompson JN. Inflammatory myofibroblastic tumour of the gallbladder. World J Surg Oncol. 2005;3:24. 25. Vasiliadis K, Fortounis K, Papavasiliou C, et al. Mid common bile duct inflammatory pseudotumor mimicking cholangiocarcinoma. A case report and literature review. Int J Surg Case Rep. 2014;5:12–5. 26. Meng X, Wang R. Inflammatory myofibroblastic tumor occurs in the mediastinum. J Can Res Ther. 2013;9:721–3. 27. Megumi M, Yasuhisa O, Goryu M, et al. Inflammatory pseudotumor of the liver: case report and review of literature. Tokai J Exp Clin Med. 2008;33:70–4. 28. Derici H, Kara C, Bozdag AD, et al. Diagnosis and treatment of gallbladder perforation. World J Gastroenterol. 2006;12:7832–6. 29. Tsou YK, Lin CJ, Liu NJ, et al. Inflammatory pseudotumor of the liver: report of eight cases, including three unusual cases, and a literature review. J Gastroenterol Hepatol. 2007;22:2143–7. 30. Bamber J, Cosgrove D, Dietrich CF, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: basic principles and technology. Ultraschall Med. 2013;34:169–84. 31. Cosgrove D, Piscaglia F, Bamber J, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 2: clinical applications. Ultraschall Med. 2013;34:238–53. 32. Bhargava S, Bhargava SK, Sharma S, Prakash M. Elastography: a new imaging technique and its application. JIMSA. 2013;26:25–30. 33. Dietrich CF. Real-time tissue elastography. Multiple clinical applications. Multiple clinical solutions. Endo Heute. 2011;8:48–67. 34. Dietrich CF. Elastography, the new dimension in ultrasonography. Praxis (Bern 1994). 2011;100:1533–42. 35. Colangelo M, Di Renzo D, Persico A, et al. Case report: inflammatory myofibroblastic tumor of pancreatic origin in a patient with down syndrome: the role of diagnostic ultrasound. J Ultrasound. 2011;14:7–9. 36. Chen CK, Jan CI, Tsai JS, et al. Inflammatory myofibroblastic tumor of the lung—a case report. J Cardiothorac Surg. 2010;5:55. 37. Pecorella I, Ciardi A, Memeo L, et al. Inflammatory pseudotumour of the liver—evidence for malignant transformation. Pathol Res Pract. 1999;195:115–20. 38. Mathiak G, Meyer-Pannwitt U, Mathiak M, et al. Inflammatory pseudotumor of the liver—rare differential diagnosis of undetermined hepatic space-occupying lesion. Case report and review of the literature. Langenbecks Arch Chir. 1996;381:309–17. 39. Yamaguchi J, Sakamoto Y, Sano T, et al. Spontaneous regression of inflammatory pseudotumor of the liver: report of three cases. Surg Today. 2007;37:525–9.
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CASE REPORT
Inflammatory myofibroblastic tumor of the gallbladder: imaging aspects Radu Badea • Antonia Alexandra Veres • Vasile Andreica • Cosmin Caraiani • Nadim Al-Hajjar • Roxana Sechel • Liliana Chiorean
Received: 2 May 2014 / Accepted: 1 July 2014 Ó The Japan Society of Ultrasonics in Medicine 2014
Abstract Inflammatory myofibroblastic tumors (IMT) are rare benign lesions that may often be mistaken for malignancies due to their imaging resemblance. There are a limited number of case reports in the literature on the location at the level of the gallbladder. We present a case of IMT of the gallbladder that emphasizes the importance of conventional ultrasound as the primary method of detection, as well as the role of contrast-enhanced ultrasound and strain elastography in describing the lesion, thus contributing to the differential diagnosis. Keywords Inflammatory myofibroblastic tumor Contrast-enhanced ultrasound Elastography Gangrenous cholecystitis Gallbladder tumor R. Badea L. Chiorean (&) Ultrasonography Department, ‘‘Octavian Fodor’’ Institute of Gastroenterology and Hepatology, ‘‘Iuliu Hatieganu’’ University of Medicine and Pharmacy, 21 Croitorilor str., 400 162 Cluj-Napoca, Romania e-mail: [email protected] A. A. Veres V. Andreica Gastroenterology Department, ‘‘Octavian Fodor’’ Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania C. Caraiani Radiology and Computed Tomography Department, ‘‘Octavian Fodor’’, Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania N. Al-Hajjar General Surgery Department, ‘‘Octavian Fodor’’ Institute of Gastroenterology and Hepatology, ‘‘Iuliu Hatieganu’’ University of Medicine and Pharmacy, Cluj-Napoca, Romania R. Sechel Morphopathology Department, ‘‘Octavian Fodor’’ Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
Abbreviations IMT Inflammatory myofibroblastic tumor US Ultrasound CEUS Contrast-enhanced ultrasound CT Computed tomography
Introduction Inflammatory myofibroblastic tumors (IMT) (also known as inflammatory pseudotumors—IPT) are very rare benign lesions. Brunn first described them in 1939 [1]. IMT may occur in almost any organ, such as the lungs, liver, orbit, mediastinum, bronchus, small intestine, mesentery, kidney, spleen, stomach, meninges, spine, thyroid gland, and urinary bladder [2]. The location at the level of the gallbladder is extremely rare [3]. Even if the pathogenesis has not yet been established, possible risk factors are reported in the literature, such as infections (including hepatitis B and C) and vascular or autoimmune diseases [4–6]. Their origin has been widely debated concerning the neoplastic or post-inflammatory nature, consequently being regarded as ‘‘intermediate malignancy’’ [7]. Due to the fact that it has no specific clinical or radiological features, when located in the liver, this lesion can often be mistaken as a malignant tumor, the differential diagnosis being difficult in most of the cases. It includes a variety of neoplastic and reactive lesions [7] such as: hepatocellular carcinoma (especially in patients with chronic viral B or C infection), cholangiocarcinoma, metastatic tumor or inflammatory lesions, for instance liver abscesses [5, 8–11]. The diagnosis management involves multimodality imaging, and is finally based on histopathological examination [2, 5, 7, 12].
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Fig. 1 Ultrasound examination. a Gray-scale: a structural change encompassing the gallbladder and affecting also the 4th and 5th segments of the liver. The gallbladder wall is uniformly thickened (up
to 6 mm), with a discontinuity on the superior wall; b strain elastography: high rigidity of the described structure
We present the case of an IMT of the gallbladder that raised problems of differential diagnosis, the final diagnosis being established by histopathology.
examination evidenced the presence of blood vessels inside the previously described zone. Manual compression strain elastography was performed with a GE Logiq E9 ultrasound system, using the 1.0–5.0 MHz transducer. The elastographic image was displayed in real time as color images (red, green, and blue) in a region-of-interest box (ROI) that was superimposed over the conventional grayscale B-mode US image. The ROI was sufficiently large to contain the area to be evaluated (the previously described structural change within the liver, encompassing the gallbladder) and enough surrounding ‘‘normal’’ liver parenchyma for comparison. The qualitative color map showed the analyzed structure color-coded in blue, representing a harder consistency than the surrounding liver parenchyma (Fig. 1b). Contrast-enhanced ultrasound (CEUS) centered at the level of the described structural change was performed using a high-frequency transducer, the i.v. contrast agent SonoVue (Bracco), and tissue harmonic imaging in the presence of a low mechanical index (MI). After injection of the contrast agent in the peripheral vein (1.6 ml, followed by 10 ml of saline solution), enhancement of the followed structural change started in approximately 14 s, and proceeded up to 28 s, when the peak intensity was reached. The entire zone presenting the described structural changes was uniformly enhanced (Fig. 2a—imaging at 28 s shown). In the venous phase, the contrast agent concentration decreased faster at the level of the followed structural change compared to the surrounding liver parenchyma (Fig. 2b—imaging at 51 s shown). During the late venous phase, the liver parenchyma was evaluated, without evidence of other hypo-enhanced lesions. A tumoral mass of the gallbladder, most probably malignant due to the hepatic invasion, was highly suspected, without the total exclusion of an inflammatory process, especially considering the stone depicted at the level of the main bile duct.
Case report A 65-year-old woman with known ischemic heart disease, aortic stenosis, obesity, and type II diabetes was referred to our Institute for evaluation of a gallbladder mass, initially detected on the occasion of an abdominal ultrasound performed at another medical institution. There she had been diagnosed with endocarditis, for which she received antibiotic treatment (penicillin G, 12 million U/d i.v. in 6 equally divided doses for a 4-week period). Her complaints occurred 2 months previously, with mild abdominal pain (rather a discomfort), asthenia, and moderate body weight loss (5 kg during the last month). On physical examination, she had tenderness in the right flank. Laboratory tests revealed mild anemia (hemoglobin level of 10.8 g/dl), unspecific inflammatory syndrome [the erythrocyte sedimentation rate (ESR) was elevated to 80 mm/h; normal range 0–11 mm/h], and important cholestasis (alkaline phosphatase 1025 IU/l; normal range 100–256 IU/l). Tests for serum alpha-fetoprotein (aFP), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 were between normal ranges. Serology for virus infection B or C was negative. Abdominal ultrasound (US) revealed a structural change encompassing the gallbladder and affecting also the 4th and 5th segments of the liver. The gallbladder wall was uniformly thickened (up to 6 mm), with a discontinuity on the superior wall (Fig. 1a). No stones were detected inside the gallbladder, but a stone inside the retro pancreatic segment of the main biliary duct was detected, causing upstream expansion of the biliary ducts. Doppler
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J Med Ultrasonics Fig. 2 Contrast-enhanced ultrasound. a The structural change encompassing the gallbladder and the 4th and 5th liver segments shows uniform arterial enhancement, with the peak intensity reached at 28 s after contrast agent injection; b in the venous phase, the contrast agent concentration decreased faster at the level of the followed structural change compared to the surrounding liver parenchyma (imaging at 51 s shown)
Computed tomography (CT) revealed a zone of hypodense hepatic parenchyma close to the gallbladder (Fig. 3a), with a maximum width of 25 mm, and a continuity solution at the level of the gallbladder wall (dimensions of B2 mm) (Fig. 3b). The wall of the gallbladder was circumferentially thickened (up to 13 mm) (Fig. 3a, b), and thin septa inside the gallbladder could be seen. Intrahepatic bile ducts were dilated at the level of both hepatic lobes (Fig. 3b). Also, the main bile duct was dilated, with a diameter of 15 mm, and could be followed till close to the ampulla of Vater, where a stone could be seen on the native examination (Fig. 3a). Multiple lymph nodes at the level of the hepatic hilum were present, having an inflammatory aspect. A diagnosis of gangrenous cholecystitis was taken into consideration, but a gallbladder tumor could not be ruled out. At this point, since the existence of a malignant proliferative process could not be totally excluded, the patient underwent surgery. Laparoscopy revealed intense adhesions between the gallbladder, omentum, and liver, and required conversion to classical surgery. After the gallbladder was freed from its adhesions, the hepatic parenchyma infiltration could be seen, and also the enlarged cystic and main bile ducts (Fig. 4a). Resection of the 4th
and 5th liver segments in block with cholecystectomy (Fig. 4b) and lymphadenectomy of the hepatic hilum lymph nodes were performed. The cut section of the surgical specimen showed an eccentrically tumoral mass of 6.5 9 5.2 9 4 cm with a light grayish color, bulging from the fundus of the gallbladder (Fig. 5a). The tumor infiltrated the surrounding liver parenchyma to a depth of 4 cm. The walls of the cholecyst were thickened and indurated with a tan-yellowish discoloration. Microscopic examination of the gallbladder revealed a heavily fibrosed wall with a mucosa presenting extensive areas of ulceration and a rich subjacent inflammatory infiltrate, composed of lymphocytes, plasma cells, and numerous foamy macrophages. The eccentrically located tumor consisted of a spindleshaped cell proliferation mainly represented by myofibroblasts and fibroblasts, alongside with inflammatory cells (Fig. 5b). No cholesterol clefts, hemosiderin deposits, or giant cells were seen. The lack of significant nuclear atypia, the absence of abnormal mitotic figures, and the reactive changes in the lymph nodes were indicators of a benign lesion. Immunohistochemical (IHC) staining detected a strong and
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Fig. 3 Computed tomography. a Native examination: axial section at the level of the gallbladder showing a zone of hypo-dense hepatic parenchyma close to the gallbladder and a stone at the level of the main biliary duct, close to the Vater papilla; b contrast-enhanced examination: portal phase, coronal reconstruction showing the hypo-
enhanced structural change, affecting the liver at the level of the 4th and the 5th segments with maximum width of 25 mm; the gallbladder walls are circumferentially thickened (up till 13 mm), and a continuity solution at the level of gallbladder wall, with dimensions of B2 mm can be visualized; the left intrahepatic duct is dilated
Fig. 4 Intraoperatory findings: a enlarged cystic and main biliary ducts; b the hepatic parenchyma infiltration can be seen. Resection of the 4th and 5th liver segments en bloc with cholecystectomy was performed
uniform reactivity to the smooth muscle actin (SMA) (Fig. 5c) of the spindle-cell component of the tumor, while staining for anaplastic lymphoma kinase (ALK) was equivocal. A diagnosis of IMT was proposed. In this case, the alternate hypothesis of xanthogranulomatous cholecystitis was ruled out based on the macroscopic presentation (unique eccentric mass) and on the histology appearance (dense myofibroblastic proliferation with strong reactivity to SMA and significantly lighter inflammatory infiltrate in the tumor compared to the gallbladder wall itself).
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Discussion Conventional ultrasound is widely used in the diagnosis of gallbladder diseases. More recently developed techniques such as CEUS and elastography have improved the chances of a more accurate diagnosis, allowing at the same time an earlier detection and a better characterization of gallbladder tumors [13, 14]. IMT has been known under different names: inflammatory granuloma, inflammatory histiocytoma, plasmocytoma, plasma cell granuloma, pseudolymphoma and fibroxanthoma [15, 16]. Umiker et al. named it
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Fig. 5 Histopathological findings: a the tumoral mass (6.5 9 5.2 9 4 cm) of a light grayish color, infiltrating the surrounding liver parenchyma; b H&E 9200: fibroblast and myofibroblast cells alongside mild inflammatory infiltrate; c immunohistochemical staining with SMA
‘inflammatory pseudotumor’ in 1954 [3, 17], but when the cell origin was established as a myofibroblast by immunohistochemical markers and electron microscopic studies, this designation has been replaced with the current ‘inflammatory myofibroblastic tumor’ [18]. Histologically, IMT represents a combination of myofibroblasts, fibroblasts, lymphocytes, and plasma cells in varying proportions [9]. In the recent literature, IMTs are classified by the World Health Organization as tumors of intermediate biological potential due to a tendency for local recurrence and its small risk for distant metastasis [19]. Primary IMTs of the gallbladder are rather infrequent; therefore, present knowledge is based on case reports [20]. The first case of an IPT affecting both the gallbladder and the bile duct was cited in the literature by Ikeda et al. [21]. A 43-year-old man with obstructive jaundice had thickened walls of the gallbladder and common bile duct due to diffuse granulomatous lesions composed mainly of plasma cells, lymphocytes, and fibroblasts identical with IPT. The same histological findings also were observed in the lung and lymph nodes. All clinical and laboratory abnormalities subsided after high-dose prednisolone therapy [21]. In 1995, Coffin published a clinicopathological and immunohistochemical study of 84 cases of IMT occurring in the soft tissues and viscera of 48 female patients and 36 male patients between the ages of 3 months and 46 years. Sites of involvement included the abdomen, retroperitoneum, or pelvis (61 cases); head and neck, including the upper respiratory tract (12 cases); trunk (8 cases); and extremities (3 cases) [22]. The same year, a case of chronic cholecystitis with features of xanthogranulomatous inflammation due to the presence of a prominent inflammatory infiltrate composed of plasma cells, lymphocytes, macrophages, foamy histiocytes, and huge fibroblastic and myofibroblastic proliferation was described by Corsi and
Bosman [23]. Ten years later, Behranwala et al. [24] reported the case of a 51-year-old female who underwent excision of a gallbladder tumor in which histopathology showed it to be IMT of the gallbladder. Muduly et al. [3] also reported a case of IMT of the gallbladder in a patient with suspected cancer of the gallbladder who underwent radical cholecystectomy for a gallbladder mass lesion. In ¨ zsan et al. [20] published in the Balkan Medical 2013, O Journal a case report of a 66-year-old male patient with a mass almost completely filling the gallbladder detected by imaging studies, which subsequent to the histopathological examination of the surgical specimen revealed an IMT. Vasiliadis presented the case of a 71-year-old female patient who underwent an extra-hepatic bile duct resection en-bloc with the gallbladder and regional lymph nodes for an obstructing intraluminal growing tumor of the mid common bile duct. Histologically, the tumor proved to be an IMT arising from the bile duct epithelium, composed of inflammatory cells and reactive mesenchymal tissues [25]. Cases of liver and gallbladder IMT reported in the literature involve a reactive inflammatory process that develops in response to a previous cause such as: biliary disease, tropical parasites, gastrointestinal infection, ulcerating gastric carcinoma [10], chronic cholangitis and primary sclerosing cholangitis [8]. There are no specific symptoms for IMT [26]. Abdominal pain (mostly in the right upper quadrant), weight loss, malaise, general weakness, jaundice, and fever may be present [2, 7, 8, 11, 12, 27]. Laboratory findings also lack specificity. However, elevation of C-reactive protein (CRP) and ESR and/or increase in white blood cell count have been observed [7]. Diabetic patients require special attention since their susceptibility to infections is well known, with very poor clinical outcomes [28]. Our patient had type II diabetes and had been treated with penicillin for endocarditis for a month. This might explain the lack of
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symptoms such as fever and intense abdominal pain and the absence of leukocytosis in this case. Imaging features of IMT are not specific and they mimic other pathologies, especially malignant tumors, and often do not provide a definitive diagnosis [3–5, 8, 27, 29]. In our case, abdominal US and CEUS raised the suspicion of a gallbladder malignant tumor due to the thickness of the wall and signs of invasion into the 4th and 5th hepatic segments, and also due to hyper-enhancement and washout at CEUS. The term ‘‘invasion’’ should be considered with caution in this case because it relies on the delineation of the tumor in relation to the surrounding liver parenchyma. The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) has recently published Guidelines and Recommendations on the clinical use of ultrasound elastography [30, 31]. It is a newly developed technique that has already proved its added value as a complementary, noninvasive imaging method, helpful to better characterize and differentiate between benign and malignant masses, by assessing their stiffness [32]. Malignant tissue exhibits increased stiffness compared to benign or normal tissue, and thus deforms to a lesser degree in response to compression [33, 34]. The suspicion of malignancy was supported by elastography in our case since it revealed a stiffer area inside the liver as compared to the surrounding normal liver parenchyma. Differential diagnosis of IMT with other malignant entities is important because surgical resection is not always mandatory [9], although it is considered to be the therapeutic gold standard [7, 35]. In most of the cases, the final diagnosis is based on histopathological and immunohistochemical studies [7, 26, 36]. Also, the histological examination excludes another possible diagnosis (a benign one): xanthogranulomatous cholecystitis. This entity represents a chronic inflammatory disease of the gallbladder consisting of multiple yellow–brown intramural nodules that are composed of extensive fibrosis and foam cells. Like IMT, it is a rare condition with unclear origin. The differential diagnosis between the two conditions depends exclusively on the pathological examination. In our case, the patient was also diagnosed with choledochal lithiasis. Although cholestasis and chronic inflammation are considered responsible factors for eventually developing IMT, in our patient the tumor was located at the fundus of the gallbladder and no vesicular stones were found. Therefore, we could not establish a connection between the gallbladder IMT and the choledochal stone. Some cases of spontaneous remission have been reported in the literature [2, 29]. Extremely rare malignant transformations of IMT have been encountered [3, 37]. Conservative treatment with antibiotics [2, 8, 29] and steroidal or non-steroidal anti-inflammatory drugs [2, 3, 35]
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has been proposed [2, 5, 9, 12, 29, 35, 38, 39] in cases of IMT at other locations (liver, lung, pancreas, spleen). Chemotherapy and radiation therapy have also been tried but proved to be useful only in cases of incomplete resection [26]. However, there are no case reports of gallbladder IMT being treated by conservative methods [3]. Complete surgical excision of the tumor and long-term multidisciplinary follow-up is the safer approach [2, 3, 7, 26]. Our patient underwent complete surgical resection of the tumor, and 3-month follow-up did not indicate recurrence or metastatic disease.
Conclusion IMT of the gallbladder is an extremely rare entity, and should be considered in the differential diagnosis of a gallbladder mass. Our case was a rare example of a complex pathology: main bile duct lithiasis, diabetes, endocarditis, and IMT. Despite the fact that imaging features of IMT are heterogeneous, conventional US and CEUS are useful tools in the diagnostic process (primary detection, characterization) and in the long-term follow-up of the patient. Acknowledgments The authors thank Mrs. Szasz Zsoka for the implication in follow-up of the patient. Conflict of interest There are no financial or other relations that could lead to a conflict of interest. Consent Written informed consent was obtained from the patient for the publication of this manuscript and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal. Human rights statements and informed consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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