Clinical Imaging xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature Antonio Corvino a,⁎, Fabio Corvino a, Leonardo Radice a, Orlando Catalano b a Department of Advanced Medical Biosciences, University Federico II of Napoli (UNINA), Biostructures and Bioimmages Institution (IBB), National Research Council (CNR), via Pansini 5 I-80131 Naples, Italy b Department of Radiology, National Cancer Institute, Pascale Foundation, via M. Semmola I-80131, Naples, Italy
a r t i c l e
i n f o
Article history: Received 2 October 2014 Received in revised form 16 December 2014 Accepted 28 December 2014 Available online xxxx Keywords: Diagnostic imaging Computed tomography Synchronous intestinal adenocarcinomas Multiple primary malignancy (MPM) Krukenberg tumor
a b s t r a c t With the wide use of diagnostic imaging modalities, multiple primary malignancies frequently occur; different associations of malignancies have been reported. We describe the case of a primary mucinous adenocarcinoma of large bowel synchronous with three primary poorly differentiated adenocarcinomas of ileum. This type of association has not been described yet; since computed tomography increasingly is proving to be highly accurate in detection of colon cancer, this technique is recommended in such patients. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Synchronous cancers in the small and large bowel with different histological characteristics are rare. In this paper, we present their occurrence in a young patient who presented with vaginal bleeding and an iron-deficiency anemia and in which a rare association of malignancies was found; in fact, a primary adenocarcinoma of large bowel was simultaneous with three primary adenocarcinomas of small bowel (ileum), discovered at laparotomy and all treated in the same session. The first report about multiple primary malignancies (MPMs) was on 1889 by Billroth which described a patient with a spinocellular epithelioma of the right ear and a gastric carcinoma [1,2]. Since that time, numerous series and case reports in the literature have cited similar occurrences involving a single organ or multiple organ systems. In particular, the technical innovation of diagnostic imaging has been employed in this setting, and thus, several cases have been described [3]. The majority of MPM involving multiple organs are metachronous lesions, with synchronous lesions occurring less frequently. More than two primary synchronous malignancies involving two or more organs are extremely rare [4]. 2. Case report A 29-years-old woman was admitted to our hospitals with a 2-month history of vaginal bleeding, changes in bowel habits, and moderate weight ⁎ Corresponding author. Via B. Croce n. 82, 81033 Casal di Principe (CE), Italy. Tel.: +393471710762; fax: +39-0818921778. E-mail address: [email protected] (A. Corvino).
loss. Her past medical history was clear of any serious health problems. Regarding family history, her father died of colon cancer shortly after diagnosis at the age of 40. The other family members were healthy. Physical examination revealed a fully alert patient with a soft and nontender abdomen and normal bowel sounds. The remaining of the physical examination was unremarkable. Laboratory studies revealed an iron-deficiency anemia (haemoglobin 7,40 g/dl, red blood cell 3,12×10 ^6/μl, hematocrit 24%, mean corpuscular volume 75 fl) and abnormal liver function tests (aspartate aminotransferase 108 IU/l, alanine aminotransferase 115 IU/l, total bilirubin 5.5 mg/dl, alkaline phosphatase 618 U/l). Tumor marker tests showed elevated serum Carcinoembryonic antigen (CEA) (228.5 ng/ml; normal rangeb5.0 ng/ml) and serum CA19-9 (6 U/ml; normal rangeb2.5 U/ml) values and normal serum CA125 values (33.6 U/ml; normal rangeb35 U/ml). His chest X-ray was normal, plain abdominal films were free of any pathology, and electrocardiogram was normal. Ultrasound (US) scan of the abdomen showed the presence of bilateral adnexial complex masses measuring 9.5×5.5 and 5.5×4.5 cm. Ovarian masses were characterized by anechoic cystic portions and hypoechoic solid components with pronounced vascularity at Color-Doppler and Power-Doppler examination. In addition, multiple well-defined, relatively homogeneous, hyperechoic nodular lesions of variable size suggestive of liver metastases were found in in both lobes of liver. Nevertheless, as a definite diagnosis had not been made, a liver biopsy was carried out. Pathological examination of a biopsy specimen revealed a well-differentiated adenocarcinoma with cells arranged in a glandular acinar pattern and focal mucin production; however, the morphologic pattern was not specific to define the site of metastases origin (liver metastases of primary ovarian mucinous tumor vs. liver
http://dx.doi.org/10.1016/j.clinimag.2014.12.019 0899-7071/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
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A. Corvino et al. / Clinical Imaging xxx (2015) xxx–xxx
metastases of tumor with a undefined primary localization). Immunohistochemical analysis, showing a citokeratin pattern CK20 +/CK7 −, was instead helpful to suggest a primary tumour localization in the gastrointestinal tract [colorectal cancer (CRC)]. Consequently, searching for the unknown primary tumor, an abdomino-pelvic computed tomography (CT) with a 16-detector row Multi-Slice Computed Tomography (MSCT) scanner was performed (Somatom Volume Zoom; Siemens Medical Solutions, Erlangen, Germany). Bowel preparation was not performed. No orally or rectally administrable contrast medium was used. A frontal 512-mm scout view was first obtained with 120 kVp and 50 mA. This was followed by helical scanning from the top of the liver to the symphysis pubis with 4×2.5 mm collimation, 120 kVp and 100 mAs (effective). The table feed was 15 mm per 0.5 s of scanner rotation (30 mm/s), resulting in a pitch of 1.5:1. From the raw data of the acquisition, 3-mm-thick transverse sections were reconstructed with 1.5-mm increments. Arterial, portal and late phase acquisitions were performed with fix scan delays of 35, 80, and 180 s after iv bolus injection (2,5 cc/s) of only 100 cc of nonionic iodinated contrast media (Ultravist 370; Bayer, Berlin, Germany) followed by 200 cc of saline solution with a dualhead injector (Stellant Injection System, Medrad Inc., United States). Contrast-enhanced CT scan showed marked and asymmetric thickening of colonic wall with heterogeneous enhancement involving both the caecum and the proximal portion of ascending colon. A retrocecal appendix with cystic dilatation of appendiceal lumen “mucocele-like” was also noted (Figs. 1 and 2). In addition, CT images demostrated a moderate distension of terminal ileum with feces-like intestinal content (small bowel feces sign), suggesting an ileo-cecal junction involvement (Fig. 3). Furthermore, CT views clearly depicted bilateral huge and oval-shaped ovarian masses with a complex internal structure and vivid enhancement of multiple intralesional solid portions (Fig. 4). In addition, CT confirmed the presence of multiple hypovascular liver metastases in the II, III, IV, and VI segments of liver (Fig. 5) and revealed a previously undiagnosed biliary dilatation of intrahepatic ducts of the left hepatic lobe due to compression by hepatic lesions (Fig. 5d). Peritoneal carcinomatosis appearing as nodular soft-tissue thickening of great omentum (omental cake sign) and a small amount of ascites were also found (Fig. 3). Following that, a full-length colonoscopy was performed which showed a stenotic malignant tumor almost totally obstructing the lumen of caecum and the proximal tract of ascendent colon, infiltrating the colonic wall. The rest of the colon was clear of any pathology.
Fig. 1. Contrast-enhanced CT scan shows marked and asymmetric thickening of colonic wall with heterogeneous enhancement involving the cecum (arrows). CT view also demonstrates a retrocecal appendix with cystic dilatation of appendiceal lumen by mucin accumulation, nearly associated with the cecum (arrowheads). Surgical resection revealed a mucinous adenocarcinoma of right colon with mucinous lakes found to be more than 50%.
Fig. 2. Transverse multidetector row CT image obtained at lower level shows thickening of caecum wall (arrows). Dilatation of appendiceal lumen by mucin accumulation was also evident (arrowheads).
Surprisingly, at laparotomy, as well as the previously mentioned malignant growth in the large bowel, other three partially obstructing lesions in the ileum were discovered. At this time, the decision was taken to excise all tumors as radically as possible. Consequently, an extended right hemicolectomy and an ileal resection incorporating the discovered tumors with an end-to side ileo-colic anastomosis were carried out. In total, the cecum, the ascending colon, the hepatic flexure, the first one third of the transverse colon, and 67 cm of small bowel were resected. In addition, an extended regional lymphadenectomy, hysterectomy with bilateral salpingoophorectomy, and a total omentectomy were performed. Histological examination of the excised lesions revealed: (a) The colonic lesion was a mucinous adenocarcinoma of right colon with mucinous lakes found to be more than 50%. It was diffusely infiltrating full thickness the colonic wall with focal expansion into the surrounding mesenteric adipose tissue. The extended right hemicolectomy specimen included in total 14 regional lymph nodes, 7 of which were found to be occupied by metastatic mucinous adenocarcinoma. The surgical excisional margins were free of cancer. (b) The three ileal lesions, instead, were proved to be poorly differentiated adenocarcinomas of small bowel with extensive areas of necrosis. Histologically these tumors were clearly different from that seen in the large bowel which
Fig. 3. Transverse CT scan shows a dilated loop of terminal ileum with internal feces-like material (small bowel feces sign) (arrow). CT reveals also a nodular soft-tissue thickening of great omentum (omental cake sign) (thick arrow). A small amount of free peritoneal fluid was evident (arrowheads).
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
A. Corvino et al. / Clinical Imaging xxx (2015) xxx–xxx
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hereditary nonpolyposis CRC (HNPCC, Lynch syndrome) was suggested. Although the patient's family history did not satisfy Amsterdam Criteria II [5] for HNPCC, the early age-of-onset and presence of synchronous tumors fulfilled the Revised Bethesda Criteria [5]. Accordingly, immunohistochemistry on surgical specimens was performed which exhibited positive MLH1 and MSH2 staining. The patient was also referred for genetic counseling and germline mutation testing, but no genetic mutations were detected in DNA mismatch repair (MMR) genes. Consequently, a Lynch syndrome was excluded. 3. Discussion
Fig. 4. Transverse CT scan shows bilateral huge and oval-shaped ovarian masses with a complex internal structure and enhancement of multiple intralesional solid portions.
showed abundant mucin production with formation of mucinous lakes. There was no macroscopic connection between the tumors. The regional lymph nodes showed reactive changes with no metastatic spread. The surgical excisional margins were free of cancer. There was no evidence of Crohn's or coeliac disease in the adjacent small bowel mucosa. (c) Microscopically, the histology of the bilateral ovarian tumors and nodules in the omentum was similar to that of the colon cancer. Histology and immune histochemistry showed that both the colon cancer and the ovarian tumor were positive for CK7 and CK20. Based on these similarities, the patient was diagnosed with right colon cancer that had metastasized to the ovaries. Instead, small bowel tumors stained positive for both cytokeratins (CK7+/CK20+), demonstrating a distinct organ of origin and thus discounting the possibility that either tumor type is a metastasis of the other. The patient made an excellent postoperative recovery. She was assessed by the clinical oncologist to estabilish adjuvant chemotherapy in the near future. She was discharged home on the 10th postoperative day. Retrospectively, in order to diagnose a hereditary syndrome, detailed medical histories were obtained through interviews with the patient and family members. In particular, baseline information on demographics, personal characteristics, personal and family history of cancer, cancer screening history, and history of polyps, polypectomy, hysterectomy, and/or other surgeries were investigated, but a family history of cancer was not found, except in the single case of father. Based on family history of colon cancer, young age at presentation and presence of multiple synchronous tumours, a diagnosis of
CRC is the third most common cancer and the third leading cause of cancer deaths among men and women in the United States [6]. In addition, colon is the most common site for multiple primary malignant tumors. The reported incidence of multiple primary cancers in extracolonic sites among CRC patients range from 2.4% to 8.7%. In this regard, the the most common extracolonic site of synchronous multiple primary cancers among CRC patients is stomach (Asia) and lung/breast (Europe) [4]. On the contrary, malignant small intestine tumors are very rare, and they account for 0.1–0.3% of all malignancies and 1–3% of all gastrointestinal malignancies [7,8]. The rarity of the small bowel tumors and their nonspecific symptomatology render their preoperative diagnosis very difficult. MPM were found in 20%–25% of enteric cancers [9]. Although it is unusual to have multiple synchronous enteric and colon malignancies, these have been reported. In a series of 65 patients with adenocarcinoma of the small intestine, it has been found that associated malignancies were present in 16 patients (25%), the malignancy being colonic adenocarcinoma in 12 patients [10]. Reddy et al. described a case of synchronous appearance of adenocarcinomas of jejunum and cecum, in a patient previously treated with transverse colectomy for cancerous polyps [11]. Lee et al. reported a similar case of caecal adenocarcinoma with multiple synchronous small intestinal adenocarcinomas [12]. A further similar case regarding three synchronous primary adenocarcinomas with different histological characteristics—two in the large bowel (Sigmoid and Transverse colon) and one in the jejunum—was described also by Penopoulos et al. [9]. Synchronous cancers in the small and large bowel have been described in patients with HNPCC, an autosomal dominantly inherited disorder of cancer susceptibility [13]. Lynch syndrome is characterised by the development of predominantly right sided colorectal carcinomas at an early age and an excess of synchronous or metachronous colorectal carcinomas and extracolonic malignancies. The condition is caused by a germ-line mutation in one of the DNA MMR genes. To date, four MMR genes have been found to cause HNPCC: MLH1, MSH2, PMS2, and MSH6. Of these, the MLH1 and MSH2 mutations account for 70–90% of the families with HNPCC [14]. Cancer of the small intestine is one of the Lynch syndrome–spectrum tumors, with a lifetime risk in carriers of 4% independent of development of CRC [14]. Win et al. observed that the second most common primary cancers following CRC, for both men and women who were Lynch syndrome carriers, were small bowel cancers and reported a risk at more than 70 times the population risk. However, in our case, Lynch syndrome was excluded [13]. We herein describe a case of a 29-year-old patient with a 2-month history of vaginal bleeding as initial manifestation of disease, a symptom believed to be caused by the presence of ovarian metastases, detected on US examination. However, colorectal carcinoma metastasis to the ovaries (Krukenberg tumor) mimicking a primary ovarian neoplasm as initial presentation is common, especially because metastases are difficult to differentiate from primary tumors on the basis of imaging, as they share many morphostructural and vascular features [15]. In this setting, Petru et al. reported that the ovarian metastases preceded the detection of the primary site in 38% of cases, most commonly in patients with colon cancer, as in our case [16]. Therefore, when radiologist encounter ovarian masses before a diagnosis of the
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
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A. Corvino et al. / Clinical Imaging xxx (2015) xxx–xxx
Fig. 5. Contrast-enhanced CT scan showing multiple hypoenhanced nodules in both the hepatic lobes (arrows) corresponding to hypovascular secondarities. A dilatation of intrahepatic ducts of the left hepatic lobe was also evident (arrowheads).
primary disease is made, an intensive search for the primary site should be performed [15]. At present, the initial diagnosis of CRC is usually made with colonoscopy. However, with the increased use of CT, the radiologist may become the first to suggest or confirm the diagnosis of colon cancer on the basis of CT findings, as resulted in our case. Nevertheless, at this time, CT is not routinely performed for detection of colon cancer although continued advancements in scanner and computer technology may allow CT to improve its usefulness. Instead, in patients with known colon cancer CT remains the modality of choice in preoperative assessment and staging of CRC as well as in postoperative surveillance for recurrence [17]. At the moment, there is no universal diagnostic technique with overall oncologic accuracy, neither there are diagnostic guidelines to detect synchronous MPM. As such, the diagnostic approach must be adapted on a case-by-case basis. A rational approach is needed for those patients in whom MPM is clinically suspected, especially in the case of lesions of the colon. CT, especially if combined with CT-Positron Emission Tomography (PET) may be the strategy of choice to identify additional lesions in these patients, as in our case [3]. To date, there is no universal diagnostic CT protocol [3]. In our experience, when evaluating a patient with suspected synchronous or metachronous intestinal tumors, the patient should be scanned in the supine position from the diaphragm to the symphysis pubis. At our institution, a helical scanning with 4×2.5-mm collimation, table feed of 15 mm per 0.5 s of scanner rotation (30 mm/s) resulting in a pitch of 1.5:1, and reconstruction of the data at 3-mm-thick transverse sections are routinely performed. Administration of intravenous contrast material is essential. We administer 100–120 ml of nonionic iodinated contrast media (Ultravist 370; Bayer, Berlin, Germany) intravenously at a rate of 2–3 ml/s. Our standard spiral CT protocol is to acquire data during the portal venous phase of liver enhancement, 70–80 s after the start of
contrast material injection, in order to maximize detection and staging of each lesion in the context of MPM and for evaluation of eventual metastatic disease. At last, as regards therapeutical approach, in this case intestinal resection, regional lymphadenectomy, hysterectomy with bilateral salpingoophorectomy, and total omentectomy in combination with adjuvant chemotherapy have represented the only way to improve prognosis and patient's survival and the only tools in our hands to deal with this problem. 4. Conclusion It should be stressed that multiple primary synchronous adenocarcinomas, one in the large bowel and three in the small bowel, as in this case, have not yet reported. In fact, despite an extensive search, we were unable to find a similar case in literature in which a primary adenocarcinoma of large bowel already with ovarian, hepatic, and peritoneal metastases developed “synchronously” with three primary adenocarcinomas of small bowel (ileum), surprisingly discovered at laparotomy and all treated surgically on the same occasion. By the way, the surgeon should always be alert for the possibility of MPM in the abdomen during laparotomies. In conclusion, large and small adenocarcinomas with different histological characteristics may occur simultaneously; this association should thus be considered in the context of the MPMs. References [1] Billroth Th. Die allgemeine chirurgische Pathologic und Therapie in 51 Vorlesungen Ein Handbuch ffir Studierende und Arzte. Berlin: Verlag von Georg Reimer; 1863 908[Auflage]. [2] Maurea S, Corvino A, Imbriaco M, Avitabile G, Mainenti P, Camera L, et al. Simultaneous non-functioning neuroendocrine carcinoma of the pancreas and extra-
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
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[3]
[4]
[5]
[6]
[7] [8]
hepatic cholangiocarcinoma. A case of early diagnosis and favorable post-surgical outcome. JOP 2011;12(3):255–8. Tammaro V, Spiezia S, D'Angelo S, Maurea S, Ciolli G, Salvatore M. Diagnostic imaging techniques for synchronous multiple tumors. In: Renda A, editor. Updates in Surgery. Multiple Primary MalignanciesMilano, Italia: Springer-Verlag; 2009. p. 231–44 [Chapter 16, ISBN 978–8847010949]. Lee SH, Ahn BK, Baek SU. Multiple primary cancers in extracolonic sites with colorectal cancer. Int J Colorectal Dis 2009;24(3):301–4. http://dx.doi.org/10.1007/ s00384-008-0583-0 [Epub 2008 Sep 17]. Julié C, Trésallet C, Brouquet A, Vallot C, Zimmermann U, Mitry E, et al. Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening. Am J Gastroenterol 2008;103(11):2825–35. http://dx.doi.org/10.1111/j. 1572-0241.2008.02084.x [quiz 2836. Epub 2008 Aug 27]. Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 2009;22(4):191–7. http://dx.doi. org/10.1055/s-0029-1242458. Pan SY, Morrison H. Epidemiology of cancer of the small intestine. World J Gastrointest Oncol 2011;3(3):33–42. http://dx.doi.org/10.4251/wjgo.v3.i3.33. Hong SH, Koh YH, Rho SY, Byun JH, Oh ST, Im KW, et al. Primary adenocarcinoma of the small intestine: presentation, prognostic factors and clinical outcome. Jpn J Clin Oncol 2009;39(1):54–61. http://dx.doi.org/10.1093/jjco/hyn122 [Epub 2008 Nov 8].
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[9] Penopoulos V, Gougoulias N, Walonga J, Christianopoulos G, Pistevou-Gobaki K, et al. Synchronous adenocarcinomas of the small (Jejunum) and large (Transverse and Sigmoid Colon) bowel. A case study. Ann Gastroenterol 2003;16(2):166–9. [10] Ouriel K, Adams JT. Adenocarcinoma of the small intestine. Am J Surg 1984;147(1):66–71. [11] Reddy VB, Husain AN, Gattuso P, Abraham K, Castelli MJ. Synchronous adenocarcinomas of jejunum and cecum following transverse colon carcinoma. A case study. Mt Sinai J Med 1990;57(1):34–6. [12] Lee J, Tamhane R, Parks TG. Caecal adenocarcinoma with multiple synchronous small intestinal adenocarcinoma. Postgrad Med J 1997;73(865):729–31. [13] Win AK, Lindor NM, Young JP, Macrae FA, Young GP, Williamson E, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst 2012;104(18):1363–72 [Epub 2012 Aug 28]. [14] ten Kate GL, Kleibeuker JH, Nagengast FM, Craanen M, Cats A, Menko FH, et al. Is surveillance of the small bowel indicated for Lynch syndrome families? Gut 2007; 56(9):1198–201 [Epub 2007 Apr 4]. [15] Choi HJ, Lee JH, Seo SS, Lee S, Kim SK, Kim JY, et al. Computed tomography findings of ovarian metastases from colon cancer: comparison with primary malignant ovarian tumors. J Comput Assist Tomogr 2005;29(1):69–73. [16] Petru E, Pickel H, Heydarfadai M, Lahousen M, Haas J, et al. Nongenital cancers metastatic to the ovary. Gynecol Oncol 1992;44(1):83–6. [17] Horton KM, Abrams RA, Fishman EK. Spiral CT of colon cancer: imaging features and role in management. Radiographics 2000;20(2):419–30.
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature Antonio Corvino a,⁎, Fabio Corvino a, Leonardo Radice a, Orlando Catalano b a Department of Advanced Medical Biosciences, University Federico II of Napoli (UNINA), Biostructures and Bioimmages Institution (IBB), National Research Council (CNR), via Pansini 5 I-80131 Naples, Italy b Department of Radiology, National Cancer Institute, Pascale Foundation, via M. Semmola I-80131, Naples, Italy
a r t i c l e
i n f o
Article history: Received 2 October 2014 Received in revised form 16 December 2014 Accepted 28 December 2014 Available online xxxx Keywords: Diagnostic imaging Computed tomography Synchronous intestinal adenocarcinomas Multiple primary malignancy (MPM) Krukenberg tumor
a b s t r a c t With the wide use of diagnostic imaging modalities, multiple primary malignancies frequently occur; different associations of malignancies have been reported. We describe the case of a primary mucinous adenocarcinoma of large bowel synchronous with three primary poorly differentiated adenocarcinomas of ileum. This type of association has not been described yet; since computed tomography increasingly is proving to be highly accurate in detection of colon cancer, this technique is recommended in such patients. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Synchronous cancers in the small and large bowel with different histological characteristics are rare. In this paper, we present their occurrence in a young patient who presented with vaginal bleeding and an iron-deficiency anemia and in which a rare association of malignancies was found; in fact, a primary adenocarcinoma of large bowel was simultaneous with three primary adenocarcinomas of small bowel (ileum), discovered at laparotomy and all treated in the same session. The first report about multiple primary malignancies (MPMs) was on 1889 by Billroth which described a patient with a spinocellular epithelioma of the right ear and a gastric carcinoma [1,2]. Since that time, numerous series and case reports in the literature have cited similar occurrences involving a single organ or multiple organ systems. In particular, the technical innovation of diagnostic imaging has been employed in this setting, and thus, several cases have been described [3]. The majority of MPM involving multiple organs are metachronous lesions, with synchronous lesions occurring less frequently. More than two primary synchronous malignancies involving two or more organs are extremely rare [4]. 2. Case report A 29-years-old woman was admitted to our hospitals with a 2-month history of vaginal bleeding, changes in bowel habits, and moderate weight ⁎ Corresponding author. Via B. Croce n. 82, 81033 Casal di Principe (CE), Italy. Tel.: +393471710762; fax: +39-0818921778. E-mail address: [email protected] (A. Corvino).
loss. Her past medical history was clear of any serious health problems. Regarding family history, her father died of colon cancer shortly after diagnosis at the age of 40. The other family members were healthy. Physical examination revealed a fully alert patient with a soft and nontender abdomen and normal bowel sounds. The remaining of the physical examination was unremarkable. Laboratory studies revealed an iron-deficiency anemia (haemoglobin 7,40 g/dl, red blood cell 3,12×10 ^6/μl, hematocrit 24%, mean corpuscular volume 75 fl) and abnormal liver function tests (aspartate aminotransferase 108 IU/l, alanine aminotransferase 115 IU/l, total bilirubin 5.5 mg/dl, alkaline phosphatase 618 U/l). Tumor marker tests showed elevated serum Carcinoembryonic antigen (CEA) (228.5 ng/ml; normal rangeb5.0 ng/ml) and serum CA19-9 (6 U/ml; normal rangeb2.5 U/ml) values and normal serum CA125 values (33.6 U/ml; normal rangeb35 U/ml). His chest X-ray was normal, plain abdominal films were free of any pathology, and electrocardiogram was normal. Ultrasound (US) scan of the abdomen showed the presence of bilateral adnexial complex masses measuring 9.5×5.5 and 5.5×4.5 cm. Ovarian masses were characterized by anechoic cystic portions and hypoechoic solid components with pronounced vascularity at Color-Doppler and Power-Doppler examination. In addition, multiple well-defined, relatively homogeneous, hyperechoic nodular lesions of variable size suggestive of liver metastases were found in in both lobes of liver. Nevertheless, as a definite diagnosis had not been made, a liver biopsy was carried out. Pathological examination of a biopsy specimen revealed a well-differentiated adenocarcinoma with cells arranged in a glandular acinar pattern and focal mucin production; however, the morphologic pattern was not specific to define the site of metastases origin (liver metastases of primary ovarian mucinous tumor vs. liver
http://dx.doi.org/10.1016/j.clinimag.2014.12.019 0899-7071/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
2
A. Corvino et al. / Clinical Imaging xxx (2015) xxx–xxx
metastases of tumor with a undefined primary localization). Immunohistochemical analysis, showing a citokeratin pattern CK20 +/CK7 −, was instead helpful to suggest a primary tumour localization in the gastrointestinal tract [colorectal cancer (CRC)]. Consequently, searching for the unknown primary tumor, an abdomino-pelvic computed tomography (CT) with a 16-detector row Multi-Slice Computed Tomography (MSCT) scanner was performed (Somatom Volume Zoom; Siemens Medical Solutions, Erlangen, Germany). Bowel preparation was not performed. No orally or rectally administrable contrast medium was used. A frontal 512-mm scout view was first obtained with 120 kVp and 50 mA. This was followed by helical scanning from the top of the liver to the symphysis pubis with 4×2.5 mm collimation, 120 kVp and 100 mAs (effective). The table feed was 15 mm per 0.5 s of scanner rotation (30 mm/s), resulting in a pitch of 1.5:1. From the raw data of the acquisition, 3-mm-thick transverse sections were reconstructed with 1.5-mm increments. Arterial, portal and late phase acquisitions were performed with fix scan delays of 35, 80, and 180 s after iv bolus injection (2,5 cc/s) of only 100 cc of nonionic iodinated contrast media (Ultravist 370; Bayer, Berlin, Germany) followed by 200 cc of saline solution with a dualhead injector (Stellant Injection System, Medrad Inc., United States). Contrast-enhanced CT scan showed marked and asymmetric thickening of colonic wall with heterogeneous enhancement involving both the caecum and the proximal portion of ascending colon. A retrocecal appendix with cystic dilatation of appendiceal lumen “mucocele-like” was also noted (Figs. 1 and 2). In addition, CT images demostrated a moderate distension of terminal ileum with feces-like intestinal content (small bowel feces sign), suggesting an ileo-cecal junction involvement (Fig. 3). Furthermore, CT views clearly depicted bilateral huge and oval-shaped ovarian masses with a complex internal structure and vivid enhancement of multiple intralesional solid portions (Fig. 4). In addition, CT confirmed the presence of multiple hypovascular liver metastases in the II, III, IV, and VI segments of liver (Fig. 5) and revealed a previously undiagnosed biliary dilatation of intrahepatic ducts of the left hepatic lobe due to compression by hepatic lesions (Fig. 5d). Peritoneal carcinomatosis appearing as nodular soft-tissue thickening of great omentum (omental cake sign) and a small amount of ascites were also found (Fig. 3). Following that, a full-length colonoscopy was performed which showed a stenotic malignant tumor almost totally obstructing the lumen of caecum and the proximal tract of ascendent colon, infiltrating the colonic wall. The rest of the colon was clear of any pathology.
Fig. 1. Contrast-enhanced CT scan shows marked and asymmetric thickening of colonic wall with heterogeneous enhancement involving the cecum (arrows). CT view also demonstrates a retrocecal appendix with cystic dilatation of appendiceal lumen by mucin accumulation, nearly associated with the cecum (arrowheads). Surgical resection revealed a mucinous adenocarcinoma of right colon with mucinous lakes found to be more than 50%.
Fig. 2. Transverse multidetector row CT image obtained at lower level shows thickening of caecum wall (arrows). Dilatation of appendiceal lumen by mucin accumulation was also evident (arrowheads).
Surprisingly, at laparotomy, as well as the previously mentioned malignant growth in the large bowel, other three partially obstructing lesions in the ileum were discovered. At this time, the decision was taken to excise all tumors as radically as possible. Consequently, an extended right hemicolectomy and an ileal resection incorporating the discovered tumors with an end-to side ileo-colic anastomosis were carried out. In total, the cecum, the ascending colon, the hepatic flexure, the first one third of the transverse colon, and 67 cm of small bowel were resected. In addition, an extended regional lymphadenectomy, hysterectomy with bilateral salpingoophorectomy, and a total omentectomy were performed. Histological examination of the excised lesions revealed: (a) The colonic lesion was a mucinous adenocarcinoma of right colon with mucinous lakes found to be more than 50%. It was diffusely infiltrating full thickness the colonic wall with focal expansion into the surrounding mesenteric adipose tissue. The extended right hemicolectomy specimen included in total 14 regional lymph nodes, 7 of which were found to be occupied by metastatic mucinous adenocarcinoma. The surgical excisional margins were free of cancer. (b) The three ileal lesions, instead, were proved to be poorly differentiated adenocarcinomas of small bowel with extensive areas of necrosis. Histologically these tumors were clearly different from that seen in the large bowel which
Fig. 3. Transverse CT scan shows a dilated loop of terminal ileum with internal feces-like material (small bowel feces sign) (arrow). CT reveals also a nodular soft-tissue thickening of great omentum (omental cake sign) (thick arrow). A small amount of free peritoneal fluid was evident (arrowheads).
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
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hereditary nonpolyposis CRC (HNPCC, Lynch syndrome) was suggested. Although the patient's family history did not satisfy Amsterdam Criteria II [5] for HNPCC, the early age-of-onset and presence of synchronous tumors fulfilled the Revised Bethesda Criteria [5]. Accordingly, immunohistochemistry on surgical specimens was performed which exhibited positive MLH1 and MSH2 staining. The patient was also referred for genetic counseling and germline mutation testing, but no genetic mutations were detected in DNA mismatch repair (MMR) genes. Consequently, a Lynch syndrome was excluded. 3. Discussion
Fig. 4. Transverse CT scan shows bilateral huge and oval-shaped ovarian masses with a complex internal structure and enhancement of multiple intralesional solid portions.
showed abundant mucin production with formation of mucinous lakes. There was no macroscopic connection between the tumors. The regional lymph nodes showed reactive changes with no metastatic spread. The surgical excisional margins were free of cancer. There was no evidence of Crohn's or coeliac disease in the adjacent small bowel mucosa. (c) Microscopically, the histology of the bilateral ovarian tumors and nodules in the omentum was similar to that of the colon cancer. Histology and immune histochemistry showed that both the colon cancer and the ovarian tumor were positive for CK7 and CK20. Based on these similarities, the patient was diagnosed with right colon cancer that had metastasized to the ovaries. Instead, small bowel tumors stained positive for both cytokeratins (CK7+/CK20+), demonstrating a distinct organ of origin and thus discounting the possibility that either tumor type is a metastasis of the other. The patient made an excellent postoperative recovery. She was assessed by the clinical oncologist to estabilish adjuvant chemotherapy in the near future. She was discharged home on the 10th postoperative day. Retrospectively, in order to diagnose a hereditary syndrome, detailed medical histories were obtained through interviews with the patient and family members. In particular, baseline information on demographics, personal characteristics, personal and family history of cancer, cancer screening history, and history of polyps, polypectomy, hysterectomy, and/or other surgeries were investigated, but a family history of cancer was not found, except in the single case of father. Based on family history of colon cancer, young age at presentation and presence of multiple synchronous tumours, a diagnosis of
CRC is the third most common cancer and the third leading cause of cancer deaths among men and women in the United States [6]. In addition, colon is the most common site for multiple primary malignant tumors. The reported incidence of multiple primary cancers in extracolonic sites among CRC patients range from 2.4% to 8.7%. In this regard, the the most common extracolonic site of synchronous multiple primary cancers among CRC patients is stomach (Asia) and lung/breast (Europe) [4]. On the contrary, malignant small intestine tumors are very rare, and they account for 0.1–0.3% of all malignancies and 1–3% of all gastrointestinal malignancies [7,8]. The rarity of the small bowel tumors and their nonspecific symptomatology render their preoperative diagnosis very difficult. MPM were found in 20%–25% of enteric cancers [9]. Although it is unusual to have multiple synchronous enteric and colon malignancies, these have been reported. In a series of 65 patients with adenocarcinoma of the small intestine, it has been found that associated malignancies were present in 16 patients (25%), the malignancy being colonic adenocarcinoma in 12 patients [10]. Reddy et al. described a case of synchronous appearance of adenocarcinomas of jejunum and cecum, in a patient previously treated with transverse colectomy for cancerous polyps [11]. Lee et al. reported a similar case of caecal adenocarcinoma with multiple synchronous small intestinal adenocarcinomas [12]. A further similar case regarding three synchronous primary adenocarcinomas with different histological characteristics—two in the large bowel (Sigmoid and Transverse colon) and one in the jejunum—was described also by Penopoulos et al. [9]. Synchronous cancers in the small and large bowel have been described in patients with HNPCC, an autosomal dominantly inherited disorder of cancer susceptibility [13]. Lynch syndrome is characterised by the development of predominantly right sided colorectal carcinomas at an early age and an excess of synchronous or metachronous colorectal carcinomas and extracolonic malignancies. The condition is caused by a germ-line mutation in one of the DNA MMR genes. To date, four MMR genes have been found to cause HNPCC: MLH1, MSH2, PMS2, and MSH6. Of these, the MLH1 and MSH2 mutations account for 70–90% of the families with HNPCC [14]. Cancer of the small intestine is one of the Lynch syndrome–spectrum tumors, with a lifetime risk in carriers of 4% independent of development of CRC [14]. Win et al. observed that the second most common primary cancers following CRC, for both men and women who were Lynch syndrome carriers, were small bowel cancers and reported a risk at more than 70 times the population risk. However, in our case, Lynch syndrome was excluded [13]. We herein describe a case of a 29-year-old patient with a 2-month history of vaginal bleeding as initial manifestation of disease, a symptom believed to be caused by the presence of ovarian metastases, detected on US examination. However, colorectal carcinoma metastasis to the ovaries (Krukenberg tumor) mimicking a primary ovarian neoplasm as initial presentation is common, especially because metastases are difficult to differentiate from primary tumors on the basis of imaging, as they share many morphostructural and vascular features [15]. In this setting, Petru et al. reported that the ovarian metastases preceded the detection of the primary site in 38% of cases, most commonly in patients with colon cancer, as in our case [16]. Therefore, when radiologist encounter ovarian masses before a diagnosis of the
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
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Fig. 5. Contrast-enhanced CT scan showing multiple hypoenhanced nodules in both the hepatic lobes (arrows) corresponding to hypovascular secondarities. A dilatation of intrahepatic ducts of the left hepatic lobe was also evident (arrowheads).
primary disease is made, an intensive search for the primary site should be performed [15]. At present, the initial diagnosis of CRC is usually made with colonoscopy. However, with the increased use of CT, the radiologist may become the first to suggest or confirm the diagnosis of colon cancer on the basis of CT findings, as resulted in our case. Nevertheless, at this time, CT is not routinely performed for detection of colon cancer although continued advancements in scanner and computer technology may allow CT to improve its usefulness. Instead, in patients with known colon cancer CT remains the modality of choice in preoperative assessment and staging of CRC as well as in postoperative surveillance for recurrence [17]. At the moment, there is no universal diagnostic technique with overall oncologic accuracy, neither there are diagnostic guidelines to detect synchronous MPM. As such, the diagnostic approach must be adapted on a case-by-case basis. A rational approach is needed for those patients in whom MPM is clinically suspected, especially in the case of lesions of the colon. CT, especially if combined with CT-Positron Emission Tomography (PET) may be the strategy of choice to identify additional lesions in these patients, as in our case [3]. To date, there is no universal diagnostic CT protocol [3]. In our experience, when evaluating a patient with suspected synchronous or metachronous intestinal tumors, the patient should be scanned in the supine position from the diaphragm to the symphysis pubis. At our institution, a helical scanning with 4×2.5-mm collimation, table feed of 15 mm per 0.5 s of scanner rotation (30 mm/s) resulting in a pitch of 1.5:1, and reconstruction of the data at 3-mm-thick transverse sections are routinely performed. Administration of intravenous contrast material is essential. We administer 100–120 ml of nonionic iodinated contrast media (Ultravist 370; Bayer, Berlin, Germany) intravenously at a rate of 2–3 ml/s. Our standard spiral CT protocol is to acquire data during the portal venous phase of liver enhancement, 70–80 s after the start of
contrast material injection, in order to maximize detection and staging of each lesion in the context of MPM and for evaluation of eventual metastatic disease. At last, as regards therapeutical approach, in this case intestinal resection, regional lymphadenectomy, hysterectomy with bilateral salpingoophorectomy, and total omentectomy in combination with adjuvant chemotherapy have represented the only way to improve prognosis and patient's survival and the only tools in our hands to deal with this problem. 4. Conclusion It should be stressed that multiple primary synchronous adenocarcinomas, one in the large bowel and three in the small bowel, as in this case, have not yet reported. In fact, despite an extensive search, we were unable to find a similar case in literature in which a primary adenocarcinoma of large bowel already with ovarian, hepatic, and peritoneal metastases developed “synchronously” with three primary adenocarcinomas of small bowel (ileum), surprisingly discovered at laparotomy and all treated surgically on the same occasion. By the way, the surgeon should always be alert for the possibility of MPM in the abdomen during laparotomies. In conclusion, large and small adenocarcinomas with different histological characteristics may occur simultaneously; this association should thus be considered in the context of the MPMs. References [1] Billroth Th. Die allgemeine chirurgische Pathologic und Therapie in 51 Vorlesungen Ein Handbuch ffir Studierende und Arzte. Berlin: Verlag von Georg Reimer; 1863 908[Auflage]. [2] Maurea S, Corvino A, Imbriaco M, Avitabile G, Mainenti P, Camera L, et al. Simultaneous non-functioning neuroendocrine carcinoma of the pancreas and extra-
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
A. Corvino et al. / Clinical Imaging xxx (2015) xxx–xxx
[3]
[4]
[5]
[6]
[7] [8]
hepatic cholangiocarcinoma. A case of early diagnosis and favorable post-surgical outcome. JOP 2011;12(3):255–8. Tammaro V, Spiezia S, D'Angelo S, Maurea S, Ciolli G, Salvatore M. Diagnostic imaging techniques for synchronous multiple tumors. In: Renda A, editor. Updates in Surgery. Multiple Primary MalignanciesMilano, Italia: Springer-Verlag; 2009. p. 231–44 [Chapter 16, ISBN 978–8847010949]. Lee SH, Ahn BK, Baek SU. Multiple primary cancers in extracolonic sites with colorectal cancer. Int J Colorectal Dis 2009;24(3):301–4. http://dx.doi.org/10.1007/ s00384-008-0583-0 [Epub 2008 Sep 17]. Julié C, Trésallet C, Brouquet A, Vallot C, Zimmermann U, Mitry E, et al. Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening. Am J Gastroenterol 2008;103(11):2825–35. http://dx.doi.org/10.1111/j. 1572-0241.2008.02084.x [quiz 2836. Epub 2008 Aug 27]. Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 2009;22(4):191–7. http://dx.doi. org/10.1055/s-0029-1242458. Pan SY, Morrison H. Epidemiology of cancer of the small intestine. World J Gastrointest Oncol 2011;3(3):33–42. http://dx.doi.org/10.4251/wjgo.v3.i3.33. Hong SH, Koh YH, Rho SY, Byun JH, Oh ST, Im KW, et al. Primary adenocarcinoma of the small intestine: presentation, prognostic factors and clinical outcome. Jpn J Clin Oncol 2009;39(1):54–61. http://dx.doi.org/10.1093/jjco/hyn122 [Epub 2008 Nov 8].
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[9] Penopoulos V, Gougoulias N, Walonga J, Christianopoulos G, Pistevou-Gobaki K, et al. Synchronous adenocarcinomas of the small (Jejunum) and large (Transverse and Sigmoid Colon) bowel. A case study. Ann Gastroenterol 2003;16(2):166–9. [10] Ouriel K, Adams JT. Adenocarcinoma of the small intestine. Am J Surg 1984;147(1):66–71. [11] Reddy VB, Husain AN, Gattuso P, Abraham K, Castelli MJ. Synchronous adenocarcinomas of jejunum and cecum following transverse colon carcinoma. A case study. Mt Sinai J Med 1990;57(1):34–6. [12] Lee J, Tamhane R, Parks TG. Caecal adenocarcinoma with multiple synchronous small intestinal adenocarcinoma. Postgrad Med J 1997;73(865):729–31. [13] Win AK, Lindor NM, Young JP, Macrae FA, Young GP, Williamson E, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst 2012;104(18):1363–72 [Epub 2012 Aug 28]. [14] ten Kate GL, Kleibeuker JH, Nagengast FM, Craanen M, Cats A, Menko FH, et al. Is surveillance of the small bowel indicated for Lynch syndrome families? Gut 2007; 56(9):1198–201 [Epub 2007 Apr 4]. [15] Choi HJ, Lee JH, Seo SS, Lee S, Kim SK, Kim JY, et al. Computed tomography findings of ovarian metastases from colon cancer: comparison with primary malignant ovarian tumors. J Comput Assist Tomogr 2005;29(1):69–73. [16] Petru E, Pickel H, Heydarfadai M, Lahousen M, Haas J, et al. Nongenital cancers metastatic to the ovary. Gynecol Oncol 1992;44(1):83–6. [17] Horton KM, Abrams RA, Fishman EK. Spiral CT of colon cancer: imaging features and role in management. Radiographics 2000;20(2):419–30.
Please cite this article as: Corvino A, et al, Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature, Clin Imaging (2015), http://dx.doi.org/10.1016/j.clinimag.2014.12.019
