Colorectal cancer differential diagnosis

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To view the differential diagnosis of familial adenomatous polyposis (FAP), click here
To view the differential diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC), click here

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

Overview

Colorectal cancer must be differentiated from other diseases that cause unexplained weight loss, unexplained loss of appetite, nausea, vomiting, diarrhea, anemia, jaundice, and fatigue, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hemorrhoids, anal fissures, and diverticular disease. There are less common conditions that may be confused as colorectal cancer such as infectious colitis and gastrointestinal lymphoma.

Colorectal Cancer Differential Diagnosis

• Colorectal cancer must be differentiated from other diseases that cause lower abdominal pain and fever like appendicitis, diverticulitis, inflammatory bowel disease, cystitis, and endometritis.

Other conditions that can be mistaken for colorectal cancer include the following:

• Benign colon polyps
• Ischemic colitis
• Infectious colitis
• Arteriovenous malformation (AVM)
• Carcinoid/neuroendocrine tumors
• Small intestine carcinomas
• Gastrointestinal lymphoma
• Ileus
• Pregnancy
• Appendicitis
• Hernia
• Lactose intolerance
• Flatulence
• Ulcer
• Cholecystitis

Diseases	Clinical manifestations				Para-clinical findings					Gold standard
	Symptoms
					Lab Findings	Imaging			Histopathology
	Constipation/ Diarrhea	Blood in stool	Abdominal pain	Other symptoms	Anemia	Colonoscopy	CT scan	Other diagnostic study
Adenocarcinoma	Constipation and/or Diarrhea	+	Diffuse abdominal pain +/-	Tenesmus Diminished caliber of stools Mucus in stools	+	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
Arteriovenous malformation	Normal	+	No pain	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
Diverticular diseases	Constipation and/or Diarrhea	+/-	Pain in RLQ	Fever, chills Nausea/vomiting(N/V)	-	Not recommended	Outpouchings of the colonic wall (Diverticula) Inflamed diverticula Abscess formation Intraperitoneal free air (microperforation)	Barium enema: Circumferential narrowing, spiculated contour and tapered margins	N/A	CT scan
Hemorrhoids	Constipation	+	Localized pain	Perianal Itching Pain with defecation Painful, hard lump in anus	+	Anoscopy: Protruding mass from the anus	N/A	DRE: Palpable mass, tender if thrombosed	N/A	Clinical
Anal fissure	Normal	+	Localized pain	Painful defecation Itching Irritation	+/-	Anoscopy: Anal wall laceration	N/A	N/A	N/A	Clinical
Infectious colitis	Diarrhea	+	Diffuse abdominal	Fever, chills N/V Bloating	-	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
Peutz-Jeghers syndrome	Constipation and/or Diarrhea	+	Abdominal pain	Mucocutaneous hyperpigmentation (mouth, hands, and feet) Fatigue Weight loss Rectal prolapse	+	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
Carcinoids	Diarrhea	+/-	Abdominal pain	Flushing Wheezing Shortness of breath Palpitations Weight gain Hirsutism Weakness Leg edema	+	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
Juvenile Polyposis Coli	Diarrhea	+	Diffuse abdominal pain	Prolapsing polyp Intussusception Macrocephalus Hypotonia Bowel obstruction Heart or brain abnormalities Cleft palate Polydactyly Abnormalities of the genitalia or urinary tract.	+	>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
Gastrointestinal Stromal Tumors (GIST)	Normal	+/-	No pain	Mostly asymptomatic Are discovered incidentally Non-specific symptoms Early satiety and bloating	+/-	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
Hamartoma	Diarrhea	+	Depending on location	Tenesmus	-	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
Colorectal Lymphoma	Normal	+/-	Depending on location	Weight loss	+	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
Kaposi's sarcoma	Diarrhea	+	Diffuse abdominal pain	Melena Hematochezia Abdominal pain N/V	+	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
Ulcerative colitis	Diarrhea	+	Lain in LQ	Diarrhea mixed with blood and mucus Weight loss Urgency Tenesmus	+	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	Diarrhea	+	Lain in RQ	Tenesmus N/V Bowel obstruction Fever	+	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	Constipation and/or diarrhea	+	Diffuse abdominal pain	Straining during defecation Urgency Sensation of incomplete evacuation Mucus passage Bloating Weight loss	-	Not recommended	N/A	Diagnosis of exclusion with fulfilment of Rome criteria	N/A	Clinical diagnosis (Rome criteria)
Appendicitis	Diarrhea	-	Pain in RLQ	Pain starting periumbilical before localizing to the right iliac fossa N/V Fever, chills Loss of appetite	-	N/A	Appendiceal wall thickening (wall ≥ 3mm) Periappendiceal fat stranding Thickening of the lateral conal fascia and mesoappendix Extraluminal fluid Phlegmon Abscess	Tc-99m labeled anti-CD15 antibodies Ultrasound: Aperistaltic, noncompressible, dilated appendix (>6 mm outer diameter) Appendicolith Echogenic prominent pericaecal fat Periappeniceal fluid collection	N/A	CT scan
Strangulated hernia	Constipation	-	Pain in RLQ	N/V Heaviness or dull discomfort in the groin, with straining, lifting, coughing, or exercising Weakness, heaviness, burning, or aching in the groin Pain and swelling Fever	-	N/A	Defect in the abdominal wall muscles Appearance of bowel loops within the lesion Lateral crescent sign The hernia neck will be superolateral to the course of the inferior epigastric vessels.	N/A	N/A	Ultrasound: Hypoechoic mass suggesting dilated and edematous intestinal segment
Bowel endometriosis	Constipation and/or Diarrhea	+	Pelvic pain	Dyschezia Tenesmus	+	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

References

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