Management Conference

A WOMAN WITH

EPIGASTRIC PAIN,

VOMITING

Raika Jamali M.D.Gastroenterologist and hepatologist

Tehran University of Medical Sciences

• A 62 year old woman with epigastric pain, post prandial vomiting and weight loss from 2 months ago.

• The epigastric pain is constant with episodes of colicky pain after meals followed by vomiting.

• No radiation and no response to PPI is reported for epigastric pain.

• Weight loss is about 8 Kg in the past 2 months.

• There was a history of cholecystectomy and choledochodeudenostomy due to cholecystitis and cholelithiasis In 83.12.27.

• The patient had epigastric pain from one year before surgery which was aggravated in the past 2 months before admission in 83.12.27.

• Epigastric pain aggravated by eating but no vomiting was reported.

• The patient had an episode of acute abdominal pain in 84.2.30 that lead to laparotomy for evaluation of acute abdomen.

• The surgical report was: Serosanginous fluid in abdomen & pelvic.

Adhesions from previous surgery and edematous pancreas but no mass was seen in the pancreas.

• The patient discharged with the diagnosis of pancreatitis.

• The epigastric pain persisted and did not respond to PPI so endoscopy performed :

• GERD grade A + Hiatal hernia + pan gastritis + mild duodenitis

• PPI continued

• There was an episode of colicky abdominal pain which resulted in third laparotomy for evaluation of acute abdomen (85.2.29).

• The surgical diagnosis was pancreatitis.

• After 3 laparatomies the patient referred to gastroentrologist for evaluation of persistent epigastric pain, vomiting and weight loss in 85.6.25.

• OB = negative

• AST=26

• ALT=36

• ALP=612*

• UGI endoscopy: Duodenitis

• Colonoscopy: normal

• Sonography: Multiple hypoechoic lesions in liver. Enlargment of pacreatic head.

CT scan recommended.

What is the next diagnostic step ?

Small intestine follow through for evaluation of partial obstructoin and GI blood loss?

Endoscopy was performed

                                                                                                                                                                                     

Endoscopy Report:

Esophagus:Crico-pharyngeus ,  upper third and  middle third were normal. Medium-sized Hiatal hernia was found. There was a  esophagitis in  lower third. ____________________________Stomach:Fundus,  body,  incisura,  antrum and  pre-pyloric area were normal. ____________________________Duodenum:Bulb was normal. There was choledocoduodenostomy. Also there was a mass lesion  at begining of D3 with partial obstruction . The scope was not passed through the mass. ____________________________

The pathology report was:

Poorly differentiated adenocarcinoma

Prevalence of small bowel tumor

• 1.1 - 2.4 % of GI malignancies• Approximately 2/3 small intestine

tumors are malignant.• Adenocarcinoma is the most common

small bowel malignancy with incidence of 3.9 cases per year.

• Mean age at the time of diagnosis is between 50-60 years.

Distribution

• Deudenum(55%)

• Jejunum (18%)

• Ileum (13%)

• Not specified in terms of location (14%)

Histology:

• Adenocarcinoma from mucosal glands(35-50%)

• Carcinoid from argantaffin cells(20-40%)

• Lymphoma (14%)• Leiomyosarcoma from smooth muscle • Neurofibroma from neurons• Angiosarcoma from endothelial cells• GIST from mesenchymal cells

Adenocarcinomahistologic classification

• Approximately 50% of tumours will be moderately differentiated while

• 15% will be well differentiated,

• 33.9% will be poorly differentiated and 1.5% will be anaplastic.

Adenocarcinoma• Risk factors: • diets high in protein & animal fat.• Two fold increase in consumers of meat

once a week.• Smoked foods eaten one to three per month

with odds ratio of 1.7:1 .• Bile acids: synergic effect of bile acids and

germ line APC mutation to foster the high predilection of duodenal polyps and adenocarcinoma in FAP.

Clinical Risk Factors

• SBAs are reported to occur more frequently in patients with a history of CD, celiac disease,

• and hereditary gastrointestinal cancers syndrome such as familial adenomatous polyposis (FAP), HNPCC, and Peutz-Jeghers syndrome (PJS).

Pathogenesis and Risk Factors of Small Bowel

Adenocarcinoma: A Colorectal Cancer Sibling?

• Thierry Delaunoit, M.D.

• The American Journal of GastroenterologyVolume 100 Issue 3 Page 703 - March 2005

Why Are Duodenal SBAs more Frequent

• Bile acids seem to promote the development of intestinal cancer in animals studies .

• High fat and low fiber diets are often associated with bile acid excess, as well as increased risk of SBAs .

• • Distribution of proximal SI neoplasms in patients

with FAP is also suggestive of a role played by bile acids in adenoma and adenocarcinoma development, since patients with FAP have been shown to have relatively higher total and unconjugated bile acids concentrations compared to the general population .

• The capability of bile acids to produce DNA adducts in FAP patients seems pH dependent.

• Scates and colleagues studied the role of an acid environment on the development of DNA adducts in patients with FAP and compared those results to a control group.

• Bile acid from FAP patients produced higher levels of DNA adducts at pH 4–5 than at pH

6–8.

Clinical features• No specific sign or symptom

• Cramping periumbilical pain, vomiting and distention ( GI obstruction)

• Constant pain, ( back pain suggest spread to retroperitoneum, bleeding into the tumor, invasion of ganglia, ischemia and serosal involvement )

• GI bleeding is the second most frequent sign ( massive GIB with sarcoma)

• Weight loss

• Intestinal perforation ( frequent with lymphoma and sarcoma)

• Jaundice and pancreatitis ( periampulary tumor)

• Cachexia, ascites, hepatomegaly

Diagnosis • UGI Endoscopy• Small bowel follow through• Enteroclysis ( small bowel enema): with

greater accuracy• Ct scan: for detecting extramural disease• Small bowel enteroscopy: in cases with GIB• Intra operative enteroscopy• Video capsule enteroscopy: in cases with

GIB

Barium studies• The most sensitive investigation for

assessing mucosal and intraluminal abnormalities beyond the ligament of Treitz is a barium contrast study .

• Enteroclysis has been suggested as a more useful investigation than a follow-through examination for diagnosing jejunal and ileal neoplasms. It is a relatively simple and rapid (< 1 h) investigation .

CT scan• Extra-mucosal spread, lymphadenopathy and

distant metastases can all be detected .• Neoplastic disease is suspected when small

bowel thickness exceeds 1.5 cm (normal: 4 mm).

• The accuracy of CT in detecting small bowel tumours is approximately 47%.

• There is a high sensitivity but low specificity for the detection of lymphadenopathy.

Push enteroscopy• Push enteroscopy as an alternative is not

practical in most cases. It takes up to 8 h to perform, may not visualize the entire small bowel and up to 50–70% of the mucosa of the bowel examined is not seen properly.

MRI

• Magnetic resonance (MR) enteroclysis is a single investigation with no irradiation of the patient.

• It separately enhances the small bowel wall and lumen as well as giving images of the mesentery, surrounding structures and rest of the abdominal cavity.

Zhan J, et al. Gastrointestinal Division of Internal Medicine, Second Hospital, Sun Yat-Sen University,

Guangzhou 510120, Guangdong Province, China. World J Gastroenterol. 2004 Sep 1;10(17):2585-7.

Clinical analysis of primary small intestinal disease: A report of

309 cases

The major clinical symptoms included • abdominal pain (71%), • abdominal mass (14%), • vomiting (10%),• melena (10%), • and fever (9%).

• Duodenum was the most common part involved in small intestine.

• Double-contrast enteroclysis was still the simplest and the most available examination method in diagnosis of primary small intestinal disease.

What is the best management ?

• Chemotherapy

• Palliative surgery

• combination

Treatment • In the first or second portion of duodenum

usually are treated by pancreaticoduodenectomy.

• Segmental resection is sufficient for patients with tumors arising from the third and forth portion of duodenum.

• Even with large tumors and positive lymph nodes, surgeons resect the lesion for symptomatic relief.

Adenocarcinoma of the small bowel

• REVIEW ARTICLE, Robert R. Hutchins, Ahmed Bani Hani, Pipin Kojodjojo, Robyn Ho and Steven J. Snooks

• Australian and New Zealand Journal of SurgeryVolume 71 Issue 7 Page 428 - July 2001

TNM Staging system• Tx : Primary tumour not evaluated• T0 : No pathological evidence of tumour• Tis: In situ cancer• T1 : Invades lamina propria or submucosa• T2 : Invades muscularis propria• T3 : Invades < 2 cm beyond serosa

or non-peritonealized perimusculartissue (mesentery or retroperitoneum)

• T4 : Perforates visceral peritoneumor invades adjacent structure > 2 cm

• N0 : No regional nodes

• N1 : Lymph node metastases

• Mx : Metastases not evaluated

• M0 : No metastases

• M1 : Distant metastases

AJCC staging system

• Stage 0 Tis N0 M0

• Stage 1 T1or2 N0 M0

• Stage 2 T3or4 N0 M0

• Stage 3 Any T N1 M0

• Stage 4 AnyT AnyN M1

Frequency of staging

• Stage 0 is seen in 2.7% of patients,

• stage I is seen in 12% of patients,

• stage II is seen in 27% of patients,

• stage III is seen in 26% of patients

• stage IV is seen in 32.3% of patients.

Treatment• The mainstay of treatment of small bowel

cancer is surgical resection.

• This may be curative or palliative and the type of procedure depends on the site of origin and stage of the tumor.

Curative surgery

• Jejunal and ileal tumours are resected en bloc with draining regional lymph nodes in a manner similar to colorectal tumours.

• The margin of tumor, is required to be at least macroscopically and microscopically clear .

Endoscopic resection• Endoscopic resection of early duodenal

cancers and polypoid lesions up to 5 cm has been reported in studies using the submucosal saline infiltration technique.

• Although it is technically possible the long-term results of this therapy remain unknown.

• Whether or not the pancreas-preserving operation is an adequate cancer procedure is still open to debate.

The site and stage of tumour determines which operation is more appropriate.

Curative resection

• Segmental resection of duodenal cancers preserving the pancreas is generally carried out for distal duodenal tumours .

• Sohn et al. (n = 48 cases resected) found a significant improvement in survival for pancreaticoduodenectomy compared with segmental resection (P< 0.005).

• In support of this poorer survival with the pancreas-sparing operation, the Johns Hopkins Institute reported only a 14% disease-free survival in 11 cases treated by this technique.

Palliative surgery

• Locally advanced tumours, or those with distant metastases, may still be resected for palliation and to avoid obstruction.

• Palliation may also include gastric or enteric bypass procedures for unresectable, obstructing lesions or resection to relieve recurrent GI bleeding.

Endoscopic stent placement• Endoscopic, fluoroscopic or combination

endofluoroscopic metal stent insertion can be performed on an outpatient basis.

• Stents may be covered to prevent tumour ingrowth and flared at the ends to discourage migration.

• More than one stent may be placed to overcome an obstruction by placing the distal stent first and overlapping the stents by 1–2 cm.

• Over 90 patients have had duodenal and small bowel stents inserted with an

• 89% rate of improvement in nutrition,

• 3% migration rate,

• 15% tumour ingrowth • and 5% failure rate.

Gastrojejunostomy• Laparoscopic and open gastrojejunostomy

have been compared in single centre studies.

• laparoscopic cases had a significantly shorter hospital stay and less blood loss in the laparoscopic group.

Liver metastatectomy• Two reports of liver resection for

metastases from small bowel cancer exist ,but unlike colorectal tumours where this is now an established treatment with up to 40%, 5 years survival.

• little can be said to recommend this as a treatment for metastatic small bowel cancer.

Chemoradiation• The rarity of small bowel tumours and the

variety of treatments offered contributes to the lack of evidence for benefit from chemoradiotherapy in this disease.

• Only one study has looked at preoperative treatment. Thirty-one cases were offered radiotherapy combined with two cycles of chemotherapy.

• All four cases of duodenal cancer were then resected and the patients are alive at 12, 23, 35 and 90 months.

• Combination treatment (median survival 23.6 months) with surgery appeared to affect survival better than single-modality therapy (median survival: 15.9–17.2 months).

• No recommendations can be made at present on whether or not adjuvant therapy should be offered or whether palliative therapy has an effect on survival. Randomized trials probably including new agents are necessary.

Radiotherapy

• The role of radiotherapy is as yet undefined. Small bowel cancers are thought to be relatively radioresistant .

Prognosis• Resectability

• Resection margin

• Histological grade

• Lymph node involvement

• Tumor limited to submucosa has a 5 year survival rate of 100%

Poorly differentiated adenocarcinoma with signet-ring

cells of the Vater's ampulla, without jaundice but with disseminated

carcinomatosis

• Nabeshima S , Department of General Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan

• Fukuoka Igaku Zasshi. 2003 Jul;94(7):235-40.

• A 49-year-old man was hospitalized because of a 2-month history of purpura in his extremities and for back pain.

• Laboratory findings showed alkaline phosphatase to be greatly elevated, and platelet counts and coagulation factor showed that the patient had disseminated intravascular coagulation (DIC).

• Compression fractures of the thoracic vertebrae were found on radiological examination.

• The histological findings from bone marrow showed metastasis of adenocarcinoma with signet-ring cells, although the primary site was unknown.

• To reduce tumor cells in number and improve DIC, 11 cycles of 5-Fluorouracil and leucovorin therapy were done, and the patient survived for 12 months.

• Autopsy showed a 0.8 cm diameter, poorly differentiated adenocarcinoma with the signet-ring cell type in the lamina propria of the Vater's ampulla. Many metastatic foci and micro tumor emboli were found in the lung and in bone marrow.

• This is a rare case of an ampullary tumor of poorly differentiated adenocarcinoma with the signet-ring cell type, without jaundice but with multiple metastasis.

• 5-Fluorouracil and leucovorin were effective for increasing survival time and improving quality of life.

Idiopathic acute recurrent pancreatitis

• Michael J. Levy

• American Journal of GastroenterologyVolume 96 Issue 9 Page 2540 - September 2001

• In idiopathic acute recurrent pancreatitis, ERCP, endoscopic ultrasound, or magnetic resonance cholangiopancreatography typically leads to a diagnosis of microlithiasis, sphincter of Oddi dysfunction, or pancreas divisum. Less commonly, hereditary pancreatitis, cystic fibrosis, a choledochocele, annular pancreas, pancreatobiliary tumors, or chronic pancreatitis are diagnosed.

Primary adenocarcinoma of the duodenum in the elderly:Clinicopathological and

immunohistochemical study of 17 cases

• Tomio Arai, et al. Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, 2Department of Pathology,

• Pathology International 1999; 49: 23–29

• Primary adenocarcinoma of the duodenum, excluding that of ampulla of Vater, is extremely rare, with an incidence of only 0.35% of all gastrointestinal carcinomas and 33–45% of all small intestinal carcinomas.

• the incidence of duodenal carcinoma detected at autopsy is between 0.019 and 0.5%.

• We reviewed 17 elderly patients (older than 65 years) with primary adenocarcinoma of the duodenum.

• True or doubtful carcinomas of the papilla of Vater and cases of familial adenomatous polyposis (FAP) were excluded from the study.

• Table 1 Summary of clinical and pathological findingsa • Age (yr)/ Follow-

up (Periods and • No. Gender Location Gross feature Size (mm) Histologyd Depthf Metastasis Symptoms or signs

aliveg or cause of death) • 1b 75/F First Polypoid 15 15 � Well M – No symptom 2

weeks, lung cancer • 2b 76/F First Polypoid 38 20 � Well M – Appetite loss 24

months, lung cancer • 3b 81/F First Polypoid 12 7 � Well M – Appetite loss 3 days,

gastrointestinal •

hemorrhage • 4 83/M First Polypoid 17 10 � Well M – Anemia ?,

Gastric cancer • 5c 104/F First Polypoid 47 38 � Well M – No symptom Acute

myocardial •

infarction • 6 76/M First Flat-elevated 55 40 � Well M – No symptom 60

months, alive • 7b 86/F First Vegetated and 30 15 � Well SI Lymph nodes Appetite loss 28

months, duodenal • ulcerative-invasive

cancer • 8b 69/M First Ulcerative-invasive 20 20 � Well SS Liver, lungs,

Virchow metastasis 22 months, duodenal • lymph nodes cancer

• 9 70/F First Ulcerative-invasive 45 30 � Welle SI – Epigastralgia 60 months, alive

• 10 72/F First Ulcerative-invasive 135 60 � Well SS – Appetite loss Unknown

• 11 74/M First Ulcerative-invasive 83 64 � Poorly SI Lymph nodes Dysphagia Unknown

• 12 80/M First Ulcerative-invasive 18 18 � Welle SI – Epigastralgia 24 months, alive

• 13b 84/F First Ulcerative-invasive 50 45 � Well SI Lungs, bone, Epigastric discomfort 4 months, duodenal

• lymph nodes cancer

• 14 71/M Second Polypoid 20 15 � Well SM – No symptom Unknown

• 15b 66/M Second Flat-elevated with 30 25 � Well M – Unknown 34 months, acute

• granular surface myocardial infarction

• 16 74/M Second Flat-elevated 13 8 � Well M – No symptom 23 months, alive

• 17 74/M Third Flat-elevated 23 12 � Well M – No symptom 33 months, alive

Table 3 Ki-67-positive rates of primary

adenocarcinoma of the duodenum

Intramucosal area Invasive area Gross feature • Polypoid 35.6 (30.8) n = 6 27.0 n• Flat-elevated 36.1 (16.2) n = 4 – • Ulcerative invasive 36.1 (28.5) n = 7 32.7 (34.4) n = 5 Distant metastasis • Positive 46.0 (32.0)* n = 4 38.4 (13.7) n = 2

• Negative 31.6 (30.8) n = 12 30.9 (33.1) n = 4

Table 2- Results of immunohistochemistry of p53 in primary

duodenal cancer

Intramucosal cancer Invasive cancer • p53-Positive, diffuse 2 5* • p53-Positive, focal 5 3 • p53-Negative 2 0

• The mean age of the patients in the present study was higher than that of previously reported series.

• The data of the present series indicate that the peak age of patients with duodenal adenocarcinoma is in the eighth decade, while the published consensus places the disease as appearing mostly in the fifth, sixth or seventh decades.

The duodenum is divided into three anatomical segments:

• (i) suprapapillary (from pylorus to the ampulla of Vater)

• (ii) peripapillary (around the ampulla)

• (iii) infrapapillary (below the ampulla to the duodenojejunal flexure).

• the incidence of peripapillary and infrapapillary carcinomas of the duodenum has been reported to vary widely: from 32 to 87% and from 2 to 56%, respectively.

• the data of the present series indicate that suprapapillary carcinomas comprise approximately 80% of duodenal carcinomas.

• A recent study reported that the mean age of patients with duodenal carcinoma of the first or second duodenal portions was higher than that of patients with cancer of the third or fourth portions.

• In the present study, the mean age of patients with suprapapillary adenocarcinoma was 79.3 years versus 71.3 years for patients with cancer in the other portions. Moreover, all carcinomas in patients older than 80 years occurred in the suprapapillary portion.

• we conclude that a proximal shift of the primary duodenal carcinomas may occur in elderly patients.

• There are a few probable causes for a proximal shift in the elderly; for example, a slow flow time of chyme throughout the duodenum, repeated ulceration in the duodenal bulb, and cholelithiasis(?).

• Macroscopically, three types of lesion have been described:

• ulcerative-invasive, polypoid and flat-elevated (or sessile).2,4,12 In the present study, most advanced cancers (88.9%) exhibited an ulcerative-invasive morphology.

• duodenal cancer of the polypoid type can occur as intramucosal neoplasms even though they may be relatively large.

• Close attention should therefore be paid to accurate histological diagnosis, as this type occasionally invades the duodenal wall.

• Polypoid type tumors tend to occupy the duodenal lumen, are often reddish and friable, and bleed easily due to the associated marked vascularization.

• Most flat-elevated type cancers are also intramucosal. However, flat-elevated type tumors may show microinvasion of the lamina propria, as described earlier.

• There have also been a few reports describing depressed type carcinomas of the duodenum as well as in the large intestine.

• Microscopically, well- or moderately differentiated adenocarcinoma are the most common. However, poorly differentiated adenocarcinoma is often observed in the infiltrating area of tumors even though intramucosal areas are well

differentiated.

• The present study described p53 positivity in approximately 40% of duodenal adenocarcinomas, while previous reports have estimated this figure at approximately 20–30%.

• The mutational frequency of the p53 gene in small intestinal carcinomas has been reported as being lower than in colorectal carcinomas.

• a poor prognosis for ulcerative-invasive type carcinomas, whereas polypoid carcinomas were associated with a relatively good prognosis.

• The most important prognostic factors include tumor stage and location.