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A Rare Cause of Diarrhea and Polyposis
Accepted Manuscript A Rare Cause of Diarrhea and Polyposis N. Jewel Samadder, MD, MSC, John F. Valentine, MD, Kajsa Affolter, MD
PII: DOI: Reference:
S0016-5085(17)36075-4 10.1053/j.gastro.2017.08.042 YGAST 61388
To appear in: Gastroenterology Accepted Date: 11 August 2017 Please cite this article as: Samadder NJ, Valentine JF, Affolter K, A Rare Cause of Diarrhea and Polyposis, Gastroenterology (2017), doi: 10.1053/j.gastro.2017.08.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT A Rare Cause of Diarrhea and Polyposis
N. Jewel Samadder, MD, MSC1,3, John F. Valentine, MD1 and Kajsa Affolter, MD2
Key Words: Cronkhite Canada syndrome, diarrhea, polyposis
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Conflicts of Interest:
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Departments of 1Internal Medicine (Gastroenterology) and 2Pathology, University of Utah, Salt Lake City, UT, USA, 3Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona.
Word Count: 582
References: 3
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NJS is a consultant for Cook Medical Inc. JFV and KA have no conflicts to disclose.
Figures: 8
Guarantor of the article: N. Jewel Samadder, MD, MSc
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Corresponding Author:
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Specific author contributions: All authors approved the final draft submitted. Study concept and design, interpretation, article preparation and manuscript review: NJS, JV, KA.
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N. Jewel Samadder, MD, MSc Division of Gastroenterology and Hepatology Mayo Clinic Scottsdale, Arizona Email: [email protected] Tel: 801-213-4206 Fax: 801-581-7476
ACCEPTED MANUSCRIPT Clinical Case: A 71-year-old diabetic woman presented with newly developed anorexia with noted weight loss of approximately 60 pounds, alopecia (Figure A), atrophy of the fingernails (Figure B) and toenails, increased pigmentation on the palms, and chronic diarrhea. Laboratory tests revealed mild
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leukopenia (WBC 3.2), a mild anemia (10.4 g/dL) and hypoalbuminemia (2.3 g/dL). Stool infectious studies were negative. She underwent an upper and lower endoscopy for investigation of these findings. Her upper endoscopy revealed multiple 5-15mm pedunculated polyps and associated
SC
erythema in the gastric antrum and duodenum. Her colonoscopy revealed over 50 pedunculated polyps throughout the entire large bowel (Figure C) and marked erythema in the cecum (Figure D) and terminal ileum (Figure E). Biopsies were taken to rule out an inflammatory colitis. Histology from
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the sampled mucosa revealed edematous and expanded lamina propria with prominent eosinophils and mononuclear cells, the glands were consistently tortuous and cystically dilated with mucin and involved both the polypoid and the intervening nonpolypoid mucosa (Figure F: Left colon nonpolypoid mucosal biopsy, H&E, 40x; Figure G: Terminal ileum nonpolypoid mucosal biopsy, H&E, 100x).
1) Crohn’s disease
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What is the diagnosis?
2) Familial Adenomatous Polyposis (FAP) 3) Juvenile Polyposis
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4) Cronkhite Canada Syndrome
ACCEPTED MANUSCRIPT Answer: This pathology in constellation with the patient’s presenting symptoms are consistent with a diagnosis of Cronkhite Canada syndrome (CCS). Although the polyps are histologically indistinguishable from juvenile polyps, a key feature in the tissue diagnosis of Cronkhite Canada Syndrome is the involvement of the intervening nonpolypoid intestinal mucosa, which is unlike
RI PT
Juvenile Polyposis. She was initially started on prednisone (1mg/kg) along with 6-MP. However, without clinical improvement in symptoms and continued deterioration in weight, she was initiated on infliximab 5mg/kg with a standard loading regimen and every 8 week infusion thereafter and both prednisone and 6-MP were discontinued. After 12 months of therapy, she had marked improvement in
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energy, alopecia, nail atrophy and laboratory parameters (Hb 11.4 g/dL, albumin 3.5 g/dL). Her colonoscopy showed marked resolution of inflammation in the cecum and terminal ileum and reduced
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polyp burden throughout the colon. Histology showed continued inflammation and appearance of low grade dysplasia in areas of colitis not consistent with adenomas (Figure H: left colon mucosa with low grade dysplasia, H&E 100x). Since she was felt to be a high risk surgical candidate, she was continued on infliximab with surveillance colonoscopy every 6 months for detection of dysplasia. CCS is a rare syndrome that presents with inflammatory polyposis, leading to a protein losing
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enteropathy and diarrhea [1]. Extraintestinal manifestations include alopecia, atrophy of fingernails, and increased pigmentation of the palms. No genetic cause has been identified and it is not believed to be familial. Presentation with polyposis can overlap with other genetic conditions such as Juvenile polyposis and Familial Adenomatous Polyposis, though histology is distinctly different as described
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above. The erythematous mucosa can also be mistaken for inflammatory bowel diseases. CCS is believed to be autoimmune in etiology [1], and prior studies have suggested that prednisone,
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antibiotics, nutritional therapy and recently tumor necrosis factor inhibitors may provide prolonged remission of symptoms [2-3]. CCS has a high mortality rate due to complications such as malnutrition, GI bleeding, and infection. Due to the rarity of the condition, there are no evidence based recommendations for endoscopic screening, though the risk of CRC is thought to be moderately increased [1]. This case provides physicians with an overview of a rare autoimmune condition that can mimic polyposis syndromes and IBD, it further supports the role of TNF inhibitors in the management and suggests an increased risk of cancer due to colitis associated dysplasia.
ACCEPTED MANUSCRIPT References: 1. Cronkhite LW, Canada WJ. Generalized gastro-intestinal polyposis: an unusual syndrome of polyposis, pigmentation, alopecia, and onychotrophia. N Engl J Med. 1955;252:1011–5. 2. Sweetser S, Ahlquist DA, Osborn NK, et al. Clinicopathologic features and treatment
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outcomes in Cronkhite-Canada syndrome: support for autoimmunity. Dig Dis Sci. 2012;57:496–502.
3. Boland BS, Bagi P, Valaske MA, et al. Cronkhite Canada syndrome: Significant response to
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infliximab and a possible clue to pathogenesis. Am J Gastroenterol. 2016; 111(5): 746-8.
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PII: DOI: Reference:
S0016-5085(17)36075-4 10.1053/j.gastro.2017.08.042 YGAST 61388
To appear in: Gastroenterology Accepted Date: 11 August 2017 Please cite this article as: Samadder NJ, Valentine JF, Affolter K, A Rare Cause of Diarrhea and Polyposis, Gastroenterology (2017), doi: 10.1053/j.gastro.2017.08.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT A Rare Cause of Diarrhea and Polyposis
N. Jewel Samadder, MD, MSC1,3, John F. Valentine, MD1 and Kajsa Affolter, MD2
Key Words: Cronkhite Canada syndrome, diarrhea, polyposis
SC
Conflicts of Interest:
RI PT
Departments of 1Internal Medicine (Gastroenterology) and 2Pathology, University of Utah, Salt Lake City, UT, USA, 3Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona.
Word Count: 582
References: 3
M AN U
NJS is a consultant for Cook Medical Inc. JFV and KA have no conflicts to disclose.
Figures: 8
Guarantor of the article: N. Jewel Samadder, MD, MSc
EP
Corresponding Author:
TE D
Specific author contributions: All authors approved the final draft submitted. Study concept and design, interpretation, article preparation and manuscript review: NJS, JV, KA.
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N. Jewel Samadder, MD, MSc Division of Gastroenterology and Hepatology Mayo Clinic Scottsdale, Arizona Email: [email protected] Tel: 801-213-4206 Fax: 801-581-7476
ACCEPTED MANUSCRIPT Clinical Case: A 71-year-old diabetic woman presented with newly developed anorexia with noted weight loss of approximately 60 pounds, alopecia (Figure A), atrophy of the fingernails (Figure B) and toenails, increased pigmentation on the palms, and chronic diarrhea. Laboratory tests revealed mild
RI PT
leukopenia (WBC 3.2), a mild anemia (10.4 g/dL) and hypoalbuminemia (2.3 g/dL). Stool infectious studies were negative. She underwent an upper and lower endoscopy for investigation of these findings. Her upper endoscopy revealed multiple 5-15mm pedunculated polyps and associated
SC
erythema in the gastric antrum and duodenum. Her colonoscopy revealed over 50 pedunculated polyps throughout the entire large bowel (Figure C) and marked erythema in the cecum (Figure D) and terminal ileum (Figure E). Biopsies were taken to rule out an inflammatory colitis. Histology from
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the sampled mucosa revealed edematous and expanded lamina propria with prominent eosinophils and mononuclear cells, the glands were consistently tortuous and cystically dilated with mucin and involved both the polypoid and the intervening nonpolypoid mucosa (Figure F: Left colon nonpolypoid mucosal biopsy, H&E, 40x; Figure G: Terminal ileum nonpolypoid mucosal biopsy, H&E, 100x).
1) Crohn’s disease
TE D
What is the diagnosis?
2) Familial Adenomatous Polyposis (FAP) 3) Juvenile Polyposis
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EP
4) Cronkhite Canada Syndrome
ACCEPTED MANUSCRIPT Answer: This pathology in constellation with the patient’s presenting symptoms are consistent with a diagnosis of Cronkhite Canada syndrome (CCS). Although the polyps are histologically indistinguishable from juvenile polyps, a key feature in the tissue diagnosis of Cronkhite Canada Syndrome is the involvement of the intervening nonpolypoid intestinal mucosa, which is unlike
RI PT
Juvenile Polyposis. She was initially started on prednisone (1mg/kg) along with 6-MP. However, without clinical improvement in symptoms and continued deterioration in weight, she was initiated on infliximab 5mg/kg with a standard loading regimen and every 8 week infusion thereafter and both prednisone and 6-MP were discontinued. After 12 months of therapy, she had marked improvement in
SC
energy, alopecia, nail atrophy and laboratory parameters (Hb 11.4 g/dL, albumin 3.5 g/dL). Her colonoscopy showed marked resolution of inflammation in the cecum and terminal ileum and reduced
M AN U
polyp burden throughout the colon. Histology showed continued inflammation and appearance of low grade dysplasia in areas of colitis not consistent with adenomas (Figure H: left colon mucosa with low grade dysplasia, H&E 100x). Since she was felt to be a high risk surgical candidate, she was continued on infliximab with surveillance colonoscopy every 6 months for detection of dysplasia. CCS is a rare syndrome that presents with inflammatory polyposis, leading to a protein losing
TE D
enteropathy and diarrhea [1]. Extraintestinal manifestations include alopecia, atrophy of fingernails, and increased pigmentation of the palms. No genetic cause has been identified and it is not believed to be familial. Presentation with polyposis can overlap with other genetic conditions such as Juvenile polyposis and Familial Adenomatous Polyposis, though histology is distinctly different as described
EP
above. The erythematous mucosa can also be mistaken for inflammatory bowel diseases. CCS is believed to be autoimmune in etiology [1], and prior studies have suggested that prednisone,
AC C
antibiotics, nutritional therapy and recently tumor necrosis factor inhibitors may provide prolonged remission of symptoms [2-3]. CCS has a high mortality rate due to complications such as malnutrition, GI bleeding, and infection. Due to the rarity of the condition, there are no evidence based recommendations for endoscopic screening, though the risk of CRC is thought to be moderately increased [1]. This case provides physicians with an overview of a rare autoimmune condition that can mimic polyposis syndromes and IBD, it further supports the role of TNF inhibitors in the management and suggests an increased risk of cancer due to colitis associated dysplasia.
ACCEPTED MANUSCRIPT References: 1. Cronkhite LW, Canada WJ. Generalized gastro-intestinal polyposis: an unusual syndrome of polyposis, pigmentation, alopecia, and onychotrophia. N Engl J Med. 1955;252:1011–5. 2. Sweetser S, Ahlquist DA, Osborn NK, et al. Clinicopathologic features and treatment
RI PT
outcomes in Cronkhite-Canada syndrome: support for autoimmunity. Dig Dis Sci. 2012;57:496–502.
3. Boland BS, Bagi P, Valaske MA, et al. Cronkhite Canada syndrome: Significant response to
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EP
TE D
M AN U
SC
infliximab and a possible clue to pathogenesis. Am J Gastroenterol. 2016; 111(5): 746-8.
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