|
1
|
Kővári BP, Lauwers GY. Mesenchymal Tumors of the Tubular Gastrointestinal Tract (Non-GIST): The GI Pathologist's Approach. Adv Anat Pathol 2025; 32:110-131. [PMID: 39588681 DOI: 10.1097/pap.0000000000000469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
Mesenchymal neoplasms of the gastrointestinal tract are rare compared with epithelial lesions. However, over the past few decades, the increasing volume of gastrointestinal endoscopy has expedited the recognition of several novel entities with varying clinical significance. Its spectrum extends from reactive changes and benign neoplasms to highly aggressive sarcomas. At the malignant end of the spectrum, the importance of correctly diagnosing these tumors is underscored by the specific therapeutic implications available for some tumor types (eg, tyrosine kinase inhibitors for gastrointestinal stromal tumors) that allow personalized treatments. Benign lesions frequently surface among routine polypectomy specimens, sometimes offering diagnostic challenges. However, precise classification is the only way to avoid prognostic uncertainty and overtreatment, and to recognize possible syndromic associations. Hereby, we offer a pragmatic review of the topic from the gastrointestinal pathologist's perspective, who, although more accustomed to epithelial neoplasms, can use an algorithmic approach to diagnose mesenchymal entities successfully.
Collapse
Affiliation(s)
- Bence P Kővári
- Department of Pathology, Mass General Brigham, Harvard Medical School, Boston, MA
| | - Gregory Y Lauwers
- Department of Pathology, Henry Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| |
Collapse
|
|
2
|
Sakai Y, Nakayama Y, Kurasawa S, Sado T, Kato S, Hidaka N, Takamizawa S, Yoshizawa K, Yoshimaru K, Taguchi T. Multiple endocrine neoplasia type 2B diagnosed after small intestinal volvulus with progressive megacolon in an adolescent. Clin J Gastroenterol 2024; 17:640-646. [PMID: 38753051 PMCID: PMC11284186 DOI: 10.1007/s12328-024-01979-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/02/2024] [Indexed: 07/29/2024]
Abstract
Multiple endocrine neoplasia type 2B is a rare autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, Marfan-like fatigue, a peculiar face with thickening of the lips, mucosal neuromas on the lips and tongue, and gastrointestinal phenomena. Most patients harbor pathological variants of the RET gene. Herein, we present the first case of a 14 year-old boy who experienced small intestinal volvulus along with a megacolon, and he was diagnosed with multiple endocrine neoplasia type 2B. The patient complained of constipation since he was 2 years old and slowly progressive abdominal distension at school age. At 14 years of age, he presented with remarkable megacolon mimicking Hirschsprung's disease and complicated with small intestinal volvulus. The volvulus was successfully repaired, and the particularly dilated transverse colon was resected following a rectal biopsy. Histopathological evaluation of the resected transverse colon revealed to be compatible with ganglioneuromatosis. After emergency surgery, the patient was diagnosed with multiple endocrine neoplasia type 2B with medullary thyroid carcinoma, and a de novo variant of RET was confirmed. Gastroenterologists should consider it when treating patients with constipation, especially those with megacolon. Therefore, timely diagnosis may lead to appropriate treatment of medullary thyroid carcinoma and improve mortality.
Collapse
Affiliation(s)
- Yusuke Sakai
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan
| | - Yoshiko Nakayama
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan.
| | - Shingo Kurasawa
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan
| | - Tomomitsu Sado
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan
| | - Sawako Kato
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan
| | - Nao Hidaka
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan
| | - Shigeru Takamizawa
- Department of Surgery, Nagano Children's Hospital, 3100 Toyoshina, Azumino, Nagano, Japan
| | - Katsumi Yoshizawa
- Department of Surgery, Nagano Children's Hospital, 3100 Toyoshina, Azumino, Nagano, Japan
| | - Koichiro Yoshimaru
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
- Fukuoka College of Health Sciences, Fukuoka, Japan
| |
Collapse
|
|
3
|
Isolated diffuse intestinal ganglioneuromatosis presented as a redundant sigmoid colon: a case report. Ann Med Surg (Lond) 2023; 85:219-224. [PMID: 36845810 PMCID: PMC9949766 DOI: 10.1097/ms9.0000000000000195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 12/25/2022] [Indexed: 02/28/2023] Open
Abstract
Diffuse intestinal ganglioneuromtosis is a benign tumor of the enteric nervous system, that almost always occurs in children with systemic syndromes. Whereas isolated cases in adults are exceedingly rare. Case Presentation A 38-year-old man presented with refractory chronic constipation. An abdominal computed tomography scan revealed a redundant sigmoid colon, then he underwent a sigmoid colectomy. Histopathologic examination showed diffuse ganglioneuromatosis. However, the patient was in good health 18 months after surgery. Clinical Discussion Intestinal ganglioneuromas commonly occur in children with systemic syndromes such as multiple endocrine neoplasia type 2B and neurofibromatosis type 1. The most frequent symptoms are abdominal discomfort, constipation, ileus, weight loss, appendicitis, and obstruction in more severe cases. surgical resection is the standard management in diffuse ganglioneuromatosis. Conclusion Although diffuse ganglioneuromatosis is uncommon, it should be considered in patients with refractory constipation.
Collapse
|
|
4
|
Jiang S, Song CY, Feng MX, Lu YQ. Adult patients with allied disorders of Hirschsprung’s disease in emergency department: An 11-year retrospective study. World J Gastrointest Surg 2022; 14:656-669. [PMID: 36158276 PMCID: PMC9353751 DOI: 10.4240/wjgs.v14.i7.656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/21/2021] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In the past years, only a few studies with a limited number of adult patients analyzed clinical features of allied disorders of Hirschsprung’s disease (ADHD), most of which were individual case reports or lacked detailed clinical information. Although many studies have reported patients presenting to the emergency department (ED) with recurrent abdominal symptoms for a number of disorders, there are few data involving ADHD. However, owing to a lack of awareness of the disease, misdiagnoses and mistreatments are common. Severe complications such as perforation, bleeding, malabsorption, and even death in ADHD had been reported by many studies.
AIM To assist ED clinicians in having a more comprehensive understanding of this disease and making an early suspected diagnosis of ADHD more effectively.
METHODS We enrolled 53 patients who visited the ED and were eventually diagnosed with ADHD over the past 11 years in our hospital. Their basic information, clinical manifestations, and imaging findings were analyzed. Blood indices were compared between the ADHD and irritable bowel syndrome (IBS) groups.
RESULTS Adult patients with ADHD had a mean age of 48.8 ± 14.3 years, and 77.4% had been treated before admission. The transverse colon was the most common dilated part (73.6%), and constipation (67.9%) was the most common symptom. ADHD patients can present with uncommon symptoms and false-negative imaging findings. Logistic regression analysis indicated that body mass index (BMI) [odds ratio (OR) = 0.786, P = 0.013], cholinesterase (per 1000 units; OR = 0.693, P = 0.008), and blood chlorine (OR = 0.816, P = 0.022) were determined to be independent related factors between the ADHD and IBS groups. The area under the receiver operating characteristics curve of these three indices combined was 0.812 (P < 0.001).
CONCLUSION Emergency physicians should be vigilant regarding patients with chronic constipation, abdominal pain, or abdominal distension, and consider the possibility of ADHD despite its rarity. Abdominal computed tomography examination is recommended as a useful tool in the suspected diagnosis of ADHD. BMI, cholinesterase, and blood chlorine have good discriminative abilities between ADHD and IBS. The nutritional status of adult patients with ADHD is worthy of further attention. Surgical treatment for adult patients with ADHD is important and inevitable.
Collapse
Affiliation(s)
- Shuai Jiang
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
| | - Cong-Ying Song
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
| | - Meng-Xiao Feng
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
| | - Yuan-Qiang Lu
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
| |
Collapse
|
|
5
|
Fang Y, Zhang Y, Dong R, Wang YZ, Chen L, Chen G. A Case Series of Pediatric Intestinal Ganglioneuromatosis With Novel Phenotypic and Genotypic Profile. Front Med (Lausanne) 2022; 9:883958. [PMID: 35783634 PMCID: PMC9243541 DOI: 10.3389/fmed.2022.883958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 05/09/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction Intestinal ganglioneuromatosis (IGN) is a rare condition with enteric involvement. Herein, we report a case series of pediatric IGN with a novel phenotypic and genotypic profile. Methods The clinical presentation, histopathology, immunochemistry, molecular features, treatment, and prognosis of 3 cases of IGN were assessed. Results The cases involved 3 boys with an age range of 1 year and 4 months to 8 years, mimicking juvenile polyps or pseudomembranous enteritis. One patient carried a novel germline mutation in RTEL1 (c.296C > T/p.Pro99Leu) along with variants in F11 (c.1489C > T/p.Arg497Xaa), NBAS (c.1514delC/p.Pro505Hisfs*15), and FECH (c.315-48T > C/splicing), who died due to intractable inflammation. The other two patients underwent recurrence without significant signs of systemic syndrome or malignant progression. Conclusion This case series added to the phenotypic and genotypic spectrum of pediatric IGN, which requires the accumulation of more cases and research for in-depth understanding.
Collapse
Affiliation(s)
- Yuan Fang
- Department of Pathology, Anhui Provincial Children’s Hospital, Hefei, China
| | - Ye Zhang
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai, China
| | - Rui Dong
- Department of Oncological Surgery, Children’s Hospital of Fudan University, Shanghai, China
| | - Yi-zhen Wang
- Department of Pathology, Anhui Provincial Children’s Hospital, Hefei, China
| | - Lian Chen
- Department of Pathology, Children’s Hospital of Fudan University, Shanghai, China
- *Correspondence: Lian Chen,
| | - Gong Chen
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai, China
- Gong Chen,
| |
Collapse
|
|
6
|
Saravana-Bawan B, Pasternak JD. Multiple endocrine neoplasia 2: an overview. Ther Adv Chronic Dis 2022; 13:20406223221079246. [PMID: 35237400 PMCID: PMC8882936 DOI: 10.1177/20406223221079246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 01/20/2022] [Indexed: 11/17/2022] Open
Abstract
This review article discusses the diagnosis and treatment of patients with
multiple endocrine neoplasia type 2 (MEN2). The most common tumors associated
with MEN2 are those of the parathyroid, thyroid, and adrenal glands. Additional
manifestations include characteristic clinical phenotypes or features as
described in the article. This review provides an overview of clinical
manifestations, screening, diagnosis, treatment, and surveillance of patients
with MEN2.
Collapse
Affiliation(s)
- B Saravana-Bawan
- University Health Network, University of Toronto, Toronto, ON, Canada
| | - JD Pasternak
- Section Head, Endocrine Surgery and Oncology, Division of General Surgery, Sprott Department of Surgery, Toronto General Hospital, University Health Network, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada
| |
Collapse
|
|
7
|
van den Broek MFM, van Santen HM, Valk GD, Verrijn Stuart AA. Children with multiple endocrine neoplasia type 2B: Not tall and marfanoid, but short with normal body proportions. Clin Endocrinol (Oxf) 2021; 95:453-459. [PMID: 34160841 PMCID: PMC8456974 DOI: 10.1111/cen.14536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/16/2021] [Accepted: 05/25/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Multiple endocrine neoplasia 2B (MEN2B) is characterised by early-onset medullary thyroid carcinoma (MTC), pheochromocytoma and several nonendocrine manifestations. Unfortunately, MEN2B is often diagnosed late, after the development of clinically significant MTC. Marfanoid habitus is considered an important related feature, which may lead to the assumption that patients with MEN2B have tall stature. Here, we describe the longitudinal growth and body proportions of eight MEN2B patients during childhood. DESIGN It is a retrospective case series. METHODS Patients were under the care of a Dutch MEN expertise centre. Growth patterns were assessed and interpreted in relation to body mass index (BMI), age at diagnosis and at thyroidectomy, extensiveness of disease manifestations and parental height. RESULTS Seven patients were short during childhood, of whom four showed growth below target height range (THR) and three at the lowest margin of THR. Only one patient grew well within THR. All patients who attained final height (n = 4) ended within THR, despite short stature during childhood. Arm span/height ratio was not increased and upper segment/lower segment ratio was not reduced in any patient. Short stature in childhood in this study did not seem to be associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, endocrine deficiencies or BMI. CONCLUSIONS This study shows that children with MEN2B may well present with short rather than tall stature. Thereafter, final height within THR was attained in those who already reached adulthood, but none had tall stature. Finally, body proportions were normal in all children and adults in this case series, not underlining a 'marfanoid' body habitus.
Collapse
Affiliation(s)
| | - Hanneke M. van Santen
- Department of Pediatric Endocrinology, Wilhelmina Children's HospitalUniversity Medical Center UtrechtUtrechtThe Netherlands
- Princess Maxima Center for Pediatric OncologyUtrechtThe Netherlands
| | - Gerlof D. Valk
- Department of Endocrine OncologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Annemarie A. Verrijn Stuart
- Department of Pediatric Endocrinology, Wilhelmina Children's HospitalUniversity Medical Center UtrechtUtrechtThe Netherlands
| |
Collapse
|
|
8
|
Baiomi A, Abbas H, Niazi M, Remotti H, Daniel M, Balar B. Colonic Ganglioneuroma: A Rare Lesion With Extremely Different Presentations and Outcomes in Two Patients. Gastroenterology Res 2021; 14:194-198. [PMID: 34267836 PMCID: PMC8256904 DOI: 10.14740/gr1379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 04/16/2021] [Indexed: 01/17/2023] Open
Abstract
Ganglioneuroma (GN) of the gastrointestinal tract is an extremely rare neuroectodermal tumor. Patients with ganglioneuromas have different presentations depending on the location, extent and size of the lesion. We present two cases of ganglioneuromas that had different clinical presentations and outcomes.
Collapse
Affiliation(s)
- Ahmed Baiomi
- Department of Medicine, BronxCare Health System, 1650 Selwyn Ave, Bronx, NY 10457, USA.,Division of Gastroenterology, BronxCare Health System, 1650 Grand Concourse, Bronx, NY 10457, USA
| | - Hafsa Abbas
- Department of Medicine, BronxCare Health System, 1650 Selwyn Ave, Bronx, NY 10457, USA.,Division of Gastroenterology, BronxCare Health System, 1650 Grand Concourse, Bronx, NY 10457, USA
| | - Masooma Niazi
- Department of Medicine, BronxCare Health System, 1650 Selwyn Ave, Bronx, NY 10457, USA.,Division of Pathology, BronxCare Health System, 1650 Grand Concourse, Bronx, NY 10457, USA
| | - Helen Remotti
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY 10032, USA
| | - Myrta Daniel
- Department of Medicine, BronxCare Health System, 1650 Selwyn Ave, Bronx, NY 10457, USA.,Division of Gastroenterology, BronxCare Health System, 1650 Grand Concourse, Bronx, NY 10457, USA
| | - Bhavna Balar
- Department of Medicine, BronxCare Health System, 1650 Selwyn Ave, Bronx, NY 10457, USA.,Division of Gastroenterology, BronxCare Health System, 1650 Grand Concourse, Bronx, NY 10457, USA
| |
Collapse
|
|
9
|
Nagy N, Guyer RA, Hotta R, Zhang D, Newgreen DF, Halasy V, Kovacs T, Goldstein AM. RET overactivation leads to concurrent Hirschsprung disease and intestinal ganglioneuromas. Development 2020; 147:dev190900. [PMID: 32994173 PMCID: PMC7657479 DOI: 10.1242/dev.190900] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 09/08/2020] [Indexed: 12/17/2022]
Abstract
Appropriately balanced RET signaling is of crucial importance during embryonic neural crest cell migration, proliferation and differentiation. RET deficiency, for example, leads to intestinal aganglionosis (Hirschsprung disease), whereas overactive RET can lead to multiple endocrine neoplasia (MEN) syndromes. Some RET mutations are associated with both intestinal aganglionosis and MEN-associated tumors. This seemingly paradoxical occurrence has led to speculation of a 'Janus mutation' in RET that causes overactivation or impairment of RET activity depending on the cellular context. Using an intestinal catenary culture system to test the effects of GDNF-mediated RET activation, we demonstrate the concurrent development of distal colonic aganglionosis and intestinal ganglioneuromas. Interestingly, the tumors induced by GDNF stimulation contain enteric neuronal progenitors capable of reconstituting an enteric nervous system when transplanted into a normal developmental environment. These results suggest that a Janus mutation may not be required to explain co-existing Hirschsprung disease and MEN-associated tumors, but rather that RET overstimulation alone is enough to cause both phenotypes. The results also suggest that reprogramming tumor cells toward non-pathological fates may represent a possible therapeutic avenue for MEN-associated neoplasms.
Collapse
Affiliation(s)
- Nandor Nagy
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, 1094, Hungary
| | - Richard A Guyer
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Ryo Hotta
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Dongcheng Zhang
- Neural Crest Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia
| | - Donald F Newgreen
- Neural Crest Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia
| | - Viktoria Halasy
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, 1094, Hungary
| | - Tamas Kovacs
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, 1094, Hungary
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| |
Collapse
|
|
10
|
Redlich A, Lessel L, Petrou A, Mier P, Vorwerk P. Multiple endocrine neoplasia type 2B: Frequency of physical stigmata-Results of the GPOH-MET registry. Pediatr Blood Cancer 2020; 67:e28056. [PMID: 31724322 DOI: 10.1002/pbc.28056] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 09/28/2019] [Accepted: 10/09/2019] [Indexed: 01/20/2023]
Abstract
BACKGROUND Multiple endocrine neoplasia (MEN) 2B is characterized by early development of aggressive medullary thyroid carcinoma (MTC), visible physical stigmata, and associated symptoms. In most cases, de novo mutations are revealed. There are premonitory symptoms and stigmata that enable early diagnosis, before an inoperable MTC develops. The German Society for Paediatric Oncology and Haematology (GPOH)-Malignant Endocrine Tumours (MET) registry maintains records of children with MTC in Germany since 1997. METHODS Children with a diagnosis of MTC in MEN 2B recorded in the GPOH-MET study were analyzed retrospectively. Stigmata and symptoms associated with MEN 2B were examined. RESULTS From inception through 2017, 24 patients aged 0.2-17.3 years were included. Symptoms affecting the oral/dental (88.0%), musculoskeletal (79.2%), and gastrointestinal (70.8%) systems were recognized most frequently. Gastrointestinal and musculoskeletal symptoms preceded symptoms of MTC. Twelve patients had short stature. Regarding the prevalence of single symptoms, neuromas of the lips and the oral cavity were mentioned most frequently. Five patients died from MTC. Patients diagnosed by tumor symptoms showed more advanced disease than those with disease detected by other means. Children diagnosed via associated stigmata and symptoms or positive family history had significantly improved overall survival (OS) compared to children diagnosed via symptoms of MTC (OS 100% vs 53.3%). CONCLUSIONS In children with MEN 2B, oral/dental, musculoskeletal, and gastrointestinal symptoms are most common. If children are diagnosed via associated symptoms and stigmata, OS is improved. Most of the children were diagnosed with growth disturbances; this finding requires verification and ranging in other patient cohorts.
Collapse
Affiliation(s)
- Antje Redlich
- Department of Paediatric Oncology and Haematology, GPOH-MET registry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Lienhard Lessel
- Department of Paediatric Oncology and Haematology, GPOH-MET registry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Artemis Petrou
- Department of Paediatric Oncology and Haematology, GPOH-MET registry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Pascal Mier
- Department of Paediatric Oncology and Haematology, GPOH-MET registry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Peter Vorwerk
- Department of Paediatric Oncology and Haematology, GPOH-MET registry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| |
Collapse
|
|
11
|
Fernando AR, Samarasekera DN, Bulathsinghela RP. Constipation with megacolon in a 36-year-old man: a rare presentation of MEN2B from Sri Lanka. BMJ Case Rep 2019; 12:12/1/bcr-2018-227081. [PMID: 30642858 PMCID: PMC6340592 DOI: 10.1136/bcr-2018-227081] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Diffuse intestinal ganglioneuromatosis is a rare condition associated with MEN2B. It is also seen in conditions like neurofibromatosis type 1 and Cowden syndrome. This is a report of a patient who underwent total colectomy with end ileostomy creation for a megacolon. He was diagnosed to have diffuse ganglioneuromatosis on histological examination of the resected segment of colon. The definitive management of diffuse ganglioneuromatosis is to resect and anastomose.
Collapse
|
|
12
|
Abraham D, Raam M, Cherian A, Paul M. An update on medullary carcinoma thyroid. JOURNAL OF HEAD & NECK PHYSICIANS AND SURGEONS 2019. [DOI: 10.4103/jhnps.jhnps_4_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
|
|
13
|
Paediatric Intestinal Pseudo-obstruction: Evidence and Consensus-based Recommendations From an ESPGHAN-Led Expert Group. J Pediatr Gastroenterol Nutr 2018; 66:991-1019. [PMID: 29570554 DOI: 10.1097/mpg.0000000000001982] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Chronic intestinal pseudo-obstructive (CIPO) conditions are considered the most severe disorders of gut motility. They continue to present significant challenges in clinical care despite considerable recent progress in our understanding of pathophysiology, resulting in unacceptable levels of morbidity and mortality. Major contributors to the disappointing lack of progress in paediatric CIPO include a dearth of clarity and uniformity across all aspects of clinical care from definition and diagnosis to management. In order to assist medical care providers in identifying, evaluating, and managing children with CIPO, experts in this condition within the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition as well as selected external experts, were charged with the task of developing a uniform document of evidence- and consensus-based recommendations. METHODS Ten clinically relevant questions addressing terminology, diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to June 2017 using a number of established electronic databases as well as repositories. The approach of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to evaluate outcome measures for the research questions. Levels of evidence and quality of evidence were assessed using the classification system of the Oxford Centre for Evidence-Based Medicine (diagnosis) and the GRADE system (treatment). Each of the recommendations were discussed, finalized, and voted upon using the nominal voting technique to obtain consensus. RESULTS This evidence- and consensus-based position paper provides recommendations specifically for chronic intestinal pseudo-obstruction in infants and children. It proposes these be termed paediatric intestinal pseudo-obstructive (PIPO) disorders to distinguish them from adult onset CIPO. The manuscript provides guidance on the diagnosis, evaluation, and treatment of children with PIPO in an effort to standardise the quality of clinical care and improve short- and long-term outcomes. Key recommendations include the development of specific diagnostic criteria for PIPO, red flags to alert clinicians to the diagnosis and guidance on the use of available investigative modalities. The group advocates early collaboration with expert centres where structured diagnosis and management is guided by a multi-disciplinary team, and include targeted nutritional, medical, and surgical interventions as well as transition to adult services. CONCLUSIONS This document is intended to be used in daily practice from the time of first presentation and definitive diagnosis PIPO through to the complex management and treatment interventions such as intestinal transplantation. Significant challenges remain to be addressed through collaborative clinical and research interactions.
Collapse
|
|
14
|
Wasserman JD, Tomlinson GE, Druker H, Kamihara J, Kohlmann WK, Kratz CP, Nathanson KL, Pajtler KW, Parareda A, Rednam SP, States LJ, Villani A, Walsh MF, Zelley K, Schiffman JD. Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res 2018; 23:e123-e132. [PMID: 28674121 DOI: 10.1158/1078-0432.ccr-17-0548] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 05/02/2017] [Accepted: 05/16/2017] [Indexed: 12/19/2022]
Abstract
Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the multiple endocrine neoplasia (MEN) syndromes, including MEN1, MEN2A and MEN2B, MEN4, and hyperparathyroid-jaw tumor (HPT-JT) syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic MEN1 variants (11q13), MEN2A and MEN2B are due to pathogenic RET variants (10q11.21), MEN4 is due to pathogenic CDKN1B variants (12p13.1), and the HPT-JT syndrome is due to pathogenic CDC73 variants (1q25). Although each of these genetic syndromes share the presence of neuroendocrine tumors, each syndrome has a slightly different tumor spectrum with specific surveillance recommendations based upon tumor penetrance, including the age and location for which specific tumor types most commonly present. Although the recommended surveillance strategies for each syndrome contain similar approaches, important differences do exist among them. Therefore, it is important for caregivers of children and adolescents with these syndromes to become familiar with the unique diagnostic criteria for each syndrome, and also to be aware of the specific tumor screening and prophylactic surgery recommendations for each syndrome. Clin Cancer Res; 23(13); e123-e32. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Collapse
Affiliation(s)
- Jonathan D Wasserman
- Division of Endocrinology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
| | - Gail E Tomlinson
- Department of Pediatrics, Division of Hematology and Oncology and Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Harriet Druker
- Division of Haematology-Oncology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Junne Kamihara
- Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Wendy K Kohlmann
- Huntsmann Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Christian P Kratz
- Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Katherine L Nathanson
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kristian W Pajtler
- Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany.,Division of Pediatric Neuro-Oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andreu Parareda
- Division of Oncology, Predisposition and Survivorship Units, Sant Joan de Déu - Barcelona Children's Hospital, Barcelona, Spain
| | - Surya P Rednam
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas
| | - Lisa J States
- Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Anita Villani
- Division of Haematology-Oncology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Michael F Walsh
- Departments of Medicine and Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kristin Zelley
- Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Joshua D Schiffman
- Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| |
Collapse
|
|
15
|
Hutson JM, Farmer PJ, Peck CJ, Chow CW, Southwell BR. Multiple endocrine neoplasia 2B: Differential increase in enteric nerve subgroups in muscle and mucosa. World J Gastrointest Pathophysiol 2017; 8:142-149. [PMID: 28868184 PMCID: PMC5561435 DOI: 10.4291/wjgp.v8.i3.142] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 05/24/2017] [Accepted: 07/17/2017] [Indexed: 02/06/2023] Open
Abstract
Multiple endocrine neoplasia 2B (MEN2B) is a rare syndrome caused by an activating mutation of the RET gene, leading to enteric gangliomatosis. This child presented with constipation at 1-mo old, was diagnosed with MEN2B by rectal biopsy at 4 mo, had thyroidectomy at 9 mo and a colectomy at 4 years. We studied the extent of neuronal and nerve fibre proliferation and which classes of enteric nerves are affected by examining the colon with multiple neuronal antibodies. Resected transverse colon was fixed, frozen, sectioned and processed for fluorescence immunohistochemistry labelling with antibodies against TUJ1, Hu, ChAT, NOS, VIP, SP and CGRP and cKit. Control transverse colon was from the normal margin of Hirschsprung (HSCR) colon (4-year-old) and a child with familial adenomatous polyposis (FAP, 12 year). Myenteric ganglia were increased in size to as wide as the circular muscle. There was a large increase in nerve cells and nerve fibres. ChAT-, NOS-, VIP- and SP-immunoreactive nerve fibres all increased in the myenteric ganglia. NOS-IR nerves preferentially increased in the muscle, while VIP and SP increased in submucosal ganglia and mucosal nerve fibres. The density of ICC was normal. RET overactivation in MEN2B lead to a large increase in intrinsic nerve fibres in the myenteric and submucosal ganglia, with a relative increase in NOS-IR nerve fibres in the circular muscle and VIP and SP in the submucosal ganglia and mucosa. The changes were associated with severe constipation resulting in colectomy at 4 years.
Collapse
|
|
16
|
Gfroerer S, Theilen TM, Fiegel H, Harter PN, Mittelbronn M, Rolle U. Identification of intestinal ganglioneuromatosis leads to early diagnosis of MEN2B: role of rectal biopsy. J Pediatr Surg 2017; 52:1161-1165. [PMID: 27899172 DOI: 10.1016/j.jpedsurg.2016.10.054] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Revised: 10/05/2016] [Accepted: 10/07/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND/PURPOSE Gastrointestinal symptoms are very common in patients with multiple endocrine neoplasia type 2B (MEN2B) syndrome. Herein, we present a case of intestinal ganglioneuromatosis (IGN) in MEN2B syndrome and a systematic literature review with a special focus on gastrointestinal symptoms prior to the diagnosis of MEN2B. METHODS Literature search was performed (years 1966-2015) using the "Pubmed" and "Scopus" databases. Search terms used were gastrointestinal, intestinal and MEN2B. RESULTS Literature search revealed 188 publications on MEN2B patients with gastrointestinal symptoms, providing a total of 55 patients including our own case. The far most common gastrointestinal symptom was constipation (72.7%). The onset of gastrointestinal symptoms occurred in 29 out of 55 cases (52.3%) below the age of 1year. However, MEN2B diagnosis was established at a median age of 13.0years (range 0-46years). The histological finding of IGN led to the diagnosis of MEN2B In 15 of 55 patients (27.3%) at a median age of 3years (range 0-31years). CONCLUSION Paying close attention to gastrointestinal problems in early childhood and taking a rectal biopsy that precisely screens for IGN offers the chance of diagnosing MEN2B syndrome early in infancy.
Collapse
Affiliation(s)
- Stefan Gfroerer
- Department of Pediatric Surgery and Pediatric Urology, Goethe University Hospital, Frankfurt, Germany
| | - Till-Martin Theilen
- Department of Pediatric Surgery and Pediatric Urology, Goethe University Hospital, Frankfurt, Germany
| | - Henning Fiegel
- Department of Pediatric Surgery and Pediatric Urology, Goethe University Hospital, Frankfurt, Germany
| | - Patrick N Harter
- Edinger Institute, Neurological Institute, Goethe University Hospital, Frankfurt, Germany
| | - Michel Mittelbronn
- Edinger Institute, Neurological Institute, Goethe University Hospital, Frankfurt, Germany
| | - Udo Rolle
- Department of Pediatric Surgery and Pediatric Urology, Goethe University Hospital, Frankfurt, Germany.
| |
Collapse
|
|
17
|
Moore SW. Advances in understanding functional variations in the Hirschsprung disease spectrum (variant Hirschsprung disease). Pediatr Surg Int 2017; 33:285-298. [PMID: 27988850 DOI: 10.1007/s00383-016-4038-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/05/2016] [Indexed: 12/11/2022]
Abstract
Hirschsprung disease (HSCR) is a fairly well understood congenital, genetically based functional obstruction due to the congenital absence of ganglion cells in the distal bowel. However, although over 90% of Hirschsprung cases conform to the normally accepted histological diagnostic criteria, it has become increasingly clear that in addition to HSCR, there is a group of functional disturbances relating to a number of other congenital neurodysplastic conditions causing some degree of gastrointestinal tract malfunction. Although these represent a variety of possibly separate conditions of the enteric nervous system, this spectrum it would appear to be also influenced by similar developmental processes. The term "variant Hirschsprung" is commonly used to describe these conditions, but ganglion cells are mostly present if abnormal in number and distribution. These conditions are a problem group being amongst the most difficult to diagnose and treat with possible practical and legal consequences. The problem appears to be possibly one of definition which has proven difficult in the relative paucity of normal values, especially when correlated to age and gestation. It is the purpose of this paper to review the current position on these conditions and to explore possible shared common pathogenetic and genetic mechanisms. This article explores those conditions where a similar pathogenetic mechanisms to HSCR can be demonstrated (e.g. hypoganglionosis) as well as other neural features, which appear to represent separate conditions possibly linked to certain syndromes.
Collapse
Affiliation(s)
- S W Moore
- Division of Paediatric Surgery, Faculty of Medicine, University of Stellenbosch, P.O. Box 19063, Tygerberg, 7505, South Africa.
| |
Collapse
|
|
18
|
Abdelfatah M, Sangah G, Harvin G. What Do We Need to Know About Colonic Polypoid Ganglioneuroma? A Case Report and A Comprehensive Review. J Gastrointest Cancer 2016; 49:327-332. [PMID: 27888390 DOI: 10.1007/s12029-016-9892-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Mohamed Abdelfatah
- Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Brody School of Medicine at East Carolina University, Suite 338, Mail Stop 734, Greenville, NC, USA.
| | - George Sangah
- Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Brody School of Medicine at East Carolina University, Suite 338, Mail Stop 734, Greenville, NC, USA
| | - Glenn Harvin
- Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Brody School of Medicine at East Carolina University, Suite 338, Mail Stop 734, Greenville, NC, USA
| |
Collapse
|
|
19
|
Ernani V, Kumar M, Chen AY, Owonikoko TK. Systemic treatment and management approaches for medullary thyroid cancer. Cancer Treat Rev 2016; 50:89-98. [PMID: 27664392 DOI: 10.1016/j.ctrv.2016.09.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 08/18/2016] [Accepted: 09/01/2016] [Indexed: 10/21/2022]
Abstract
Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival. MTC is either sporadic (∼75%) or inherited (∼25%) as an autosomal dominant disease. Regardless, germline and somatic mutations, particularly in the rearranged during transfection (RET) proto-oncogene, are key factors in the neoplastic process. Gain-of-function RET mutations result in overactive proteins that lead to abnormal activation of downstream signal transduction pathways, resulting in ligand-independent growth and resistance to apoptotic stimuli. Specific RET mutation variants have been found to correlate with phenotype and natural history of MTC with some defects portending a more aggressive clinical course. Greater understanding of the consequence of the aberrant signaling pathway has fostered the development of targeted therapies. Two small-molecule tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival. Since there have been no head-to-head comparisons, clinicians often select between these agents on the basis of familiarity, patient characteristics, comorbidities, and toxicity profile.
Collapse
Affiliation(s)
- Vinicius Ernani
- Department of Hematology/Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365-C Clifton Road NE, Atlanta, GA, USA.
| | - Mukesh Kumar
- Department of Hematology/Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365-C Clifton Road NE, Atlanta, GA, USA.
| | - Amy Y Chen
- Department of Otolaryngology, Head and Neck Surgery, Emory University School of Medicine, Winship Cancer Institute, 1365-A Clifton Road NE, Atlanta, GA, USA.
| | - Taofeek K Owonikoko
- Department of Hematology/Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365-C Clifton Road NE, Atlanta, GA, USA.
| |
Collapse
|
|
20
|
Gonzalez RS, Riddle ND. Syndrome-Associated Tumors by Organ System. J Pediatr Genet 2016; 5:105-15. [PMID: 27617151 PMCID: PMC4918701 DOI: 10.1055/s-0036-1580597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 08/26/2015] [Indexed: 12/20/2022]
Abstract
Certain tumors suggest the possibility of a patient harboring a genetic syndrome, particularly in children. Syndrome-associated tumors of the gastrointestinal tract, genitourinary tract, gynecologic tract, heart, lungs, brain, eye, endocrine organs, and hematopoietic system will be briefly discussed.
Collapse
Affiliation(s)
- Raul S. Gonzalez
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States
| | - Nicole D. Riddle
- Department of Pathology, Cunningham Pathology LLC, Birmingham, Alabama, United States
| |
Collapse
|
|
21
|
Goldstein AM, Thapar N, Karunaratne TB, De Giorgio R. Clinical aspects of neurointestinal disease: Pathophysiology, diagnosis, and treatment. Dev Biol 2016; 417:217-28. [PMID: 27059882 DOI: 10.1016/j.ydbio.2016.03.032] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/21/2016] [Accepted: 03/31/2016] [Indexed: 02/07/2023]
Abstract
The enteric nervous system (ENS) is involved in the regulation of virtually all gut functions. Conditions referred to as enteric neuropathies are the result of various mechanisms including abnormal development, degeneration or loss of enteric neurons that affect the structure and functional integrity of the ENS. In the past decade, clinical and molecular research has led to important conceptual advances in our knowledge of the pathogenetic mechanisms of these disorders. In this review we consider ENS disorders from a clinical perspective and highlight the advancing knowledge regarding their pathophysiology. We also review current therapies for these diseases and present potential novel reparative approaches for their treatment.
Collapse
Affiliation(s)
- Allan M Goldstein
- Department of Pediatric Surgery, Center for Neurointestinal Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Nikhil Thapar
- Division of Neurogastroenterology and Motility, Department of Gastroenterology, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK
| | - Tennekoon Buddhika Karunaratne
- Department of Medical and Surgical Sciences and Gastrointestinal System, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy; Centro di Ricerca BioMedica Applicata (C.R.B.A.), University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Roberto De Giorgio
- Department of Medical and Surgical Sciences and Gastrointestinal System, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy; Centro di Ricerca BioMedica Applicata (C.R.B.A.), University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
| |
Collapse
|
|
22
|
Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25:567-610. [PMID: 25810047 PMCID: PMC4490627 DOI: 10.1089/thy.2014.0335] [Citation(s) in RCA: 1438] [Impact Index Per Article: 143.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. METHODS The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. RESULTS The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. CONCLUSIONS The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice.
Collapse
Affiliation(s)
- Samuel A. Wells
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sylvia L. Asa
- Department of Pathology, University Health Network, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Henning Dralle
- Department of General, Visceral, and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Halle/Saale, Germany
| | - Rossella Elisei
- Department of Endocrinology, University of Pisa, Pisa, Italy
| | - Douglas B. Evans
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Robert F. Gagel
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nancy Lee
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Andreas Machens
- Department of General, Visceral, and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Halle/Saale, Germany
| | - Jeffrey F. Moley
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Furio Pacini
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, University of Siena, Policlinico Santa Maria alle Scotte, Siena, Italy
| | - Friedhelm Raue
- Endocrine Practice, Moleculargenetic Laboratory, Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Karin Frank-Raue
- Endocrine Practice, Moleculargenetic Laboratory, Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Bruce Robinson
- University of Sydney School of Medicine, Sydney, New South Wales, Australia
| | - M. Sara Rosenthal
- Departments of Internal Medicine, Pediatrics and Behavioral Science, University of Kentucky, Lexington, Kentucky
| | - Massimo Santoro
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita' di Napoli “Federico II,” Napoli, Italy
| | - Martin Schlumberger
- Institut Gustave Roussy, Service de Medecine Nucleaire, Université of Paris-Sud, Villejuif, France
| | - Manisha Shah
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Steven G. Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| |
Collapse
|
|
23
|
Gizard E, Kalouche I, Merlin P, Peyrin-Biroulet L. Ileal ulcers not responding to infliximab therapy: think about intestinal ganglioneuromatosis. Dig Liver Dis 2015; 47:257-8. [PMID: 25499657 DOI: 10.1016/j.dld.2014.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 10/26/2014] [Accepted: 11/01/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Emmanuel Gizard
- Inserm U954 and Department of Hepato-Gastroenterology, Lorraine University, Vandoeuvre-lès-Nancy, France; Verdun Hospital, Verdun, France
| | | | | | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Hepato-Gastroenterology, Lorraine University, Vandoeuvre-lès-Nancy, France.
| |
Collapse
|
|
24
|
Sheley MF, Higgins RJ, Mete A. Transmural ileal ganglioneuromatosis in a young Boer goat (Capra hircus). J Comp Pathol 2014; 151:190-4. [PMID: 24975898 DOI: 10.1016/j.jcpa.2014.04.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 04/11/2014] [Accepted: 04/21/2014] [Indexed: 10/25/2022]
Abstract
A diagnosis of transmural ileal ganglioneuromatosis was made in a 15-day-old goat that was found dead following a period of diarrhoea and inappetence. Grossly, the entire length of the wall of the ileum was pale and firm with a variably segmental to transmural thickening. Microscopically, the ileal transmural thickening was due to a diffuse proliferation of both ganglionic and glial cells forming cell nests or packets that infiltrated the wall and into the mesentery surrounding a mesenteric lymph node. The neoplastic ganglionic cells were immunoreactive for S100, synaptophysin and triple neurofilament, while the glial spindle cells were immunoreactive with glial fibrillary acidic protein, S100 and laminin confirming their Schwann cell identity. Nerve fibres expressing neurofilament protein 200 and phosphorylated neurofilament (SMI-31) were observed rarely. Ganglioneuromatosis is defined as diffuse exuberant proliferation of all components of the intestinal ganglionic plexuses. In man, the transmural form has more grave clinical consequences than a focal pattern and is commonly associated with germline mutations in the RET proto-oncogene. Whether there is any comparable molecular genetic abnormality in animals remains unknown; however, ganglioneuromatosis needs to be included in the differential diagnosis of tumours of the autonomic enteric nervous system.
Collapse
Affiliation(s)
- M F Sheley
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - R J Higgins
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - A Mete
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
| |
Collapse
|
|
25
|
Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective. Ann Surg 2014; 259:800-6. [PMID: 23979292 DOI: 10.1097/sla.0b013e3182a6f43a] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE This investigation aimed at exploring the suitability of nonendocrine manifestations preceding medullary thyroid cancer (MTC) for early diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). BACKGROUND MEN 2B patients, running a high risk of metastatic MTC, must be diagnosed early for biochemical cure. METHODS Forty-four MEN 2B patients carrying inherited (3 patients) and de novo (41 patients) M918T RET mutations were examined for signs and symptoms prompting MEN 2B. RESULTS All 3 patients with inherited mutations were diagnosed before the age of 1 year and cured of their C-cell disease. Among 41 patients with de novo mutations, MEN 2B was diagnosed in 12 patients after recognition of nonendocrine manifestations [intestinal ganglioneuromatosis (6 patients), oral symptoms (5 patients), ocular ("tearless crying") (4 patients), and skeletal stigmata (1 patient) alone or concomitantly]. In the remaining 29 patients with de novo mutations, the diagnosis of MEN 2B was triggered by symptomatic MTC (28 patients) or pheochromocytoma (1 patient). The former patients, being significantly (P < 0.001) younger (means of 5.3 vs 17.6 years) and having lower calcitonin levels (means of 115 vs 25,519 pg/mL), smaller tumors (67% vs 0% were ≤10 mm) and less often extrathyroidal extension (0% vs 81%), lymph node (42% vs 100%), and distant metastases (8% vs 79%), were biochemically cured more often (58% vs 0%). CONCLUSIONS MTC is curable in patients with de novo mutations when nonendocrine MEN 2B components are quickly appreciated and surgical intervention is performed before patients turn 4 years old.
Collapse
|
|
26
|
Schäppi MG, Staiano A, Milla PJ, Smith VV, Dias JA, Heuschkel R, Husby S, Mearin ML, Papadopoulou A, Ruemmele FM, Vandenplas Y, Koletzko S. A practical guide for the diagnosis of primary enteric nervous system disorders. J Pediatr Gastroenterol Nutr 2013; 57:677-686. [PMID: 24177787 DOI: 10.1097/mpg.0b013e3182a8bb50] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field. RESULTS Although the diagnostic criteria for Hirschsprung disease are well established, those for other forms of dysganglionosis remain ill-defined. Appropriate tissue sampling, handling, and expert interpretation are crucial to maximize diagnostic accuracy and reduce interobserver variability. The absence of validated age-related normal values for neuronal density, along with the lack of correlation between clinical and histological findings, result in significant diagnostic uncertainties while diagnosing quantitative aberrations such as hypoganglionosis or ultrashort Hirschsprung disease. Intestinal neuronal dysplasia remains a histological description of unclear significance. CONCLUSIONS The evaluation of cellular quantitative or qualitative abnormalities of the ENS for clinical diagnosis remains complex. Such analysis should be carried out in laboratories that have the necessary expertise and access to their own validated reference values.
Collapse
Affiliation(s)
- M G Schäppi
- Pediatric Center, Clinique des Grangettes, and Centre Médical Universitaire, Geneva, Switzerland
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Abstract
"Variants of Hirschsprung's disease" are conditions that clinically resemble Hirschsprung's disease (HD), despite the presence of ganglion cells in rectal suction biopsies. The diagnosis and management of these patients can be challenging. Specific histological, immunohistochemical and electron microscopic investigations are required to characterize this heterogeneous group of functional bowel disorders. Variants of HD include intestinal neuronal dysplasia, intestinal ganglioneuromatosis, isolated hypoganglionosis, immature ganglia, absence of the argyrophil plexus, internal anal sphincter achalasia and congenital smooth muscle cell disorders such as megacystis microcolon intestinal hypoperistalsis syndrome. This review article systematically classifies variants of HD based on current diagnostic criteria with an additional focus on pathogenesis, epidemiology, clinical presentation, management and outcome.
Collapse
|
|
28
|
Wells SA, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab 2013; 98:3149-3164. [PMID: 23744408 PMCID: PMC5399478 DOI: 10.1210/jc.2013-1204] [Citation(s) in RCA: 210] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 05/30/2013] [Indexed: 02/08/2023]
Abstract
CONTEXT Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients. EVIDENCE ACQUISITION We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin. EVIDENCE SYNTHESIS Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confounded decisions about the timing of prophylactic thyroidectomy for MTC, the dominant endocrinopathy associated with these syndromes. A distinct advance has been the demonstration through phase II and phase III clinical trials that molecular targeted therapeutics are effective in the treatment of patients with locally advanced or metastatic MTC. CONCLUSIONS The effective management of patients with MEN2A, MEN2A, and FMTC depends on an understanding of the variable behavior of disease expression in patients with a specific RET mutation. Information gained from molecular testing, biochemical analysis, and clinical evaluation is important in providing effective management of patients with either early or advanced-stage MTC.
Collapse
Affiliation(s)
- Samuel A Wells
- Cancer Genetics Branch, National Cancer Institute, National Institutes of Health, Building 37, Room 10106A, 37 Convent Drive, Bethesda, Maryland 20814, USA.
| | | | | | | |
Collapse
|
|
29
|
Matthews MA, Adler BH, Arnold MA, Kumar S, Carvalho R, Besner GE. Diffuse intestinal ganglioneuromatosis in a child. J Pediatr Surg 2013; 48:1129-33. [PMID: 23701793 PMCID: PMC4076949 DOI: 10.1016/j.jpedsurg.2013.03.066] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 03/14/2013] [Accepted: 03/17/2013] [Indexed: 12/26/2022]
Abstract
A 7 year old male with a history of congenital neutropenia and growth hormone deficiency presented with abdominal pain, fevers, and diarrhea. Imaging and endoscopy revealed significant inflammation of the ascending colon with stenosis at the level of the hepatic flexure. A right hemicolectomy was performed, and pathologic findings were consistent with diffuse intestinal ganglioneuromatosis. Due to recurrent mass effect at the intestinal anastomotic site detected radiologically, a second intestinal resection was performed 7 months later. Genetic testing was negative for mutations in the RET protooncogene, NF1 and PTEN tumor suppressor genes. We report a case of diffuse intestinal ganglioneuromatosis in a child with congenital neutropenia.
Collapse
Affiliation(s)
- Mika A.B. Matthews
- Department of Pediatric Surgery, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA
| | - Brent H. Adler
- Department of Radiology, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA
| | - Michael A. Arnold
- Department of Pathology, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA
| | - Soma Kumar
- Department of Gastroenterology, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA
| | - Ryan Carvalho
- Department of Gastroenterology, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA
| | - Gail E. Besner
- Department of Pediatric Surgery, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA,Corresponding author. Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, ED321, Columbus, OH 43205. Tel.: +1 614 722 3900; fax: +1 614 722 3903. (G.E. Besner)
| |
Collapse
|
|
30
|
|
|
31
|
Bernardini N, Ippolito C, Segnani C, Mattii L, Bassotti G, Villanacci V, Blandizzi C, Dolfi A. Histopathology in gastrointestinal neuromuscular diseases: methodological and ontological issues. Adv Anat Pathol 2013; 20:17-31. [PMID: 23232568 DOI: 10.1097/pap.0b013e31827b65c0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Gastrointestinal neuromuscular diseases (GINMDs) comprise a heterogenous group of chronic conditions associated with impaired gut motility. These gastrointestinal (GI) disorders, differing for etiopathogenic mechanisms, pathologic lesions, and region of gut involvement, represent a relevant matter for public health, because they are very common, can be disabling, and determine major social and economic burdens. GINMDs are presumed or proven to arise as a result of a dysfunctioning GI neuromuscular apparatus, which includes myenteric ganglia (neurons and glial cells), interstitial cells of Cajal and smooth muscle cells. Despite the presence of symptoms related to gut dysmotility in the clinical phenotype of these patients, in the diagnostic setting scarce attention is usually paid to the morphologic pattern of the GI neuromuscular apparatus. It is also objectively difficult to collect full-thickness gut tissue samples from patients with GINMDs, because their disease, which can be only functional in nature, may not justify invasive diagnostic procedures as a first-line approach. As a consequence, whenever available, bioptic gut specimens, retrieved from these patients, must be regarded as a unique chance for obtaining relevant diagnostic information. On the basis of these arguments, there is an urgent need of standardized and validated histopathologic methods, aiming at overcoming the discrepancies affecting current approaches, which usually lead to conflicting definitions of normality and hamper the identification of disease-specific pathologic patterns. This review article intends to address current methodological and ontological issues in the histopathologic diagnosis of GINMDs, to foster the debate on how to discriminate normal morphology from abnormalities.
Collapse
Affiliation(s)
- Nunzia Bernardini
- Unit of Histology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Chalazonitis A, Kessler JA. Pleiotropic effects of the bone morphogenetic proteins on development of the enteric nervous system. Dev Neurobiol 2012; 72:843-56. [PMID: 22213745 DOI: 10.1002/dneu.22002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Formation of the enteric nervous system (ENS) from migratory neural crest-derived cells that colonize the primordial gut involves a complex interplay among different signaling molecules. The bone morphogenetic proteins (BMPs), specifically BMP2 and BMP4, play a particularly important role in virtually every stage of gut and ENS development. BMP signaling helps to pattern both the anterior-posterior axis and the radial axis of the gut prior to colonization by migratory crest progenitor cells. BMP signaling then helps regulate the migration of enteric neural crest-derived precursors as they colonize the fetal gut and form ganglia. BMP2 and -4 promote differentiation of enteric neurons in early fetal ENS development and glia at later stages. A major role for BMP signaling in the ENS is regulation of responses to other growth factors. Thus BMP signaling first regulates neurogenesis by modulating responses to GDNF and later gliogenesis through its effects on GGF-2 responses. Furthermore, BMPs promote growth factor dependency for survival of ENS neurons (on NT-3) and glia (on GGF-2) by inducing TrkC (neurons) and ErbB3 (glia). BMP signaling limits total neuron numbers, favoring the differentiation of later born neuronal phenotypes at the expense of earlier born ones thus influencing the neuronal composition of the ENS and the glia/neuron ratio. BMP2 and -4 also promote gangliogenesis via modification of neural cell adhesion molecules and promote differentiation of the circular and then longitudinal smooth muscles. Disruption of BMP signaling leads to defects in the gut and in ENS function commensurate with these complex developmental roles.
Collapse
Affiliation(s)
- Alcmène Chalazonitis
- Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
| | | |
Collapse
|
|
33
|
Small intestinal ganglioneuromatosis in a dog. J Comp Pathol 2012; 148:323-8. [PMID: 22925263 DOI: 10.1016/j.jcpa.2012.07.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2012] [Revised: 07/02/2012] [Accepted: 07/10/2012] [Indexed: 12/31/2022]
Abstract
A 9-year-old female neutered collie-cross dog was presented with a 2-month history of persistent diarrhoea, weight loss and intermittent vomiting. Abdominal ultrasonography revealed one loop of jejunum with a markedly thickened and multifocally hyperechoic wall, without loss of wall layering. Laparotomies were performed for biopsy and resection of affected intestine. Histopathological examination revealed small intestinal ganglioneuromatosis (GN). The dog recovered well from surgery and the diarrhoea resolved. Eleven months later the dog has gained weight and remains asymptomatic. This is the first report of small intestinal GN affecting a mature dog, in which pathology was localized to the mucosal lamina propria and surgical treatment resulted in a successful outcome.
Collapse
|
|
34
|
Gockel HR, Gockel I, Schimanski CC, Schier F, Schumacher J, Nöthen MM, Lang H, Müller M, Eckardt AJ, Eckardt VF. Etiopathological aspects of achalasia: lessons learned with Hirschsprung's disease. Dis Esophagus 2012; 25:566-72. [PMID: 22050474 DOI: 10.1111/j.1442-2050.2011.01277.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The etiology of primary esophageal achalasia is largely unknown. There is increasing evidence that genetic alterations might play an important but underestimated role. Current knowledge of the genetic base of Hirschsprung's disease in contrast is far more detailed. The two enteric neuropathies have several clinical features in common. This association may also exist on a cellular and molecular level. The aim of this review is to enlighten those etiopathogenetic concepts of Hirschsprung's disease that seem to be useful in uncovering the pathological processes causing achalasia. Three aspects are looked at: (i) the genetic base of Hirschsprung's disease, particularly its major susceptibility gene rearranged during transfection and its potential reference to achalasia; (ii) the altered motor functions in both conditions with loss of inhibitory innervation and interstitial cell pathology; and (iii) the involvement of these motility disorders in genetic syndromes.
Collapse
Affiliation(s)
- H R Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University of Mainz, Mainz, Germany.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Montedonico S, Cáceres P, Muñoz N, Yáñez H, Ramírez R, Fadda B. Histochemical staining for intestinal dysganglionosis: over 30 years experience with more than 1,500 biopsies. Pediatr Surg Int 2011; 27:479-86. [PMID: 21327554 DOI: 10.1007/s00383-010-2849-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Intestinal dysganglionosis are a group of anomalies of the enteric nervous system that constitute infrequent but severe forms of constipation. Histochemical stainings are the gold standard diagnostic procedure for intestinal dysganglionosis. This study describes our experience with histochemistry in a large series of patients. METHODS Between 1977 and 2010, 1,589 biopsies from children with persistent chronic constipation were studied. The specimens were snap frozen, sectioned and stained with acetylcholinesterase (AChE), acetylcholinesterase counterstained with hematoxilin and succinic dehydrogenase (SDH) histochemical stainings. RESULTS Among the 1,589 biopsies, 946 (59.5%) were rectal biopsies, 242 (15.2%) were internal sphincter biopsies, 346 (21.8%) were intestinal mapping studies and 42 (2.7%) of them were colon specimens from surgical resections. From the rectal biopsy group, 544 (57.5%) patients were reported as normal. Hirschsprung disease was found in 163 (17.2%) patients with a median age at diagnosis of 8 months and a male to female ratio of 3:1. Intestinal neuronal dysplasia was found in 162 (17.2%) patients, hypoganglionosis in 3 (0.3%) of them and ganglioneuromatosis in 1 (0.1%). In 73 (7.7%) patients, the biopsy was not conclusive for different reasons. 34 out of the 42 resected colon specimens were Hirschsprung disease. Intestinal neuronal dysplasia was found in the proximal segment of the aganglionic bowel in 15 out of 34 (44%) patients. All the aganglionic resected colon specimens had a previous aganglionic rectal biopsy. There were no false positive results in this group. CONCLUSIONS Histochemical stainings continue to be the gold standard in the diagnosis of intestinal dysganglionosis. The combination of two histochemical staining techniques provides a high level of accuracy in the diagnosis of intestinal dysganglionosis.
Collapse
Affiliation(s)
- Sandra Montedonico
- Department of Biomedical Sciences, School of Medicine, Universidad de Vaparaíso, Edificio Bruno Ghünter, Hontaneda 2664, Valparaíso, Chile.
| | | | | | | | | | | |
Collapse
|
|
36
|
|
|
37
|
Lee MJ, Chung KH, Park JS, Chung H, Jang HC, Kim JW. Multiple Endocrine Neoplasia Type 2B: Early Diagnosis by Multiple Mucosal Neuroma and Its DNA Analysis. Ann Dermatol 2010; 22:452-5. [PMID: 21165219 DOI: 10.5021/ad.2010.22.4.452] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2009] [Revised: 01/27/2010] [Accepted: 01/28/2010] [Indexed: 10/18/2022] Open
Abstract
Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disease caused by germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. It is characterized by medullary thyroid carcinoma, pheochromocytoma and mucosal neuroma developing in the tongue, lip, intestinal tract, palate etc. Among these neoplasias, mucosal neuroma generally develops from early childhood. Therefore, early detection and proper treatment can minimize the disease course. Here we describe a 9-year-old male who presented with multiple verrucous papules and nodules on his lips, tongue and gingiva that were there since birth. Histologic findings of his lips and tongue showed well-defined nerve bundles and DNA analysis revealed a M918T mutation at codon 918 of the RET oncogene. He was diagnosed early as having MEN 2B according to his genetic and phenotypic features.
Collapse
Affiliation(s)
- Min Jung Lee
- Department of Dermatology, College of Medicine, The Catholic University of Daegu, Daegu, Korea
| | | | | | | | | | | |
Collapse
|
|
38
|
Traugott AL, Moley JF. Multiple endocrine neoplasia type 2: clinical manifestations and management. Cancer Treat Res 2010; 153:321-37. [PMID: 19957233 DOI: 10.1007/978-1-4419-0857-5_18] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
39
|
Wedel T, Büsing V, Heinrichs G, Nohroudi K, Bruch HP, Roblick UJ, Böttner M. Diverticular disease is associated with an enteric neuropathy as revealed by morphometric analysis. Neurogastroenterol Motil 2010; 22:407-14, e93-4. [PMID: 20040058 DOI: 10.1111/j.1365-2982.2009.01445.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The pathogenesis of diverticular disease (DD) is attributed to several aetiological factors (e.g. age, diet, connective tissue disorders) but also includes distinct intestinal motor abnormalities. Although the enteric nervous system (ENS) is the key-regulator of intestinal motility, data on neuropathological alterations are limited. The study aimed to investigate the ENS by a systematic morphometric analysis. METHODS Full-thickness sigmoid specimens obtained from patients with symptomatic DD (n = 27) and controls (n = 27) were processed for conventional histology and immunohistochemistry using anti-HuC/D as pan-neuronal marker. Enteric ganglia, nerve and glial cells were quantified separately in the myenteric, external and internal submucosal plexus compartments. KEY RESULTS Compared to controls, patients with DD showed significantly (P < 0.05) (i) reduced neuronal density in all enteric nerve plexus, (ii) decrease of ganglionic nerve cell content in the myenteric plexus, (iii) decreased ganglionic density in the internal submucosal plexus, (iv) reduced glial cell density in the myenteric plexus, (v) decrease of ganglionic glial cell content in the myenteric plexus and increase in submucosal plexus compartments, (vi) increased glia index in all enteric nerve plexus. About 44.4% of patients with DD exhibited myenteric ganglia displaying enteric gliosis. CONCLUSIONS & INFERENCES Patients with DD show substantial structural alterations of the ENS mainly characterized by myenteric and submucosal oligo-neuronal hypoganglionosis which may account for intestinal motor abnormalities reported in DD. The morphometric data give evidence that DD is associated with structural alterations of the ENS which may complement established pathogenetic concepts.
Collapse
Affiliation(s)
- T Wedel
- Department of Anatomy, Christian-Albrechts University of Kiel, Kiel, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
40
|
Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group. Acta Neuropathol 2009; 118:271-301. [PMID: 19360428 DOI: 10.1007/s00401-009-0527-y] [Citation(s) in RCA: 139] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2009] [Revised: 03/19/2009] [Accepted: 03/22/2009] [Indexed: 01/30/2023]
Abstract
The term gastrointestinal neuromuscular disease describes a clinically heterogeneous group of disorders of children and adults in which symptoms are presumed or proven to arise as a result of neuromuscular, including interstitial cell of Cajal, dysfunction. Such disorders commonly have impaired motor activity, i.e. slowed or obstructed transit with radiological evidence of transient or persistent visceral dilatation. Whilst sensorimotor abnormalities have been demonstrated by a variety of methods in these conditions, standards for histopathological reporting remain relatively neglected. Significant differences in methodologies and expertise continue to confound the reliable delineation of normality and specificity of particular pathological changes for disease. Such issues require urgent clarification to standardize acquisition and handling of tissue specimens, interpretation of findings and make informed decisions on risk-benefit of full-thickness tissue biopsy of bowel or other diagnostic procedures. Such information will also allow increased certainty of diagnosis, facilitating factual discussion between patients and caregivers, as well as giving prognostic and therapeutic information. The following report, produced by an international working group, using established consensus methodology, presents proposed guidelines on histological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology. The report addresses the main areas of histopathological practice as confronted by the pathologist, including suction rectal biopsy and full-thickness tissue obtained with diagnostic or therapeutic intent. For each, indications, safe acquisition of tissue, histological techniques, reporting and referral recommendations are presented.
Collapse
|
|
41
|
Abstract
The mature enteric nervous system (ENS) is composed of many different neuron subtypes and enteric glia, which all arise from the neural crest. How this diversity is generated from neural crest-derived cells is a central question in neurogastroenterology, as defects in these processes are likely to underlie some paediatric motility disorders. Here we review the developmental appearance (the earliest age at which expression of specific markers can be localized) and birthdates (the age at which precursors exit the cell cycle) of different enteric neuron subtypes, and their projections to some targets. We then focus on what is known about the mechanisms underlying the generation of enteric neuron diversity and axon pathfinding. Finally, we review the development of the ENS in humans and the etiologies of a number of paediatric motility disorders.
Collapse
Affiliation(s)
- Marlene M Hao
- Department of Anatomy & Cell Biology, University of MelbourneParkville, Victoria, Australia
| | - Heather M Young
- Department of Anatomy & Cell Biology, University of MelbourneParkville, Victoria, Australia
| |
Collapse
|
|
42
|
Wallace AS, Barlow AJ, Navaratne L, Delalande JM, Tauszig-Delamasure S, Corset V, Thapar N, Burns AJ. Inhibition of cell death results in hyperganglionosis: implications for enteric nervous system development. Neurogastroenterol Motil 2009; 21:768-e49. [PMID: 19400926 DOI: 10.1111/j.1365-2982.2009.01309.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The enteric nervous system (ENS) is derived from vagal and sacral neural crest cells (NCC) that delaminate from the neural tube and undergo extensive migration and proliferation in order to colonize the entire length of the gut and differentiate into many millions of neurons and glial cells. Although apoptotic programmed cell death is an essential physiological process during development of the majority of the vertebrate nervous system, apoptosis within early ENS development has not been comprehensively investigated. The aim of this study was to determine the presence and extent of apoptosis within the vagal NCC population that gives rise to most of the ENS in the chick embryo. We demonstrated that apoptotic cells, as shown by terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling and active caspase-3 immunoreactivity, are present within an electroporated green fluorescent protein (GFP) and human natural killer-1 (HNK-1) immunopositive NCC population migrating from the vagal region of the neural tube to the developing foregut. Inhibition of caspase activity in vagal NCC, by electroporation with a dominant-negative form of caspase-9, increased the number of vagal NCC available for ENS formation, as shown by 3-dimensional reconstruction of serial GFP or HNK-1 labelled sections, and resulted in hyperganglionosis within the proximal foregut, as shown by NADPH-diaphorase whole gut staining. These findings suggest that apoptotic cell death may be a normal process within the precursor pool of pre-enteric NCC that migrates to the gut, and as such it may play a role in the control of ENS formation.
Collapse
Affiliation(s)
- A S Wallace
- Neural Development Unit, UCL Institute of Child Health, London, UK
| | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009; 19:565-612. [PMID: 19469690 DOI: 10.1089/thy.2008.0403] [Citation(s) in RCA: 801] [Impact Index Per Article: 50.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and challenging malignancy. The American Thyroid association (ATA) chose to create specific MTC Clinical Guidelines that would bring together and update the diverse MTC literature and combine it with evidence-based medicine and the knowledge and experience of a panel of expert clinicians. METHODS Relevant articles were identified using a systematic PubMed search and supplemented with additional published materials. Evidence-based recommendations were created and then categorized using criteria adapted from the United States Preventive Services Task Force, Agency for Healthcare Research and Quality. RESULTS Clinical topics addressed in this scholarly dialog included: initial diagnosis and therapy of preclinical disease (including RET oncogene testing and the timing of prophylactic thyroidectomy), initial diagnosis and therapy of clinically apparent disease (including preoperative testing and imaging, extent of surgery, and handling of devascularized parathyroid glands), initial evaluation and treatment of postoperative patients (including the role of completion thyroidectomy), management of persistent or recurrent MTC (including the role of tumor marker doubling times, and treatment of patients with distant metastases and hormonally active metastases), long-term follow-up and management (including the frequency of follow-up and imaging), and directions for future research. CONCLUSIONS One hundred twenty-two evidence-based recommendations were created to assist in the clinical care of MTC patients and to share what we believe is current, rational, and optimal medical practice.
Collapse
|
|
44
|
Sallai A, Hosszú E, Gergics P, Rácz K, Fekete G. Orolabial signs are important clues for diagnosis of the rare endocrine syndrome MEN 2B. Presentation of two unrelated cases. Eur J Pediatr 2008; 167:441-6. [PMID: 17576593 DOI: 10.1007/s00431-007-0532-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2007] [Accepted: 05/23/2007] [Indexed: 10/23/2022]
Abstract
Multiple endocrine neoplasia syndromes (MEN) are genetic disorders with glandular hyperplasia and consecutive malignant neoplasia. MEN type 2B is the least common form of these tumor syndromes. It presents with typical dysmorphic features, mucosal neuromas, ganglioneuromatosis, medullary thyroid carcinoma (MTC) and phaeochromocytoma. The prognosis depends on the presence of MTC. We have surprisingly found two unrelated patients with this syndrome at our department within two weeks. In the medical history of a 17-year-old boy, Crohn's disease had been considered because of abdominal pain and distention. He had marfanoid appearance and previously undergone minor surgeries for a large tongue with neuromas and hypertrophic gums. Two weeks later, a 10-year-old girl presented with a hard palpable mass on her neck. She had thickened lips, neuromas on the tongue and a solitary thyroid nodule. Genetic analysis was carried out in both patients and a heterozygous M918T mutation of the RET proto-oncogene was found. Laboratory tests and imaging studies were consistent with MTC. Phaeochromocytoma was not present. Both patients underwent total thyroidectomy and lymph node dissection. Histological examination confirmed the diagnosis of MTC. In conclusion, the initial diagnosis of MEN 2B should be suspected on the presence of typical facial/oral signs and gastrointestinal symptoms. Hormonal tests and imaging techniques of the thyroid and the adrenals can confirm the clinical diagnosis of MEN 2B and genetic analysis can prove its germline origin.
Collapse
Affiliation(s)
- Agnes Sallai
- 2nd Department of Paediatrics, Faculty of Medicine, Semmelweis University, Tüzoltó u. 7-9, Budapest, 1094, Hungary.
| | | | | | | | | |
Collapse
|
|
45
|
Abstract
Congenital and acquired disorders of the enteric neuromusculature are relatively uncommon in childhood, with the exception of Hirschsprung disease. Despite this, a number of histologically well-defined phenotypes of enteric neuromuscular disease are now recognised in paediatric populations, essentially comprising enteric neuropathies and enteric myopathies. This classification is briefly discussed.
Collapse
|
|
46
|
Unruh A, Fitze G, Jänig U, Bielack S, Lochbühler H, Coerdt W. Medullary thyroid carcinoma in a 2-month-old male with multiple endocrine neoplasia 2B and symptoms of pseudo-Hirschsprung disease: a case report. J Pediatr Surg 2007; 42:1623-6. [PMID: 17848262 DOI: 10.1016/j.jpedsurg.2007.05.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
A 5-week-old male patient was seen for symptoms suggestive of Hirschsprung disease (abdominal distension, failure to thrive, and explosive defecation). Rectum biopsies revealed an intestinal ganglioneuromatosis, which is usually associated with multiple endocrine neoplasia (MEN) syndrome type 2B. The ensuing molecular genetic analysis revealed a M918T mutation of the RET protooncogene, which is associated with early-onset medullary thyroid carcinoma (MTC). Therefore, total thyroidectomy and central lymphadenectomy were performed at the age of 9 weeks. Histology showed a medullary microcarcinoma. This report of MTC occurrence within the first weeks of life underlines the importance of early diagnosis and thyroidectomy in patients with MEN 2B syndrome. Because many patients with MEN 2A and B show gastrointestinal symptoms before the development of MTC, the possibility of MEN 2 should be recognized, and genetic testing for the presence of RET mutations should be included in the explorative diagnosis for megacolon.
Collapse
Affiliation(s)
- Annika Unruh
- Department of Pediatric Surgery, Klinikum Stuttgart, Olgahospital, 70176 Stuttgart, Germany.
| | | | | | | | | | | |
Collapse
|
|
47
|
Lorenceau-Savale C, Savoye G, Pouzoulet J, Le Pessot F, Savoye-Collet C, Leblanc-Louvry I, Lerebours E. Ganglioneuromatosis: an unusual cause of ileal stricture mimicking Crohn's disease. Dig Dis Sci 2007; 52:1806-9. [PMID: 17404862 DOI: 10.1007/s10620-006-9603-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2006] [Accepted: 09/05/2006] [Indexed: 12/29/2022]
Abstract
Ileal idiopathic forms of ganglioneuromatosis in adults are extremely rare and represent a challenging pathologic condition for the clinician. We present two cases of ileal ganglioneuromatosis consisting of stricturing lesions that mimicked clinical and radiologic features commonly observed in Crohn's disease patients with ileal involvement.
Collapse
Affiliation(s)
- C Lorenceau-Savale
- Department of Gastroenterology and Hepatology, ADEN EA 32 34, University Hospital C. Nicolle, 1 rue de Germont, 76031, Rouen, France.
| | | | | | | | | | | | | |
Collapse
|
|
48
|
Abstract
Hirschsprung's disease constitutes a neural crest stem cell disorder (neurocristopathy) which is caused by absent or malfunctional intestinal intramural ganglion cells. The rostral extension of the aganglionic segment is variable. Hirschsprung's disease can be classified into type 1 (short segment) and type 2 (long segment) forms. It is limited to the gastrointestinal tract, but may occur in the syndromal context of manifold genetic diseases in 12% of patients. The prevalence is 1:5,000 with a distinct male predominance of 4-5:1. Numerous genes and non-coding polymorphous DNA sequence variants are involved in the pathogenesis of Hirschsprung's disease. The most important gene is RET. Susceptibility loci on 3p21, 9q31 and 19q12 interact with this gene. Downstream of RET, two new genes, GALNACT-2 and RASGEF1A, have also been identified. A recently described, frequent, non-coding RET variant, RET+3, is significantly associated with susceptibility to Hirschsprung's disease and carries a 20-fold increased risk of contracting the disease compared to rarer alleles.
Collapse
Affiliation(s)
- E Passarge
- Institut für Humangenetik, Universitätsklinikum Essen, 45122 Essen, Germany.
| | | |
Collapse
|
|
49
|
Chan OTM, Haghighi P. Hamartomatous polyps of the colon: ganglioneuromatous, stromal, and lipomatous. Arch Pathol Lab Med 2006; 130:1561-6. [PMID: 17090203 DOI: 10.5858/2006-130-1561-hpotcg] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2006] [Indexed: 11/06/2022]
Abstract
Intestinal ganglioneuromas comprise benign, hamartomatous polyps characterized by an overgrowth of nerve ganglion cells, nerve fibers, and supporting cells in the gastrointestinal tract. This polyposis has been divided into 3 subgroups, each with a different degree of ganglioneuroma formation: polypoid ganglioneuroma, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. The ganglioneuromatous polyposis subgroup is not known to coexist with systemic disorders that often have an associated intestinal polyposis, such as multiple endocrine neoplasia type IIb, neurofibromatosis type I, and Cowden syndrome. We report a case of ganglioneuromatous polyposis plus cutaneous lipomatosis in a 41-year-old man with no established systemic disease. However, he possessed unique anatomic findings in addition to his ganglioneuromatosis, suggesting that the ganglioneuromatosis-lipomatosis in our patient may represent an unrecognized syndrome. This case report and brief review of the literature provide an overview of intestinal ganglioneuromatosis in relation to the hereditary polyposis syndromes and describe the individual ganglioneuromatosis subgroups.
Collapse
Affiliation(s)
- Owen T M Chan
- Department of Pathology, University of California-San Diego and VA Medical Center, San Diego, Calif, USA.
| | | |
Collapse
|
|
50
|
Nguyen ATT, Zacharin MR, Smith M, Hardikar W. Isolated intestinal ganglioneuromatosis with a new mutation of RET proto-oncogene. Eur J Gastroenterol Hepatol 2006; 18:803-5. [PMID: 16772843 DOI: 10.1097/01.meg.0000224473.66675.ad] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
A 13-year-old boy with a history of juvenile polyps of the colon was subsequently found to have isolated intestinal ganglioneuromatosis without any other features characteristic of multiple endocrine neoplasia (MEN) 2B. Screening for MEN 2B revealed a polymorphism of the RET proto-oncogene at codon 691 with a glycine to serine conversion. This mutation has not been described before in association with ganglioneuromatosis and MEN 2B. The phenotype and presentation are compared with those of previous case reports.
Collapse
Affiliation(s)
- An T T Nguyen
- Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria 3050, Australia
| | | | | | | |
Collapse
|