Small intestine cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2]

In oncology, small intestine cancer, also small bowel cancer and cancer of the small bowel, is a cancer of the small intestine. It is relatively rare compared to other gastrointestinal malignancies such as gastric cancer (stomach cancer) and colorectal cancer. Small intestine cancer can be subdivided into duodenal cancer (the first part of the small intestine) and cancer of the jejunum and ileum (the later two parts of the small intestine). Several different subtypes of small intestine cancer exist. These include:adenocarcinoma,gastrointestinal stromal tumor,lymphomaand carcinoid. Surgery is the most common treatment. Additional options include chemotherapy, radiation therapy or a combination.

Small intestine cancer is a rare presentation and recent increase in its incident compelled the researchers to study it further. The information on historical perspective of small intestine cancer is limited.

Small intestine cancer may be classified according to histology into adenocarcinoma, gastrointestinal stromal tumor, lymphoma, ileal carcinoid tumor, and sarcoma (most commonly leiomyosarcoma and rarely angiosarcoma or liposarcoma).

Adenocarcinoma is the most common sub-type of small intestine cancer. Second most common is carcinoid tumor. Adenocarcinomas may be polypoid, infiltrating or they appear as annular constricting lesions in small intestine. On gross pathology, napkin ring appearance or polypoidal fungatining mass are characteristic findings of small intestine cancer. Carcinoid tumors of the smalls intestine are mostly associated with malignant tumors of the other sites. Gastrointestinal stromal tumors (GISTs) are the most common benign tumors of the gastrointestinal (GI) tract. Small intestinal lymphomas are of low-grade on histology and arise from mucosal-associated lymphoid tissues (MALT).

There are no established causes for small intestine cancer. Cancer may arise in genetically predisposed individuals or they may arise sporadically. Environmental factors may play a role as well; however, there is no study demonstrating established risk factors.

Small intestine cancer must be differentiated from Crohn’s disease, intestinal tuberculosis, ulcerative colitis, large intestine cancer, peptic ulcer disease, and irritable bowel syndrome (IBS).

Males are more commonly affected with small intestine cancer than females. Male to female ratio is approximately 1.4 to 1. Small intestine cancer usually affects individuals of the African-Americans race. Caucasian individuals are less likely to develop small intestine cancer.

Common risk factors in the development of small intestine cancer are Crohn’s disease, celiac disease, radiation exposure, hereditary cancer syndromes, smoking, and alcohol.

There are no known screening protocols for small intestinal cancer detection.

Clinical features and natural history of small intestinal tumors have not been clearly studied, as its a rare condition. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor. Small intestine adenocarcinoma is associated with a 5 year survival rate of 20%.

The diagnosis of a small intestine cancer is often made late as the symptoms are nonspecific (abdominal pain, weight loss, nausea and vomiting, occult GI tract bleeding). Early diagnosis requires a high index of suspicion. Histopathological analysis by tissue sample through biopsy of the lesion is the gold standard.

Symptoms of small intestine cancer include abdominal pain, weight loss, nausea, bloating, loss of appetite, and jaundice.

Generally, the most common signs of small intestinal cancer are emaciation, lethargy, abdominal tenderness, abdominal mass, hepatomegaly, ascites, icterus, enlarged lymph nodes and pallor. Other signs include low-grade fever, discomfort on palpation, rectal bleeding, abdominal mass, and jaundice.

Some patients with small intestine cancer may have elevated concentration of liver enzymes, which is usually suggestive of possible spread to the liver or blockage of the bile duct.

There are no specific ECG findings related to cancer of small intestine.

X-ray images may be taken after barium swallow to see the lesions in small intestine. It may show filling defects, mucosal distortion and barium hold up if tumor of small intestine is present.

Abdominal CT scan may be diagnostic of small intestine cancer. Findings on CT scan suggestive of small intestine cancer include intrinsic mass with a short segment of bowel wall thickening.

MRI and MR enteroscopy are other high definition imaging modalities that localize tumor, its boundaries, dimensions in small intestine. They are very helpful in staging the tumor.

Echocardiography has no role in establishing the diagnoses of small intestine cancer. However, ultrasound may be very useful in early stages of the presentation which may help exclude other causes of abdominal symptoms from cancer of small intestine.

Other diagnostic studies for localizing tumor of small intestine cancer include ultrasound, fluoroscopy and barium follow through x-rays.

Other diagnostic studies for small intestine cancer include enteroscopy, capsule endoscopy and double balloon enteroscopy, which may directly visualize intestinal mucosa and take pictures through cameras. It may directly show tumor in the muscosa of intestinal wall and surrounding area.

Best treatment for cure small intestine cancer is surgical resection with combination of chemotherapy or radiotherapy. If tumor is not curable palliative surgery may be done. Chemotherapy is used to reduce the likelihood of metastasis, shrink tumor size, and slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-adjuvant), or as primary therapy if surgery is not indicated (palliative). Other therapies include radiation and support therapies.

Curative surgery is the primary modality for treating small intestine cancers, in combination with chemotherapy and radiotherapy.

There are no established preventive measures to prohibit developing small intestinal cancers. However, limiting tobacco and alcohol use, moderate healthy diet consumption and treatment of gastroenteritis and other intestinal pathology with increased risk of carcinomatos changes in polyps, may decrease the incidence ofsmall intestinal cancers.

Once a patient is diagnosed with intestinal cancer preventing its recurrence is very important. Life style modification such as limiting tobacco and alcohol use, moderate healthy diet and treatment of gastroenteritis may decrease the recurrence of small intestinal cancers. Scheduled follow-up exams and tests to detect polyps and cancerous lesions in other parts of GIT are important and may detect it recurrence.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2]

Small intestine cancer is a rare presentation and recent increase in its incident compelled the researchers to study it further. The information on historical perspective of small intestine cancer is limited.

• There is no significant data on historical perspective of small intestine cancer, as it is an extremely rare condition.
• The earliest article named “On cancer of the duodenum and small intestine: Being the Presidential address” (delivered to the Medical Society of London), was published in 1914.^[1]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2]

Small intestine cancer may be classified according to histology into adenocarcinoma, gastrointestinal stromal tumor, lymphoma, ileal carcinoid tumor, and sarcoma (most commonly leiomyosarcoma and rarely angiosarcoma or liposarcoma).

Small intestine cancer may be subdivided anatomically into:

• Duodenal cancer (the first part of the small intestine)
• Cancer of the jejunum and ileum (the later two parts of the small intestine)

Small intestine cancer may be classified according to histology into 3 groups, which are further classified into sub-types:^[1]

• Benign tumors of small intestine
• Malignant tumors of small intestine
• Extra-intestinal tumors with intestinal metastasis

Tumors	Types
Benign Tumors	Leiomyoma Lipoma Hamartoma Desmoid tumors
Malignant Tumors	Adenocarcinoma Leiomyosarcoma Carcinoid tumors Neuroendocrine tumors Lymphomas
Extra- Intestinal Tumors	Metastasis to small intestine is mostly through: Contagious spread (uncommon, most common route for spread of melanoma) Peritoneal spread

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2], Parminder Dhingra, M.D. [3]

Adenocarcinoma is the most common sub-type of small intestine cancer. Second most common is carcinoid tumor. Adenocarcinomas may be polypoid, infiltrating or they appear as annular constricting lesions in small intestine. On gross pathology, napkin ring appearance or polypoidal fungatining mass are characteristic findings of small intestine cancer. Carcinoid tumors of the smalls intestine are mostly associated with malignant tumors of the other sites. Gastrointestinal stromal tumors (GISTs) are the most common benign tumors of the gastrointestinal (GI) tract. Small intestinal lymphomas are of low-grade on histology and arise from mucosal-associated lymphoid tissues (MALT).

• Small intestinal cancers is a rare condition and information on its pathophysiologic mechanisms is limited.
• Studies are being conducted to evaluate the association of small intestinal cancers with environmental risk factors.^[1]
• Pathophysiology of small intestinal cancers depends on the histological subtype.
• Duodenal tumors are more common than the tumors of jejunum and illeum.^[2]
• Adenomas arises commonly in the proximal small intestine (duodenum) whereas lymphomas arises more distally (jejunum and ileum).^[3]

• Low susceptibility of the small intestine to malignant changes may be explained as follows:
  • Short exposure of the mucosa to carcinogens due to rapid transit of contents
  • Liquid nature of the contents and less mucosal irritation
  • Low bacterial load
  • High concentration of lymphoid tissue

• Adenocarcinoma are most common neoplasm of small bowel.
• Males are more predisposed to risk of having adenocarcinoma of small intestine.^[4]
• Adenocarcinoma of small intestine is more common in patients with colorectal cancer, suggesting a common pathogenetic mechanism.
• Adenocarcinoma may develop from malignant changes in the polyps of small intestine.^[5][6]
• Long standing Crohn’s disease is known as a risk factor of small intestine cancer.^[7]
• Certain hereditary conditions with intestinal polyps such as adenomatous polyposis coli (ACP) predisposes to adenocarcinoma of small intestine.
• Adenocarcinoma are more common in duodenum.
• Development of adenocarcinoma in duodenum may be explained by vigorous exposure of that part of intestine to different carcinogens, which gets diluted in the latter part of intestine.^[8]

• Carcinoid tumors are the second most common cancer of the small intestine. It is a slow growing tumor of small intestine arising as a subset of neuroendocrine cells.
• Carcinoid tumors of the smalls intestine are mostly associated with malignant tumors of the other sites.^[9]
• Small Intestinal neuroendocrine tumors (SI-NETs) are the most common gastrointestinal neuroendocrine tumors.^[10]
• The oncofetal protein IMP3 is a marker that plays a role in the growth of neuroendocrine cells.^[11]

• Small intestinal lymphomas are of low-grade on histology and arise from mucosa-associated lymphoid tissues (MALT) present in ileum and jejunum.
• Sometimes distinct clinicopathologic entities arise from these mucosal-associated lymphoid tissues (MALT), such as immunoproliferative small intestinal disease, primary intestinal T-cell lymphoma, and multiple lymphomatous polyposis.^[12]
• Lymphoma may be present as a primary tumor of small intestine or may be a part of some systemic disease.
• After stomach, small intestine is the most common extra-nodal site of presentation of non-Hodgkin lymphomas and it represents 4% to 20% of all the non-Hodgkin lymphomas.
• The diagnosis of small intestinal lymphoma can be made using following criteria:^[13][14]
  • Absence of peripheral or mediastinal lymphadenopathy
  • White blood cell count should be normal
  • Predominant involvement of GI tract
  • Liver or spleen should not be involved

• GISTs are the most benign tumors of GIT and rarely have malignant potential.
• They typically develop in older age.
• Small intestinal GIST are second most common stromal tumors (20-25%) of GI tract only after stomach GISTs (60-70%). Colon and rectum GIST (5%) and esophageal GIST (<5%) forms the remaining.
• One of the subset of intestinal stromal cell tumors is the gastrointestinal autonomic nerve tumors (GANTs). Stromal tumors may be differentiated from other tumors of small intestine by their cell specific markers.
• GISTs express following stromal cell markers:^[15]
  • 70% of GISTs are positive for CD34
  • 20–30% are positive for smooth muscle actin (SMA)
  • 10% are positive for S100 protein
  • <5% are positive for desmin

Cancer of small intestine may arise sporadically or they may be associated with genetic diseases.

• Small intestine adenocarcinomas arise from adenomas.
• Adenoma-carcinoma sequence is hypothesized to play the role in development of small intestine adenocarcinoma; however, no studies confirms the theory.^[16]
• Adenocarcinoma is thought to be associated with some genetic diseases such as:
  • Hereditary nonpolyposis colorectal cancer (HNPCC)^[4][17]
  • Gardner’s syndrome^[18]
  • Peutz-Jeghers syndrome^[6]
  • Familial adenomatous polyposis (FAP)^[19]

• Carcinoid tumor of small intestine are part of manifestation of a genetic disorder multiple endocrine neoplasia type 1.

• Lymphomas of small intestine have no established genetic predisposition.

• Stromal tumors of small intestine may be associated with activating mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes.^[20][21]

Some GIT disorders such as inflammatory diseases of GIT may predispose to malignancy. Some of the associations include:^[22]

• Familial adenomatous polyposis coli: adenoma, adenocarcinoma
• Peutz-Jeghers syndrome: hamartomatous polyps
• Chronic intestinal inflammatory disorders (Crohn’s disease): adenocarcinoma
• Celiac sprue: lymphoma
• Von Recklinghausen’s disease: paraganglioma
• Immunoproliferative small intestinal disease: small intestinal lymphoma

• Adenocarcinoma of the smalls intestine originate locally or may be associated with malignant tumors of other sites.
• Rarely, it may develop malignant changes in polyps present in the small intestine.
• Dietary factors, tobacco, and obesity may also play a role in malignant transformation.^{[23][24][25][26][27][28]}

• Carcinoid tumors of small intestine are associated with multiple endocrine neoplasia type I (MEN I).^[29][30]

• Some of the association of non-Hodgkin lymphomas are:^[12]
  • Helicobacter pylori infection^[31]
  • Immunosuppression after solid-organ transplantation
  • Celiac disease^[32]
  • Inflammatory bowel disease
  • Human immunodeficiency virus (HIV)^[33]
  • Organ transplant^[34]

• These tumors are associated with older age and are rare before the age 40 years^[35][36][37]
• They can be sporadic or inherited.

Tumor type	Gross findings	Gross pathology
Adenocarcinoma	Adenocarcinomas may be polypoid, infiltrating, or as annular constricting lesions is small intestine. Polyps and adenomas of small intestine are considered precursor lesions of adenocarcinoma.[38]
Carcinoid Tumors	Most common location for neuroendocrine tumor of the small intestine is ileum.[39][40] They present as polypoid, ulcerating, and infiltrating masses with lymphadenopathy.[41]
Mucosa- associate lymphoid tissue Lymphoma (Non-Hodgkin)	Lymphomas of small intestine present with suspicious growths in submucosa with normal appearing muscosa. Endoscopic evaluation may show multifocal involvement and large biopsies are required for diagnoses.[42][43]
Small intestinal stromal tumors(GISTs)	Most common site for GIST is jejunum followed by ileum.[44][45] Intestinal stromal tumors should be differentiated from leiomyosarcomas and leiomyomas, which are smooth muscle cells tumors. Stromal tumors appear as sub-mucosal growths that may lead to ulceration of mucosa. GISTs often protrude out from small intestine mucosa and displace adjacent organs.[46]

Tumor type	Microscopic Findings	Microscopic pathology
Adenocarcinoma	Primary adenocarcinoma consists of 40% of cases of malignant tumors of small intestine and it is the most common histologic type.[47][48] Adenocarcinoma of the small bowel present as cluster of malignant cells distorting the normal structure of wall of small intestine.
Carcinoid Tumors	These tumors originate from enterochromaffin (EC) cells and secrete serotonin.[49] Carcinoid tumors are positive for synaptophysin or chromogranin, which can be demonstrated by immunohistochemical staining.[47]
Mucosa- associate lymphoid tissue Lymphoma (Non-Hodgkin)	Histologically, non-Hodgkin lymphomas may be low grade or high grade tumor of small intestine. They may be of B-cell or T-cell origin.[50][51] Their cell lineage can be identified using immunohistochemical staining.[52] Gastric lymphomas are divided into two histologic subtypes: Extranodal marginal zone B cell lymphoma of mucosa (MALT) Diffuse large B cell lymphoma
Small intestinal stromal tumors(GISTs)	Histologically, GISTs may resemble leiomyosarcomas, so, should be differentiated from them. The microscopic appearance of gastrointestinal stromal tumors (GISTs) resembles spindle cell or epithelioid. Spindle cell type are eosinophilic cells arranged in the form of whorls or fascicles.[53] Epithelioid GISTs are rounded cells with oval nuclei and vesicular chromatin and appears nested[54] On immunohistochemical staining they are positive for molecular markers CD117 antigen.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2]

There are no established causes for small intestine cancer. Cancer may arise in genetically predisposed individuals or they may arise sporadically. Environmental factors may play a role as well; however, there is no study demonstrating established risk factors.

• There is no established cause for small intestinal cancer.
• However, some genetic syndromes are associated with small intestine cancers.
• Intestinal cancer caused by the genetic syndrome in the presence of a family history, are diagnosed at a younger age.
• Single nucleotide mutations, either on the same chromosome or on different chromosomes are considered to be associated with such cancer-associated genetic syndromes.
• Small intestinal cancers may also be sporadic.^[1]
• According to some studies done in Europe and United States, tobacco, alcohol, and obesity are considered to play a role in the etiology of small intestine cancers.^[2]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2]

Small intestine cancer must be differentiated from Crohn’s disease, intestinal tuberculosis, ulcerative colitis, large intestine cancer, peptic ulcer disease, and irritable bowel syndrome (IBS).

• Crohn’s disease
• Intestinal tuberculosis
• Ulcerative colitis
• Colorectal cancer
• Irritable bowel syndrome (IBS)
• Peptic ulcer disease
• Pancreatic cancer
• Colon cancer
• Intestinal polypoid adenomas
• Intestinal leiomyosarcoma
• Gastric cancer

ABBREVIATIONS:

N/A: Not available, NL: Normal, Hb: Hemoglobin, Abd: Abdominal

Diseases	Clinical manifestations				Para-clinical findings						Gold standard
	Symptoms
					Lab Findings		Imaging			Histopathology
	Bowel Frequency	Blood in stool	Abd pain	Other symptoms	Hb	Tumor marker	Endoscopy	CT scan	Other diagnostic study
Adenocarcinoma of small intestine[1]	↑↓	+	+/-	Tenesmus Diminished caliber of stools Mucus in stools	↓	CEA+	Polyps (villous, tubular, tubulo-villous) Ulcerating polyps cancerous lesions	Luminal narrowing and bowel obstruction Circumferential thickening of the bowel wall Enlarged lymph nodes Pulmonary metastases Peritoneal metastases Hepatic metastases	PET scans: Detailed images and metastasis Barium enema: Cancer or a precancerous polyp Genetic testing: hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP)	Different grades of differentiation of glandular structures Sheets or cords of malignant cells, Cellular atypia, pleomorphism High mitotic rate Necrotic debris in glandular lumina Desmoplastic reaction (sign of invasion)	Biopsy and histopathological analysis
Carcinoids[2][3][4][5][6]	↑	+/-	+	Flushing Wheezing Shortness of breath Palpitations Weight gain Hirsutism Weakness Leg edema	↓	Urinary 5-hydroxyindoleacetic acid (5-HIAA) Chromogranin A (CgA) Other biochemical markers include: Substance P Neurotensin Bradykinin Human chorionic gonadotropin Neuropeptide L Pancreatic polypeptide	Infiltrating, ulcerating or fungating lesions in the wall of colon	Well-defined single or multiple lesions Round or ovoid in shape Variable in size ranges between 2-5 cm	PET scan 11C-5-hydroxytryptophan (11C-5-HTP): Deetects metastasis MRI: Nodular mass originating from the bowel wall or regional uniform bowel wall thickening with moderate intense enhancement on post gadolinium T1-weighted fat-suppressed images Mesenteric metastases presents as nodular masses with mesenteric stranding Liver metastases may show hypointense precontrast T1- and hyperintense T2-weighted images Liver metastases are commonly hypervascular Ki-67 index	Solid or spongy nests of cells accentuated by neatly outlined luminal spaces Peripheral nuclear palisading Granular eosinophilic cytoplasm.	Biopsy and histopathological analysis
Intestinal Lymphoma[7][8]	–	+/-	+	Weight loss	↓	Non-Hodgkin lymphomas: CD-20	Polypoid or ulcerated mass, intramural lesion, aphthous ulcer, stricture, extraluminal mass, or diffuse, multiple polypoid lesions	CT scan: polypoid mass, circumferential-cavitary lesions, focal mucosal nodularity, diffuse ulcerative or nodular lesions, regional lymph node involvement	Biopsy: Diffuse large B-cell lymphoma Extranodal marginal zone lymphoma (MALT) Mantle cell lymphoma Burkitt’s lymphoma Follicular lymphoma Double-contrast enema: Subtle mucosal changes, gross tumor morphology	Diffuse large B-cell lymphoma: Extranodal marginal zone lymphoma (MALT) Mantle cell lymphoma Burkitt’s lymphoma Follicular lymphoma	Biopsy and histopathological analysis
Gastrointestinal Stromal Tumors (GIST) [9][10][11] [12][13][14][15]	↑↓	+/-	–	Mostly asymptomatic Are discovered incidentally Non-specific symptoms Early satiety and bloating	↓/-	KIT protein CD 117 antigen	Subepithelial round masses Smooth margins Normal overlying mucosa may be intact or ulcerated Bulging into gastrointestinal lumen	Small GIST (< 5 cms) are homogeneous with clear boundaries and have an intraluminal pattern of growth. Intermediate GIST (size of 5-10 cms) are heterogeneous with irregular borders and intra or extra-luminal pattern of growth. Large GISTs (>10 cms) are heterogeneous with irregular borders and have local or distant spread Malignant GIST with metastasis: Size greater than 10 cm Calcifications Irregular margins Heterogeneous and lobulated Lymphadenopathy Ulceration Extraluminal and mesenteric fat infiltration	MRI: Hemorrhage, necrosis, surrounding structures and metastasis. Endoscopic ultrasonography: Mucosal ulceration or bleeding Smooth submucosal mass as hypoechoic mass Malignant GIST lesions present with: Heterogeneous mass >4 cm in size Irregular borders Intra and extraluminal growth Multiple cysts within the main lesion	Spindle cell type are eosinophilic cells arranged in the form of whorls or fascicles. Epithelioid GISTs are rounded cells with oval nuclei and vesicular chromatin and appears nested On immunohistochemical staining they are positive for molecular markers CD117 antigen and KIT protein.	Endoscopic ultrasound withBiopsy and histopathological analysis
Peutz-Jeghers syndrome[16] [17][18][19][20]	↑↓	+	+	Mucocutaneous hyperpigmentation (mouth, hands, and feet) Fatigue Weight loss Rectal prolapse	↓	N/A	Multiple polyps mucocutaneous pigmentation	Multiple polyps Intussusception Bowel obstruction	Barium enema: Multiple polyps. MRI: Multiple hamartomatous polyps	Hamartomatous mucosal polyps with central core of branching smooth muscle associated with mucosa Smaller polyps may lack the prominent arborizing smooth muscle	Genetic testing for STK11 Colonoscopy
Juvenile Polyposis Coli [21][22][23][24][25]	↑	+	+	Prolapsing polyp Intussusception Macrocephalus Hypotonia Bowel obstruction Heart or brain abnormalities Cleft palate Polydactyly Abnormalities of the genitalia or urinary tract.	↓	N/A	>5 juvenile polyps in the colon and rectum Multiple juvenile polyps in gastrointestinal tract	Multiple polyps in gastrointestinal tract	Barium study: Multiple polyps in GI tract Stool DNA test: SMAD4 or BMPR1A Diagnose if any of the following positive: More than five juvenile polyps of the colorectum Multiple juvenile polyps throughout the GI tract Any number of juvenile polyps and a family history of juvenile polyposis Heterozygous pathogenic variant in SMAD4 or BMPR1A	Numerous cystic and dilated crypts or glands with inspissated mucin and intraluminal neutrophils Lamina propria edematous with associated lymphocytes, plasma cells, eosinophils and neutrophils Filiform, multilobated forms with increased glandular-to-stroma ratio in nonclassic or atypical polyps Areas of conventional dysplasia	If any of the following positive: More than five juvenile polyps of the colorectum Multiple juvenile polyps throughout the GI tract Any number of juvenile polyps and a family history of juvenile polyposis Heterozygous pathogenic variant in SMAD4 or BMPR1A
Kaposi’s sarcoma[26]	↑	+	+	Melena Hematochezia Abdominal pain N/V	↓	CD34 CD31 D2-40 HHV-8 FHI-1 antibody LANA-1	Localized purpuric lesion	N/A	Electrophoresis: antibodies against Kaposi sarcoma herpes virus (HHV-8) Biopsy: Vascular proliferation, red blood cell and hemosiderin extravasation,lymphocytes and monocytes, neovascular lesion wrapped around a pre-existing space, intracytoplasmic PAS +ve hyaline globules	Vascular proliferation Red blood cell and hemosiderin extravasation Lymphocytes and monocytes Premonitory sign (a neovascular lesion wrapped around a pre-existing space) Intracytoplasmic PAS +ve hyaline globules	Biopsy
Arteriovenous malformation[27]	–	+	–	N/A	↓	N/A	Bright red, flat lesions Rarely, polypoid	N/A	N/A	Aberrant vessels with thickened, hypertrophic walls in the mucosa and the submucosa. Arteries directly connected to veins without capillary beds	Accidental fining
Infectious colitis[28]	↑	+	+	Fever, chills N/V Bloating	–	N/A	Patchy or diffuse erythematous mucosa Edema, hemorrhage, with or without ulcers of mucosa	N/A	Stool cultures in adequate culture media Stool analysis: Leukocytosis	N/A	Stool culture
Hamartoma[29]	↑	+	+	Tenesmus	–	S100 (mucosal Schwann cell hamartoma (MSCH)	Large polypoid mass	Isodense or hypodense solid masses Heterogeneous mass Presence of fat in a well circumscribed nodule Calcification	Biopsy: Proliferation of bland spindle cells in the lamina propria (mucosal schwann cell hamartoma (MSCH))	poorly circumscribed, short fascicles of uniform spindle cells replacing the colonic lamina propria, separating and entrapping the crypts The nuclei are bland and mostly uniform, occasional larger nuclei are found. The cytoplasmic borders are indistinct Involvement of mucosa but never the submucosa	Biopsy
Ulcerative colitis[30][31]	↑	+	+	Diarrhea mixed with blood and mucus Weight loss Urgency Tenesmus	↓	N/A	Continuous lesions Erythema (or redness of the mucosa) and friability of the mucosa Crypts, formation of residual mucosal tissue Pseudopolyps	N/A	N/A	Mucosal and submucosal inflammation Hemorrhage or inflammatory polymorphonuclear cells aggregate in the lamina propria Distorted crypts Crypt abscess	Endoscopy and a mucosal biopsy
Crohn’s disease[30]	↑	+	+	Tenesmus N/V Bowel obstruction Fever	↓	N/A	Discontinuous lesions Strictures Linear ulcerations	N/A	N/A	Transmural pattern of inflammation Mucosal damage Focal infiltration of leukocytes into the epithelium Granulomas	Endoscopy and a mucosal biopsy
Irritable bowel syndrome[32]	↑↓	+	+	Straining during defecation Urgency Sensation of incomplete evacuation Mucus passage Bloating Weight loss	–	N/A	Not recommended	N/A	Diagnosis of exclusion with fulfillment of Rome criteria	N/A	Clinical diagnosis (Rome criteria)
Bowel endometriosis[33]	↓↑	+	+	Dyschezia Tenesmus	↓	N/A	N/A	N/A	Transvaginal ultrasonography: heterogeneous, hypoechoic, spiculated mass Barium enema: Extrinsic mass compressing the bowel, fine crenulation of the mucosa, bowel strictures at the rectosigmoid junction T1-weighted or fat-suppression T1-weighted MRIs: Contrast enhanced mass or hyperintense foci, hemorrhagic foci or hyperintense cavities	N/A	Transvaginal ultrasonography
Intestinal tuberculosis[34] [35][36][37][38][39]	Chronic ↑	+/-	+	Fever Fatigue, Weight loss Anorexia Night sweats Bowel obstruction Abdominal distension Lymph node enlargement	↓	N/A	To get sample for histolopathology and culture Forms on endoscopy: Hypertrophic Ulcerative Endoscopic findings: Ulcers in mucosa Nodules in mucosa Strictures in intestinal wall Pseudopolyps formation Adhesions Fistulas Deformed ileocecal valve	Concentric thickening at the site of lesion with proximal intestinal dilatation asymmetric thickening of the intestinal wall Lymphadenopathy Thickening of the peritoneum Ascites	Small bowel follow-through or barium enema: Mucosal ulcerations Strictures in the intestinal wall Cecal deformations Incompetency of ileocecal valve Ultrasound: Bowel thickening Peritoneal nodules Peritoneal thickening Lymphadenopathy Ascitic fluid analysis: Straw-colored ascites Lymphocytes in ascitic fluid Cell count is 150 to 4000 cells/mcL with leukocyte count of 150 to 4000 cells/mm3 AFB smear ADA level Protein >3.0 g/dL Mycobacterial culture NAAT for M. tuberculosis SAAG <1.1 g/dL Ascitic fluid NAAT Ascitic fluid polymerase chain reaction (PCR)	Submucosal caseation granulomas	Endoscopic biopsy and histopathology analysis
Peptic ulcer disease[40][41] [42][43][44][45]	↑↓	+ Melena	+	Heartburn Asymptomatic Chest discomfort Early satiety Nausea and vomiting Anorexia Bloating Perforation	↓	N/A	Smooth ulcers in mucosa of intestine Ulcers with round edges Flat ulcer base filled with exudate	Shows ulcers (perforated or non-perforated) when done for the investigation of abdominal pain	.Barium swallow (infrequent) H. Pylori testing Hydrogen breath test	Endoscopic biopsy sample may show positive H. Pylori by H&E stain	Endoscopic visualization of ulcer
Pancreatic cancer[46][47][48] [49][50][51][52][53] [54][55][55][56]	Chronic ↑	+	+	Asthenia and depression Jaundice Anorexia Weight loss Nausea and vomiting Steatorrhea Dark urine Back pain Thrombophlebitis	↓	Cancer-associated antigen 19-9 (CA 19-9)	Endoscopic retrograde cholangiopancreatography (ERCP) is used: To collect tissue sample For imaging of biliary tree and pancreatic ducts Obstruction and strictures of common bile duct and pancreatic duct is suggestive of cancer (“double duct” sign)	Mass within the pancreatic parenchyma or duct Atrophy of the parenchyma	Transabdominal US Billiary dilatation Mass in pancreas Hypoechoic hypovascular mass with irregular borders Magnetic resonance cholangiopancreatography(MRCP) : Better than CT to visualize pancreatic and billiary anatomy and hepatic lesions Biopsy: Percutaneous FNA biopsy Transduodenal Endo US-guided FNA biopsy	Pancreatic tumor can show two type of histology depending on the location: Intraductal papillary mucinous neoplasms Papillary lesions Disseminated or segmental dilation of the pancreatic duct Pancreatic ductal adenocarcinoma Duct-like structures Mucin production Cell atypia Dense stromal fibrosis	Biopsy and histological analysis
Gastric cancer [57][58][59][60][61] [62][63][64][65][66] [67][68][69][70]	↓/-	+ Melena	+	Weight loss Early satiety Dysphagia Anorexia Weakness and fatigue	↓	Carcinoembryonic antigen (CEA) Glycoprotein CA 125 Carbohydrate antigen 19-9 (CA 19-9) Alpha-fetoprotein (AFP)	On endoscopy gastric cancer may appear as: Polypoid mass Ulcerating lesion Infiltrating lesion Diffuse thickening	CT is used to stage the disease extent CT can also visulaize primary lesion: Polypoid mass Ulcerating lesion Diffuse thickening (tunica plastica) Infiltrating mass	PET scan: Useful to confirm malignant involvement of CT-detected lymphadenopathy. Directly visualizes the liver surface, the peritoneum, and local lymph nodes for metastasis MRI: Better T staging of stomach cancer (better soft tissue visualization and of individual layers of stomach wall) Ultrasonography	Histologically, there are two major types of gastric cancer: Intestinal type adenocarcinoma Irregular tubular structures Multiple lumens Reduced stroma ntestinal metaplasia cellular pleomorphism Diffuse type adenocarcinoma Discohesive Secrete mucus Pools of mucus/colloid Signet ring cell appearance	Biopsy and histopathological analysis

Small intestine cancer must be differentiated from other causes of abdominal pain and diarrhea.

Diseases		Clinical manifestations												Para-clinical findings										Gold standard	Additional findings
		Symptoms						Physical examination
														Lab Findings			Imaging						Histopathology
		Abdominal pain	Diarrhea	Flushing	Dyspnea	Palpitations	Other symptoms	Wheezing	Telangiectasia	Hypotension	Tachycardia	Systolic murmur of tricuspid regurgitation	Other physical findings	Urinary 5-hydroxyindoleacetic acid (5-HIAA)	Serum Chromogranin A (CgA)	Other markers	Abdominal computed tomography (CT)	Abdominal MRI	Somatostatin receptor scintigraphy [SRS], or Octreoscan	Metaiodobenzylguanidine (MIBG) scintigraphy	Other diagnostic studies	Transthoracic echocardiography
Carcinoid Syndrome[71][72][73][74][75][76][77][78][79]	Neuroendocrine tumor of midgut [80][81][6][82]	+ Mild	+ Intermittent Secretory diarrhea	+	+	+	Pellagra Dermatitis Diarrhea Dementia Metastatic tumors in the liver: Right upper quadrant pain, hepatomegaly, and early satiety	+	+/-	+/-	+	+	–	+	+	NT-proBNP Screening of carcinoid heart disease Blood Serotonin levels	Neuroendocrine tumor of midgut are difficult to identify on CT because of their small size. Findings: mass-like process with soft tissue “spokes” radiating into the mesenteric fat toward the small bowel causing retraction. Liver metastases	Sensitive for detection of liver metastases	+ Localization of carcinoid tumor	+	68-Ga DOTATATE PET scan Positron emission tomography-computed tomography (PET-CT) using 18-fluoro-dihydroxyphenylalanine Ki-67 labeling index Endoscopy for metastatic Neuroendocrine tumour with an unknown primary site.	Valve thickening with retraction and reduction in the mobility of the tricuspid valve	Enterochromaffin cells stain with potassium chromate (chromaffin). On electron microscopy ,the cells in tumors are found to contain membrane-bound secretory granules with dense-core granules in the cytoplasm.	Somatostatin receptor scintigraphy [SRS], or Octreoscan Biopsy and histopathology	Mesenteric fibrosis Pathognomonic radiological sign of midgut NET.
	Neuroendocrine tumor of lung[83][84][85][86]	+	+	+	+	+	Cough Hemoptysis Chest pain Fever due to post -obstructuve pneuomnia	+	+/-	+/-	+	+	–	+	+	Immunohistochemical stains: Synaptophysin Neuron-specific enolase NT-proBNP Low serotonin content as compared to midgut tumors.	Atypical neuroendocrine tumors have a greater tendency to metastasize to liver,hypervascular, and becomies isodense relative to the liver parenchyma after contrast administration.		Sensitive for detection of liver metastases if present	+	+	Chest X ray: round or oval opacities from 2-5cm with sharp and notched margins Chest CT : Hilar or Perihilar Masses, Endobronchial Nodules,Related to bronchial Obstruction:peripheral atelectasis and postobstructive pneumonia Pulmonary funcation test Bronchoscopy 68-Ga DOTATATE PET scan Fluorodeoxyglucose PET scans for atypical lung NETs .	–	Typical low-grade:bland cells containing regular round nuclei with finely dispersed chromatin and inconspicuous small nucleoli.Mitotic figures are scarce and necrosis is absent. Intermediate-grade atypical: presence of Neuroendocrine morphology and either necrosis or 2 to 10 mitoses per 10 HPF	Biopsy and histopathology
Irritable Bowel Syndrome[87][88][89][90]		+ Perioidic	Intermittent Chronic history of diarhea alternating with constipation	–	–	–	Fibromyalgia Chronic fatigue syndrome Gastroesophageal reflux disease, Functional dyspepsia Non-cardiac chest pain, Major depression ,Anxiety	–	–	–	–	–		–	–		–	–	–	–	Bristol stool form scale should to record stool consistency Abdominal radiograph to assess for stool accumulation and determine the severity. Age-appropriate colorectal cancer screening in all patients	–	–	Rome IV criteria Recurrent abdominal pain, at least 1day/week in the last 3 months, a/s with 2 or more of the following criteria: •Related to defecation •Associated with a change in stool frequency •Associated with a change in stool form (appearance)
Malignant neoplasms of small intestine[91][92][93]		+/-	+/-	–	–	+/-	Constipation Fatigue Early satiety	–	–	+/-	–	* Abdominal mass Ascites	–	+	Abdominal CT scan may be diagnostic of small intestine cancer. Findings on CT scan suggestive of small intestine cancer include intrinsic mass with a short segment of bowel wall thickening	MRI and MRI enteroscopy are other advance modalities to diagnose and stage small intestinal cancers	–	–	Enteroscopy, capsule endoscopy and double balloon enteroscopy		Adenocarcinomas may be polypoid, infiltrating, or as annular constricting lesions is small intestine. Polyps and adenomas of small intestine are considered precursor lesions of adenocarcinoma. Lymphomas of small intestine present with suspicious growths in submucosa with normal appearing muscosa. Endoscopic evaluation may show multifocal involvement and large biopsies are required for diagnoses	Biopsy and histopathology
Crohn disease[94][95][96][97]		Right lower quadrant pain	+/-	–	–	–	Gross bloody diarrhea +/- Weight loss Fatigue	–	–	–	–	–	Weight loss Pallor Oral lesions Odynophagia Dysphagia Perianal skin tags Sinus tracts Gallstones Extraintestinal manifestations Arthritis Uveitis, Iritis, and Episcleritis Erythema nodosum and Pyoderma gangrenosum Primary sclerosing cholangitis Secondary amyloidosis Thromboembolism Renal stones Osteoporosis Vitamin B12 deficiency	–	–	CRP may be high p-ANCA and ASCA	CT enterography Small bowel inflammation by displaying mural hyperenhancement and thickening; engorged vasa recta; and perienteric inflammatory changes.		–	–	CBC Blood chemistry including electrolytes Renal function tests liver enzymes Blood glucose ESR CRP Serum iron Vitamin D & vitamin B12 levels Stool D/R and culture for ova and parasites, C. difficile toxin	–	Focal ulcerations and acute and chronic inflammation Granulomas	Colonoscopy:focal ulcerations adjacent to areas of normal appearing mucosa along with polypoid mucosal,skip lesions,pseudopolyps,
Benign cutaneous flushing[98]		–	–	+	–	–		–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–
Systemic mastocytosis[99][100][101][102][103]		+	+	+	+	–	Maculopapular rash Pruritus	+/-	+/-	+	–	–	Diffuse musculoskeletal pain Neuropsychiatric symptoms	–	–	Activating mutations of KIT Serum Tryptase levels			–	–
Asthma exacerbation[104][105][106][107]		–	–	–	+	+		+	–	–	+	–	Tachypnea Prolonged expiratory phase of respiration (decreased I:E ratio) Seated position with use of extended arms to support the upper chest (tripod position) +/- Pulsus paradoxus	–	–	–	—	–	–	–	Chest X ray	–	Loss of the normal pseudostratified structure of airway epithelium Increase in the proportion of goblet cells Fibrotic thickening of the sub-epithelial reticular basement membrane Increased numbers of myofibroblasts Increased vascularity Increased airway smooth muscle mass Increased extracellular matrix
Anaphylaxis[108][109][110][111][112]		+	-/+	+	+	+	Vomiting Generalized hives, Pruritus Itching	+/-	–	+	+	–	Swollen lips–tongue–uvula Periorbital edema, Conjunctival swelling	–	–	–	–	–	–	–	plasma tryptase Plasma histamine levels Take proper clinical history and medication history specially beta blockers,ACE-inhibitors,opioids Skin testing with allergen extracts enzyme-linked immunosorbent assays (ELISAs) for quantification of allergen-specific IgE levels	–	–		History of exposure to insect stings,food alllergy,rubber latex,food additives,,allergy to medications,physical factors such s excercise and cold
Histaminergic Angioedema[113][114][115][116][117]		+/-	+/-	+	+	+	Generalized pruritus Throat tightness Hoarse voice Difficulty swallowing	+	–	+	+	–	Urticaria Localized swelling of skin	–	–	–	Bowel wall edema Circumferential thickening of the small bowel wall with ascites or incomplete obstruction	–	–	–	CBC with differential, Electrolytes Liver function tests C-reactive protein Erythrocyte sedimentation rate Levels of the complement protein C4 Serum total tryptase Allergen-specific IgE immunoassays	–	–	–	Take proper clinical history of previous similar episodes Medication history Any allergy to insects stings , foods or any ingestion within previous 24 hours
Medullary Thyroid Carcinoma[118][119][120][121]		–	+/-	+/-	+/-	–	Neck pain Hoarseness Cough Difficulty swallowing Difficulty breathing Lethargy Bone pain from metastasis	–	–	–	–	–	Solitary thyroid nodule Cervical lymph node involvement Weight loss	–	–	Basal serum calcitonin concentrations Carcinoembryonic antigen (CEA) concentration Thyroid function tests: normal Germline RET testing Serum calcium Plasma fractionated metanephrines	–	–	–	–	Ultrasonography of the neck For metastasis Chest computed tomography Neck CT Three-phase contrast-enhanced liver CT Axial MRI Bone scintigraphy.	–	Immunohistochemical staining for calcitonin Spindle-shaped and frequently pleomorphic cells without follicle development	Fine-needle aspiration (FNA) biopsy TNM staging American Thyroid Association (ATA) Guidelines for Management and evaluation of Medullary Thyroid Cancer

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2], Parminder Dhingra, M.D. [3]

Males are more commonly affected with small intestine cancer than females. Male to female ratio is approximately 1.4 to 1. Small intestine cancer usually affects individuals of the African-Americans race. Caucasian individuals are less likely to develop small intestine cancer.

• Incidence of small intestine cancer has increased recently, particularly in African-American males and it is unchanged for the females.^[1]
• Age-adjusted number of new cases of small intestine cancer in 2011-2015 was 2.3 per 100,000 individuals per year.^[2]
• According to a study done among in 2014, the age standardized incidence rates for small intestinal cancers were 5.5 and 4.8 per 100,000 person-years for men and women, respectively. For the histologic subtypes, the incidence rates per 100,000 person-years were 2.2 and 1.3 for adenocarcinomas, and 2.6 and 2.9 for carcinoids, for men and women, respectively.^[3]

Incidence of small intestine cancer according to gender
Types of Intestinal cancers	Gender (incidence per 100,000 person years)
	Women	Men
Age standardized Incidence of all types	4.8	5.5
Adenocarcinoma	1.3	2.2
Carcinoid tumor	2.9	2.6

• Small intestinal cancer makes less than two percent of the gastrointestinal tract cancers.^[4]

• According to SEERS, the average annual age-adjusted mortality rate for small intestinal cancer in African-American is more than in White population (0.7 vs. 0.5 per 100,000 in males, respectively; 0.5 vs. 0.3 in females, respectively).^[2]
• Small intestine cancer contributed to 0.2% of all cancer deaths in 2018.

Age-adjusted mortality rate from small intestine cancer according to race
Race	Gender (incidence per 100,000 person years)
	Women	Men
African-American	0.7	0.5
White	0.5	0.3

• Age adjusted incidence rates were 1.2 per 100,000 individuals for men and 0.8 per 100,000 individuals for women, as shown by a study done in 2006.^[5]

• Small intestine cancer is more common in males, with male-to-female ratio of 1.4:1.^[6]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2], Parminder Dhingra, M.D. [3]

Common risk factors in the development of small intestine cancer are Crohn’s disease, celiac disease, radiation exposure, hereditary cancer syndromes, smoking, and alcohol.

• There are no established risk factors of small intestinal cancers.
• However, there are some associations and most common association is Crohn’s disease.
• Other associated factors are described below.

• Crohn disease is considered to be the most important risk factor of small intestinal cancers.^[1]

• Other associated risk factors are:^[2][3]
  • Familial Adenomatous Polyposis (FAP)
  • Lynch syndrome
  • Acquired immunodeficiency syndrome (AIDS)
  • Celiac disease
  • Peutz-Jeghers Syndrome
  • Hereditary nonpolyposis colorectal neoplasms
  • Radiation exposure
  • Hereditary cancer syndromes
    • Familial adenomatous polyposis
    • Hereditary nonpolyposis colorectal cancer
    • Peutz-Jeghers syndrome
    • MUTYH-associated polyposis
  • Smoking and alcohol use increases the risk of small intestine cancer
  • Colon cancer: Survivors of colon cancer have an increased risk of getting cancer of the small intestine

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2]

There are no known screening protocols for small intestinal cancer detection.

• There is insufficient evidence to recommend routine screening for small intestinal cancers as rarity of condition makes it a less suspected condition.^[1]
• If a person is predisposed genetically to develop small intestine adenocarcinoma, tests such as endoscopy may be done for early detection.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2], Parminder Dhingra, M.D. [3]

Clinical features and natural history of small intestinal tumors have not been clearly studied, as its a rare condition. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor. Small intestine adenocarcinoma is associated with a 5 year survival rate of 20%.

• Clinical features and natural history of small intestinal tumors have not been clearly studied, as its a rare condition.^[1]
• Although, primary adenocarcinoma is the most common type of small intestine cancer, there is no known pattern of its natural history.^[2]
• Natural history of carcinoid tumors depends on several factors:^[3]
  • Size
  • Site of origin
  • Growth pattern
  • Hormone dependence
  • Neuropeptides and amines expressed by a carcinoid
  • Amount of biologically active neuro-hormones secreted

• Small intestine cancer are diagnosed in advance stage due to absence of specific symptoms and suspicion.
• Most complications appear after the resection of the tumor post-operatively.^[4]
• When tumor grow larger to obstruct the lumen of intestine symptoms of constipation and obstruction appear.
• Tumor may invade vessels of intestine and may lead to melena and hemorrhage.

• The overall 5-year survival rate for resectable adenocarcinoma is only 20%. The 5-year survival rate for resectable leiomyosarcoma, the most common primary sarcoma of the small intestine, is approximately 50%.
• The prognosis of small intestine cancer depends on the following:
  • Whether or not the tumor can be removed by surgery.
  • The stage of the cancer, the size of the tumor, whether the cancer has spread outside the small intestine.
  • The patient’s general health.
  • Whether the cancer has just been diagnosed or has recurred.
• Adenocarcinoma of the duodenum is associated with low overall survival rate compared to the tumors located in jejunum and ileum.^[5]

Template:WH Template:WS