Appendix cancer differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Overview

Appendix cancer must be differentiated from benign appendix lesions (mucocele, acute appendicitis), colorectal cancers, adenexal masses (ovarian tumors), and carcinoid tumors of the other organs.

Differentiating appendix cancer from other Diseases

• Appendix cancer must be differentiated from benign appendix lesions (mucocele, acute appendicitis), colorectal cancers, adenexal masses (ovarian tumors), and carcinoid tumors of the other organs.
• As appendix cancer manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype.

• Carcinoid tumors must be differentiated from other diseases that cause carcinoid syndrome sign and symptoms such as palpitation, facial flushing, and diarrhea.
• In contrast, adenocarcinomas and cystadenocarcinomas must be differentiated from other diseases that cause acute appendicitis or present with pseudomyxoma peritonei, such as colorectal cancers and appendix mucoceles.

Diseases		Clinical manifestations							Para-clinical findings
		Symptoms				Physical examination
									Lab Findings		Imaging				Histo- pathology
		Abdo- minal pain	Change in girdle size	Bowel freq- uency	Other symptoms	Abdo- minal mass	Abdo- minal tender- ness	Other physical exami- nation findings	5-HIAA and/or CgA	Other lab findings	CT scan	MRI	Utra- sounography	Other diagnostic studies and imaging modalities
Appendix cancer	Adeno- carcinoma1	+/-	-/+	<math>\downarrow</math>	Generally asympto- matic Appendicitis symptoms Nausea & vomiting, decreased appetite No gas or stool pass (intestinal obstruction) Bone pain (bone metastasis) Bloating (ascites)	-	-	Ascites Shifting dullness	-	CEA CA 19-9	Soft tissue thickening Wall irregularity Presence of pseudo- myxoma peritonei Calcification Internal septations Peri appendiceal fat stranding and intra- peritoneal free fluid which is a nonspecific finding Cystic lesion	Diffusion weighted MRI has been shown to be the modality of choice for peritoneal carcino- matosis Increased fluid signal on T2 weighted sequence Soft tissue mass in the appendix Invasion to the other structures	Dilated appendix Peri- appendiceal fluid collection Distinct appendix wall layers	Positron emission tomography (PET)	Gross pathology: Gray/yellow color Cystic structures with angiolymphatic invasion Appendix might be buried within the mass Microscopic pathology: Intestinal, mucinous or signet ring cell types Coexisting acute appendicitis is common IHC: MUC 2 MUC5AC CK 8/18 CK 13 CK 19 CK 20
	Carcinoid tumor2	+/-	-	<math>\uparrow</math>	Generally asympto- matic Flushing Palpitation Dyspnea	-	-	TR murmur Wheezing	+	Ki67: a reliable marker of cell proliferation				Somatostatin scintigraphy with 111-indium- octreotide Bone scintigraphy with 99mTc- methylene diphosphonate (99mTcMDP) Positron emission tomography (PET)	Gross pathology: Prevalent at the tip of appendix Generally less than 1 cm Gray or yellow Well- demarcated firm Intramural nodules that may narrow or obliterate appendiceal lumen Proximal tumors may cause obstruction and appendicitis Microscopic pathology: Insular growth pattern of solid islands of uniform polygonal cells with minimal pleomorphism Retraction of peripheral tumor cells from stroma Angio- lymphatic invasion is common Granular eosinophilic cytoplasm with either diffusely scattered or peripherally clumped granules Two types of well differentiated tumors: EC cell (serotonin producing) and rarely L-cell (enteroglucagon or peptide YY producing) IHC: Might be positive for S100
	Goblet cell carcinoid	+	+/-	<math>\uparrow</math>	Generally asympto- matic 60% present with acute appendicitis symptoms Nausea & vomiting decreased appetite (anorexia)	+/-	+	Ascites Shifting dullness May appear anemic	+/-	CK 20 CK 7 Synap- thosin pancreatic polypeptide CEA CA 19-9 CA -125	Unfortunately, compared to the other carcinoid tumors of appendix, GCC is more aggressive and patients with GCC generally present at higher stages. Hence, in addition to the above mentioned general findings for appendix cancers, imaging studies should look for evidences of peritoneal involvement, bone metastasis, lymphadenopathy, and metastatic lesions in ovaries and/or prostate.				Gross pathology: No gross tumor might be present Thickened appendiceal wall Microscopic appearance: GCC Generally spares mucosa and infiltrates muscularis propria and peri- appendiceal fat Tumor cell clusters Crypt-like structures Tubules of mucus-secreting cells distended with mucin resembling goblet cells Eosinophilic cytoplasm resembling carcinoid tumors Pools of extracellular mucin Scattered Paneth cells in tumors with crypt like structures Extensive perineural invasion Carcinomatous growth pattern: Cribriform growth pattern, solid sheets of infiltrating signet ring cells Nuclear pleomorphism Increased mitotic activity
Diseases		Abdo- minal pain	Change in girdle size	Bowel freq- uency	Other symptoms	Abdo- minal mass	Abdo- minal tender- ness	Other physical exami- nation findings	5-HIAA and/or CgA	Other lab findings	CT scan	MRI	Utra- sounography	Other diagnostic studies and imaging modalities	Histo- pathology
Appendix Mucocele	Mucosal hyperlasia	-	-	-	Generally asympto- matic Benign even after rupture	-	+/-	N/A	-	N/A	low attenuation well defined mass in RLQ near cecum Inflammation is the key to distinguish between appendicitis and mucocele Wall thickness does not distinguish between malignant and benign mucocele Intramural nodule is a sign of neoplastic lesions. 4	Rounded right iliac fossa mass T1: The signal depends on the mucin concen- tration, may be from hypointense to isointense T2: Hyperintense	Histo- logically benign Dilated fluid filled appendix in the RLQ. Thin appendiceal wall A focus of hyper- echogenicity Since generally there is no inflammation Surrounding fat is normal. No peri- appendiceal fluid or collection	N/A	Similar to hyperplastic colon polyp
	Simple or retention cyst	-	-	-		-	+/-	-	-	N/A					Degenerative epithelial changes because of obstruction
	Mucinous cyst= adenomas	+/-	+/-	<math>\uparrow</math><math>\downarrow</math>	Generally asympto- matic Rupture may lead to Pseudo- myxoma peritonei	+/-	+/-	If develop pseudo- myxoma peritonei: Ascites Shifting dullness	-	CEA CA 19-9					Histo- logically benign Similar to colon adenomatous polyps or villous adnomas
	Mucinous cystadeno- carcinomas	+/-	+/-	<math>\uparrow</math><math>\downarrow</math>	+/-	+/-	-		-	CEA CA 19-9					Glandular invasion into the stoma Pseudo- myxoma peritonei
Diseases		Abdo- minal pain	Change in girdle size	Bowel freq- uency	Other symptoms	Abdo- minal mass	Abdo- minal tender- ness	Other physical exami- nation findings	5-HIAA and/or CgA	Other lab findings	CT scan	MRI	Utra- sounography	Other diagnostic studies and imaging modalities	Histo- pathology
Ovarian cancer		+/-	+/-	+/-<math>\downarrow</math>	Pelvic/ abdominal pain or pressure Vaginal bleeding/ discharge Dyspnea GI disturbance	+	+/-	Ascites Shifting dullness Fever Pleural effusion	-	Depends on the underlying etiology Iron HCG LDH Calcium Estrogen Progestron Testos- terone AFP CA-125 Ki 67	Adnexal mass Adenexal Cyst (simple or complex) Fluid accumulation Endometrial thickening Calcification Pleural effusion Peritoneal involvement Lympha-denopathy	Adnexal mass Adenexal cyst (simple or complex) Except for Thecoma, ovarian masses are generally hyperintense on T1 and hypo or sointense on T2 imaging Fluid accumulation Endometrial thickening Calcification Pleural effusion Peritoneal involvement Lympha- denopathy	Adnexal mass Adenexal cyst (simple or complex) Fluid accumulation Increased Doppler flow Endometrial thickening Calcification	N/A	Depends on the tumor type. You may find the details here.
Colorectal cancer		+/-	+/-	<math>\uparrow</math><math>\downarrow</math>	Weight loss Fatigue Low caliber of stools Nausea and vomiting Mucus in stools Rectal prolapse in Carcinoids: Weight loss Weakness Flushing Wheezing Shortness of breath Palpitations Leg edema	+	+/-	Colonoscopy Adeno- carcinoma Polyps (villous, tubular, tubulo- villous) Ulcerating polyps Cancerous lesions Carcinoids Infiltrating, ulcerating or fungating lesions in the wall of colon	-/+(Carcinoid tumors)	Anemia Positive fecal occult blood test High levels of CEA and CA 19-9	luminal narrowing Intestinal wall thickening, Intus- susception, Bowel obstruction, Hepatic metastases, Intestinal perforation, Enlarged lymph nodes	Tumor mass and the extension of tumor to other structures liver, lung and brain Metastasis	Generally not recommended: may evaluate liver metastasis or presence of fluid in abdominal cavity, but it is neither sensitive nor specific.	PET scan, Endoscopy, Colonoscopy, Barium enema	Depends on the tumor type. You will find more information here
Pseudomyxoma peritonei		+	+	<math>\uparrow</math><math>\downarrow</math>	Bloating	-	+	Ascites Shifting dullness	-	Nonspecific Depends on the etiology of the disease	Low- attenuation Scalloping of the visceral surfaces differentiates pseudo- myxoma from other causes of peritonitis. Typically does not invade visceral organs or spread by lymphatic or hemato- genous routes unlike mucinous carcino- matosis	Charact- erized by a mass which is hypointense on T1-weighted MRI and hyperintense on T2-weighted MRI. MRI has better sensitivity in detecting ascites fluid and mucocele.	The echoes within pseudo- myxoma peritonei are not mobile. Echogenic septations within the gelatinous ascites. Scalloping of the hepatic and splenic margins	18F-FDG PET scan	Depending on WHO classification, whether it is low or high grade with cellular atypia or acellular mucin. ( DPAM, PMCA) Gelatinous ascites in peritoneum and visceral organs, usually underneath the right hemidiaphragm, liver. Omental cake IHC: CK 20 CDX2 MUC2 MUC5AC
Carcinoid syndrome		-/+	-	<math>\uparrow</math>	Flushing Palpitation Dyspnea	-	-	TR murmur Wheezing	+	Depends on the tumor type: Ki67 N-terminal pro–B- type natriuretic peptide Substance P Neurotensin Bradykinin Human chorionic gonadotropin Neuro- peptide L Pancreatic polypeptide	Depends on the primary tumor location and type			Somatostatin scintigraphy with 111-indium- octreotide Bone scintigraphy with 99mTc- methylene diphosphonate (99mTcMDP) Positron emission tomography (PET) 123I-MIBG scintigraphy Capsule endoscopy (CE) Enteroscopy Angiography MR Angiography Endoscopic ultrasonography (EUS)	Salt and pepper nuclei Cellular uniformity Central ovoid nucleus Presence of ribbons, trabeculae, nesting, glands, gyriform, pseudorosettes Insulinoma (Amyloid deposition) Somatostatinom (Psammoma bodies) Hyaline globules IHC: Synaptophysin (almost always, strongly and diffusely expressed ) CGA CD56 and PGP ( less specific) PDX1 ISL1
Appendicitis 3		PU, RLQ	-	<math>\uparrow</math><math>\downarrow</math>	Nausea & vomiting, decreased appetite	+/-	+	Rebound tenderness Abdominal guarding Rovsing's sign Psoas sign Obturator sign TR exam might reveal tenderness in the rectovesical pouch Tachypnea Tachycardia Hypotension Diaphoresis Pallor	-	Leukocytosis Left shift	Appendiceal wall thickening /perforation Peri- appendiceal inflammation, fluid accumulation, Fat stranding	Increased fluid signal on T2 weighted sequence	Evidences of inflammation Dilated appendix Peri- appendiceal fluid collection Distinct appendix wall layers	Tc-99m labeled anti- CD15 antibodies	Evidences of inflammation
Diseases		Abdo- minal pain	Change in girdle size	Bowel frequ- f ency	Other symptoms	Abdo- minal mass	Abdo- minal tender- ness	Other physical exami- nation findings	5-HIAA and/or CgA	Other lab findings	CT scan	MRI	Utra- sounography	Other diagnostic studies and imaging modalities	Histo- pathology

¹ Adenocarcinomas usually present with appendicitis, barely they might present with Pseudomyxoma peritonei; meanwhile Pseudomyxoma peritonei is more prevalent in perforated mucocele, goblet cell tumor or high stages of adenocarcinoma.

² Generally appendix carcinoids are asymptomatic, they were only become symptomatic if they metastasize to the liver, or in rare cases make an obstruction and present with appendicitis which is quit uncommon in appendiceal carcinoids compared to appendiceal adenocarcinoma. Any patient with carcinoid syndrome should be evaluated for appendix carcinoids.

³ Every patient with appendicitis should be evaluated for appendix cancer, 0.5 in 100 appendicitis cases are because of appendix cancer.

⁴ Imaging is not a reliable method to distinguish between neoplastic and nonneoplastic lesions, hence every patient should undergo surgery, appendectomy and histopathologic evaluation of the lesion

*Abbreviations: RLQ: Right Lower Quadrant, AFP: Alpha Fetoprotein, HCG: Human chorionic gonadotropin, LDH: Lactate Dehydrogenase, CEA: Carcinoembryonic antigen, CA 125: Cancer antigen 125, 5-HIAA: Urinary 5-hydroxyindoleacetic acid , CgA: Serum Chromogranin A ,PU: Periumbelical, TR: Tricuspid regurgitation