ABSTRACT

Objective

To characterize the pattern of primary small bowel cancers in a tertiary East-European hospital.

Methods

A retrospective study of patients with small bowel cancers admitted to a tertiary emergency center, over the past 15 years.

Results

There were 57 patients with small bowel cancer, representing 0.039% of admissions and 0.059% of laparotomies. There were 37 (64.9%) men, mean age of 58 years; and 72 years for females. Out of 57 patients, 48 (84.2%) were admitted due to an emergency situation: obstruction in 21 (38.9%), perforation in 17 (31.5%), upper gastrointestinal bleeding in 8 (14.8%), and lower gastrointestinal bleeding in 2 (3.7%). There were 10 (17.5%) duodenal tumors, 21 (36.8%) jejunal tumors and 26 (45.6%) ileal tumors. The most frequent neoplasms were gastrointestinal stromal tumor in 24 patients (42.1%), adenocarcinoma in 19 (33.3%), lymphoma in 8 (14%), and carcinoids in 2 (3.5%). The prevalence of duodenal adenocarcinoma was 14.55 times greater than that of the small bowel, and the prevalence of duodenal stromal tumors was 1.818 time greater than that of the small bowel. Obstruction was the complication in adenocarcinoma in 57.9% of cases, and perforation was the major local complication (47.8%) in stromal tumors.

Conclusion

Primary small bowel cancers are usually diagnosed at advanced stages, and revealed by a local complication of the tumor. Their surgical management in emergency setting is associated to significant morbidity and mortality rates.

Intestine; small/pathology; Neoplasms; Emergencies

RESUMO

Objetivo

Caracterizar o padrão de neoplasias malignas primárias do intestino delgado em um hospital terciário de Leste Europeu.

Métodos

Estudo retrospectivo de pacientes com câncer de intestino delgado, internados em um hospital terciário e de emergência, ao longo dos últimos 15 anos.

Resultados

Foram avaliados 57 pacientes com neoplasias malignas gastrintestinais, o que representou 0,039% das admissões e 0,059% das laparotomias realizadas. Total de 37 (64,9%) pacientes masculinos, média de idade de 58 anos, e de 72 anos para mulheres. Dentre os 57 pacientes, 48 (84,2%) foram internados em situação de emergência: obstrução intestinal em 21 (38,9%), perfuração em 17 (31,5%), hemorragia digestiva alta em 8 (14,8%), e hemorragia digestiva baixa em 2 (3,7%). Houve 10 (17,5%) tumores duodenais, 21 (36,8%) jejunais e 26 (45,6%) ileais. As neoplasias mais frequentes foram tumor estromal gastrintestinal, em 24 (42,1%) pacientes, adenocarcinoma em 19 (33,3%), linfoma em 8 (14%) e carcinoides em 2 (3,5%). A prevalência de adenocarcinoma duodenal foi 14,55 vezes maior do que a do intestino delgado, e a prevalência de tumores estromais duodenais foi 1,818 vez maior do que a do intestino delgado. A obstrução intestinal foi complicação do adenocarcinoma em 57,9% dos casos, e a perfuração foi a principal complicação local (47,8%) dos tumores estromais.

Conclusão

As neoplasias malignas primárias do intestino delgado foram geralmente diagnosticadas em estado avançado e reveladas por uma complicação local do tumor. O tratamento cirúrgico em situação de emergência está associado à significativa morbimortalidade.

Intestino delgado/patologia; Neoplasias; Emergências

INTRODUCTION

Malignant tumors of the small bowel are extremely rare, and account to, in average, approximately 2 to 3% of gastrointestinal cancers.(¹1. Kummar S, Ciesielski TE, Fogarasi MC. Management of small bowel adenocarcinoma. Oncology (Williston Park). 2002;16(10):1364-9; discussion 1370, 1372-3. Review.

2. Overman MJ. Rare but real: management of small bowel adenocarcinoma. Am Soc Clin Oncol Educ Book. 2013:189-93.-³3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.) The estimated new cases per year and the estimated mortality is 5,300 and 1,210, respectively, in the United States, and 3,500 and 1,100, respectively, in Europe.(⁴4. Khan K, Peckitt C, Sclafani F, Watkins D, Rao S, Starling N, et al. Prognostic factors and treatment outcomes in patients with Small Bowel Adenocarcinoma (SBA): the Royal Marsden Hospital (RMH) experience. BMC Cancer. 2015;15:15.) Their incidence increased during the last decades, and in roughly one third of cases they are associated with prior or subsequent other tumor of the gastrointestinal tract.(⁵5. Hatzaras I, Palesty JA, Abir F, Sullivan P, Kozol RA, Dudrick SJ, et al. Small-bowel tumors: epidemiologic and clinical characteristics of 1260 cases from the connecticut tumor registry. Arch Surg. 2007;142(3):229-35.) More than 40 different histopathological types of neoplasm occur in the small bowel, but over 95% of malignancy are adenocarcinomas, gastrointestinal stromal tumors (GIST), carcinoids or lymphomas. The diagnosis of these tumors is often delayed due to their nonspecific symptoms, usually being made during an acute complication of the disease. In a symptomatic stage more than 50% of cases present metastatic disease.(⁶6. Talamonti MS, Goetz LH, Rao S, Joehl RJ. Primary cancers of the small bowel: analysis of prognostic factors and results of surgical management. Arch Surg. 2002;137(5):564-70; discussion 570-1.) Knowing the nonspecificity of the clinical picture, only a high index of suspicion may offer an early diagnosis and treatment. The reported overall 5-year survival rate was 83% for carcinoids, 25% for adenocarcinomas, 62% for lymphomas and 45% for stromal tumors.(⁷7. DiSario JA, Burt RW, Vargas H, McWhorter WP. Small bowel cancer: epidemiological and clinical characteristics from a population-based registry. Am J Gastroenterol. 1994;89(5):699-701.) However, the combined 5-year relative overall survival improved from 32.5 to 66.9%, between 1975 and 2006.(⁸8. Shenoy S. Primary small-bowel malignancy: update in tumor biology, markers, and management strategies. J Gastrointest Cancer. 2014;45(4):421-30. Review.) Out of all the periampullary tumors, duodenal adenocarcinomas have the best prognosis, with a 5-year survival of 32.8%, comparing with pancreatic head adenocarcinoma which has a 5-year survival of only 6.5%.(⁹9. Chen SC, Shyr YM, Wang SE. Long-term survival after pancreaticoduodenectomy for periampullary adenocarcinomas. HPB (Oxford). 2013;15(12):951-7.)Overall, advanced small bowel adenocarcinoma had a worse prognosis than colorectal cancer, but better than gastric or pancreatic tumors.(¹⁰10. Aparicio T, Zaanan A, Svrcek M, Laurent-Puig P, Carrere N, Manfredi S, et al. Small bowel adenocarcinoma: epidemiology, risk factors, diagnosis and treatment. Dig Liver Dis. 2014;46(2):97-104. Review.)

OBJECTIVE

The main objective of this study was to characterize the pattern of small bowel primary cancers managed in a tertiary, university affiliated, emergency center. The secondary objectives were to determine early morbidity and mortality associated with surgical resection, and to correlate the pathology of the tumor with its clinical picture.

METHODS

Retrospective study of adult patients, males and females, admitted in our hospital over the past 15 years. The selection criteria were duodenal, jejunal or ileal tumor; and histopathological examination proving the small bowel malignant neoplasm. Continuous variables are expressed as mean ± standard deviation, and the categorical ones as number (percent). Categorical variables were compared by the χ(²2. Overman MJ. Rare but real: management of small bowel adenocarcinoma. Am Soc Clin Oncol Educ Book. 2013:189-93.)tests. The distribution of continuous variables was evaluated by Kolmogorov-Smirnov test and one-way Analisys of Variance (ANOVA). The t-test or the nonparametric tests (Mann-Whitney U or Kruskal-Wallis H tests) were used for independent samples. The probability of rejecting the null hypothesis (statistical significance) was set at 0.05. For statistical analysis we used IBM Statistical Package for the Social Science (SPSS) Statistics 20 software. We also did an electronic search at the databases of the U.S. National Library of Medicine, National Institutes of Health, PubMed/MEDLINE, EMBASE, Google Scholar, and ISI Web of Knowledge, to identify original articles and reviews about the subject. The terms “intestinal”, “small bowel”, “cancer” and “tumor” were used in various combinations. The keywords were identified as truncated words in the title, abstract or in Medical Subject Heading (MeSH). Only English language literature was selected for further analysis. Electronic and manual cross-referencing was used further to find more relevant sources.

RESULTS

There were 57 patients admitted during 15 years, accounting for 0.039% from our admissions and 0.059% from our laparotomies. There were 37 (64.9%) males and 20 (35.1%) females (95% confidence interval: 95%CI − female: 23%-48%; males: 52%-77%). The mean age for males was 58±12.7 years, and 68±16,20 years for females (Figure 1). There were 10 (17.5%) duodenal, 21 (36.8%) jejunal and 26 (45.6%) ileal tumors (Figure 2). Out of 57 patients, 48 (84.2%) were admitted in emergency setting: obstruction with 21 (38.9%) cases, perforation with 17 (31.5%), upper gastrointestinal bleeding with 8 (14.8%) and lower gastrointestinal bleeding with 2 (3.7%). We observed a mean interval from onset of symptoms to surgical treatment of 73 days, with 2.2±1.32 imaging tests per patient and 1.1±0.326 prior hospital admissions for nonspecific abdominal symptoms.

The most common conditions were GIST (24/42.1%), adenocarcinoma (19/33.3%), lymphoma (8/14%), and carcinoids (7/10.6%) (Figure 3). The prevalence of duodenal adenocarcinoma was 14.55 times greater than that of the small bowel (p=0.001), the prevalence of duodenal stromal tumors was 1.818 time greater than that of the small bowel (p=0.001) (Figure 4).

Intestinal obstruction was the complication observed in adenocarcinoma in 57.9% of cases (p=0.019), and tumor rupture was the main local complication (47.8%) for GIST (p=0.024). The surgical approach for duodenal tumors was pancreatoduodenectomy (PD) in 80%, tumorectomy in 10%, and palliative by-pass in 10% of cases. PD for complicated duodenal cancers strongly correlates with a high mortality (p=0.008). All cases of jejunal and ileal tumors were managed by intestinal resection with regional lymphadenectomy and primary anastomosis. We observed a 30-day mortality of 26%.

DISCUSSION

Although the small bowel accounts for 75% of the length and 90% of the surface of the gastrointestinal tract, it very rarely presents malignancies. An explanation for this would be a more diluted content with less irritation of the mucosa, a rapid transit with a shorter exposure to the carcinogens, less bacterial flora with less conversion of the biliary acids into carcinogens, and an increased lymphoid tissue with a high local concentration of IgA, differently from the colorectal region.(¹¹11. Kopáčová M, Rejchrt S, Bureš J, Tachecí I. Small intestinal tumours. Gastroenterol Res Pract. 2013;2013:702536.,¹²12. Chow WH, Linet MS, McLaughlin JK, Hsing AW, Chien HT, Blot WJ. Risk factors for small intestine cancer. Cancer Causes Control. 1993;4(2):163-9.) The gut has an area of 300m(²2. Overman MJ. Rare but real: management of small bowel adenocarcinoma. Am Soc Clin Oncol Educ Book. 2013:189-93.), which is the largest barrier against the external environment, such as dietary components and the bacterial flora(¹³13. Günther C, Neumann H, Neurath MF, Becker C. Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut. 2013;62(7): 1062-71. Review.) (Chart 1).

The intestinal epithelium has an enormous self-renewing capacity, being completely replaced in 4 to 5 days.(²²22. van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol. 2009;71:241-60. Review.) The carcinogenesis mechanisms seem to be related to the host-bacteria interaction, with secondary changes into the intestinal stem cell function, such as activation of the JAK-STAT, JNK and Wnt pathways. Chronic inflammation and hyperproliferation of the intestinal stem cells initiate malignant transformation, maintenance and metastases.(²³23. Sun J. Enteric bacteria and cancer stem cells. Cancers (Basel). 2010;3(1):285-97.) Laforest et al. investigated the frequency of somatic mutations in 83 small bowel adenocarcinomas.(²⁴24. Laforest A, Aparicio T, Zaanan A, Silva FP, Didelot A, Desbeaux A, et al. ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma. Eur J Cancer. 2014;50(10):1740-6.) These cases were selected from two European databases; in that, 47% of cases were duodenal tumors, and, in 63% of cases, there were three or more tumors. With a frequency over 5%, there were mutations in Kras, TP53, APC, SMAD4, PIK3CA, BRAF, ERBB2, BRAF and FBXW7. ERBB2 mutations were present in 12% of patients, and significantly associated with duodenal tumor location. This study suggests that more than 10% of patients with small bowel adenocarcinoma may benefit from anti-ERBB2-targeted agent.(²⁴24. Laforest A, Aparicio T, Zaanan A, Silva FP, Didelot A, Desbeaux A, et al. ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma. Eur J Cancer. 2014;50(10):1740-6.)

Maglinte et al. investigated the reasons for primary malignancies of the small bowel being diagnosed so late. They found that the average delay is attributable, as follows: (a) if less than 2 months, to patients failing to report symptoms; (b) at 8.2 months, to physicians not ordering the appropriate diagnostic tests; (c) at 12 months, to the radiologist failing to make diagnosis.(²⁵25. Maglinte DD, O’Connor K, Bessette J, Chernish SM, Kelvin FM. The role of the physician in the late diagnosis of primary malignant tumors of the small intestine. Am J Gastroenterol. 1991;86(3):304-8.) We observed in our patients a mean interval from onset of symptoms to diagnosis of 73 days.

An analysis of the Surveillance, Epidemiology, and End Results (SEER), from 1973 to 1982, showed that the incidence of the malignant carcinoid increased during this decade by 50%.(²⁶26. Weiss NS, Yang CP. Incidence of histologic types of cancer of the small intestine. J Natl Cancer Inst. 1987;78(4):653-6.) Carcinoid tumors, lymphomas, and sarcomas were rarely located in the duodenum, while nearly half of the adenocarcinomas were found in this site. A total of 87% of carcinoids and 60% of lymphomas were in the ileum.(²⁶26. Weiss NS, Yang CP. Incidence of histologic types of cancer of the small intestine. J Natl Cancer Inst. 1987;78(4):653-6.) The analysis of 67,843 patients, from the National Cancer Data Database (1985-2005) and SEER (1973-2004) showed that 37.4% were carcinoids, 36.9% adenocarcinomas, 8.8% stromal tumors, and 17.3% lymphomas.(²⁷27. Bilimoria KY, Bentrem DJ, Wayne JD, Ko CY, Bennett CL, Talamonti MS. Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surgery. 2009;249(1):63-71.) We have found similarities for the frequency of adenocarcinoma (33.3%) and lymphoma (14%), with a significantly larger number of GIST (42.1%) and lesser for carcinoids (10.6%). These differences may be due to our hospital profile, being a tertiary emergency center, with carcinoids presenting a longer indolent clinical course and a lower complication rate comparing to GIST.

From 1974 to 2004, the incidence of carcinoids increased more than four-fold, from 2.1 to 9.3 per million, while changes in adenocarcinoma, GIST and lymphoma were less significant.(²⁷27. Bilimoria KY, Bentrem DJ, Wayne JD, Ko CY, Bennett CL, Talamonti MS. Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surgery. 2009;249(1):63-71.) A population-based study from Swedish Cancer Register analyzed 6,604 patients with small bowel malignant tumors.(²⁸28. Lu Y, Fröbom R, Lagergren J. Incidence patterns of small bowel cancer in a population-based study in Sweden: increase in duodenal adenocarcinoma. Cancer Epidemiol. 2012;36(3):e158-63.)During the study period, from 1960-2009, the incidence of the duodenal cancer increased more than three-fold, especially by a dramatically rising trend of adenocarcinoma of the duodenum.(²⁸28. Lu Y, Fröbom R, Lagergren J. Incidence patterns of small bowel cancer in a population-based study in Sweden: increase in duodenal adenocarcinoma. Cancer Epidemiol. 2012;36(3):e158-63.) In a study analyzing the data from Western Canada, most adenocarcinomas (54.7%) occurred in the duodenum, 29.9% in the jejunum and 16% in the ileum.(²⁹29. Gabos S, Berkel J, Band P, Robson D, Whittaker H. Small bowel cancer in western Canada. Int J Epidemiol. 1993;22(2):198-206.) There was an opposite trend for carcinoids, being located in only 3.9% of cases in duodenum, and in 9.2% in the jejunum and in 86.7% in ileum. The same disposition was for lymphomas: 21% in duodenum, 29.4% in jejunum and 49.5% in the ileum.(²⁹29. Gabos S, Berkel J, Band P, Robson D, Whittaker H. Small bowel cancer in western Canada. Int J Epidemiol. 1993;22(2):198-206.) Looking at the frequency of the tumors per centimeter of the small bowel, we observed an incidence, at the level of the duodenum, 14.55 times higher for adenocarcinomas and 1.818 higher for GIST.

An analysis of 1,060 patients from Connecticut Tumor Registry showed that the most common location was the ileum (29.7%), followed by duodenum (25.4%) and jejunum (15.3%). In 27.8% of cases the tumor location was not specified.(⁵5. Hatzaras I, Palesty JA, Abir F, Sullivan P, Kozol RA, Dudrick SJ, et al. Small-bowel tumors: epidemiologic and clinical characteristics of 1260 cases from the connecticut tumor registry. Arch Surg. 2007;142(3):229-35.) We have found 17.5% duodenal tumors, 36.8% jejunal tumors and 45.6% ileal tumors.

Jejunal and ileal adenocarcinomas are best managed by wide segmental resection and regional lymphadenectomy. Right hemicolectomy is indicated for distal ileal tumor. Adenocarcinomas of the first and second duodenum should be addressed by PD, while tumors of the third and fourth duodenum through a pancreas sparing duodenal resection.(⁸8. Shenoy S. Primary small-bowel malignancy: update in tumor biology, markers, and management strategies. J Gastrointest Cancer. 2014;45(4):421-30. Review.) For radical resections of the duodenal tumors we preferred PD in 80% of cases, while jejunal and ileal tumors were managed by segmental oncological resection with primary anastomosis in all cases.

Howe et al. reviewed the National Cancer Database, finding 4,995 patients with small bowel adenocarcinoma.(³⁰30. Howe JR, Karnell LH, Menck HR, Scott-Conner C. The American College of Surgeons Commission on Cancer and the American Cancer Society. Adenocarcinoma of the small bowel: review of the National Cancer Data Base, 1985-1995. Cancer. 1999;86(12):2693-706.) The overall 5-year disease specific survival was 30.5%, with a median survival of 19.7 months. Factors significantly correlated with disease specific survival were age, tumor site, disease stage, and whether cancer directed surgery was performed. The disease specific survival is reduced for duodenal adenocarcinoma compared with jejunal or ileal tumors.(³⁰30. Howe JR, Karnell LH, Menck HR, Scott-Conner C. The American College of Surgeons Commission on Cancer and the American Cancer Society. Adenocarcinoma of the small bowel: review of the National Cancer Data Base, 1985-1995. Cancer. 1999;86(12):2693-706.) Sohn et al. investigated factors influencing long-term survival in 55 patients with duodenal adenocarcinomas.(³¹31. Sohn TA, Lillemoe KD, Cameron JL, Pitt HA, Kaufman HS, Hruban RH, et al. Adenocarcinoma of the duodenum: factors influencing long-term survival. J Gastrointest Surg. 1998;2(1):79-87.) From 48 patients with radical resections there were 35 PD and 13 pancreas-sparing duodenectomies. PD was associated with increased postoperative complications (57%versus 30%). The favorable factors for long-term survival were negative resection margins, PD and tumors in the first and second portions of the duodenum.(³¹31. Sohn TA, Lillemoe KD, Cameron JL, Pitt HA, Kaufman HS, Hruban RH, et al. Adenocarcinoma of the duodenum: factors influencing long-term survival. J Gastrointest Surg. 1998;2(1):79-87.) The Cleveland Clinic group found the following negative prognostic factors for survival in adenocarcinoma of the small bowel: positive surgical margins, extramural venous spread, lymph node metastases, poor tumor differentiation, depth of tumor invasion, and history of Crohn’s disease.(³²32. Abrahams NA, Halverson A, Fazio VW, Rybicki LA, Goldblum JR. Adenocarcinoma of the small bowel: a study of 37 cases with emphasis on histologic prognostic factors. Dis Colon Rectum. 2002;45(11):1496-502.) As an adjuvant chemotherapeutic regimen it seems that the combination of capecitabine and oxaliplatin is highly effective for small bowel adenocarcinoma, with a median overall survival favoring chemotherapy for advanced jejunal or ileal tumors of 17 versus 8 months (p=0.114).(³³33. Ogata Y, Yamaguchi K, Sasatomi T, Uchida S, Akagi Y, Shirouzu K. [Treatment and outcome in small bowel cancer]. Gan To Kagaku Ryoho. 2010;37(8):1454-7. Review. Japanese.) Czaykowski and Hui reviewed the 10-year experience of the British Columbia Cancer Agency regarding the chemotherapy effect in small bowel adenocarcinoma.(³⁴34. Czaykowski P, Hui D. Chemotherapy in small bowel adenocarcinoma: 10-year experience of the British Columbia Cancer Agency. Clin Oncol (R Coll Radiol). 2007;19(2):143-9.) The chemotherapy was given to 21 of the 47 patients. Out of 19 patients treated with curative intent, 5 received adjuvant chemotherapy. The median overall survival for those who received palliative chemotherapy was 15.6 monthsversus 7.7 months(³⁴34. Czaykowski P, Hui D. Chemotherapy in small bowel adenocarcinoma: 10-year experience of the British Columbia Cancer Agency. Clin Oncol (R Coll Radiol). 2007;19(2):143-9.) (Chart 2).

Carcinoids are neuroendocrine tumors and upon diagnosis, 29% of cases are at a localized stage, 41% in a loco-regional stage, and 30% of patients present metastates.(⁴²42. Strosberg J. Neuroendocrine tumours of the small intestine. Best Pract Res Clin Gastroenterol. 2012;26(6):755-73. Review.) Of patients with midgut carcinoid tumors 40% have a second gastrointestinal neoplasm, which requires a careful diagnostic evaluation prior to surgery of these tumors.(⁴³43. Moertel CG, Sauer WG, Dockerty MB, Baggenstoss AH. Life history of the carcinoid tumor of the small intestine. Cancer. 1961;14:901-12.) The rate of lymph node and distant metastases is 12 and 5%, respectively, in tumor smaller than 1cm, and 85 and 47%, respectively, for tumor greater than 2cm.(⁸8. Shenoy S. Primary small-bowel malignancy: update in tumor biology, markers, and management strategies. J Gastrointest Cancer. 2014;45(4):421-30. Review.) Surgery represents the main approach for localized disease, with wide excision of the bowel and mesentery. Peritoneal carcinomatosis may be present in up to 30% of patients with small intestine primary neuroendocrine tumors.(⁴⁴44. de Mestier L, Lardière-Deguelte S, Brixi H, O’Toole D, Ruszniewski P, Cadiot G, et al. Updating the surgical management of peritoneal carcinomatosis in patients with neuroendocrine tumors. Neuroendocrinology. 2015;101(2):105-11.) For carefully selected patients presenting neuroendocrine tumors-related peritoneal carcinomatosis, it seems that cytoreductive surgery prolongs survival, especially when peritoneal lesions are completed resected.(⁴⁴44. de Mestier L, Lardière-Deguelte S, Brixi H, O’Toole D, Ruszniewski P, Cadiot G, et al. Updating the surgical management of peritoneal carcinomatosis in patients with neuroendocrine tumors. Neuroendocrinology. 2015;101(2):105-11.)

CONCLUSION

Primary small bowel cancers are usually diagnosed at an advanced stage, and revealed by a local complication of the tumor. Their surgical approach in emergency setting carries specific morbidity and significant mortality, but only a standard radical R0 resection with regional lymph node dissection may provide the patients the best chance for cure.

REFERENCES

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