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This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

Branched-chain amino acids (BCAAs) have been suggested to be particularly potent activators of Target of Rapamycin (TOR) signaling. Moreover, increased circulating BCAAs are associated with higher risk of insulin resistance and diabetes in both mice and humans, and with increased mortality in mice. However, it remains unknown if BCAAs play a more prominent role in longevity than do other essential amino acids (EAAs). To test for a more prominent role of BCAAs in lifespan and related traits in Drosophila, we restricted either BCAAs or a control group of three other EAAs, threonine, histidine and lysine (THK). BCAA restriction induced compensatory feeding, lipid accumulation, stress resistance and amelioration of age-related gut pathology. It also extended lifespan in a dietary-nitrogen-dependent manner. Importantly, the control restriction of THK had similar effects on these phenotypes. Our control diet was designed to have every EAA equally limiting for growth and reproduction, and our findings therefore suggest that the level of the most limiting EAAs in the diet, rather than the specific EAAs that are limiting, determines the response of these phenotypes to EAA restriction.

Plants generate a plethora of secondary compounds (toxins) that potently influence the breadth of the breeding niches of animals, including Drosophila. Capsaicin is an alkaloid irritant from hot chili peppers, and can act as a deterrent to affect animal behaviors, such as egg laying choice. However, the mechanism underlying this ovipositional avoidance remains unknown. Here, we report that Drosophila females exhibit a robust ovipositional aversion to capsaicin. First, we found that females were robustly repelled from laying eggs on capsaicin-containing sites. Second, genetic manipulations show that the ovipositional aversion to capsaicin is mediated by activation of nociceptive neurons expressing the painless gene. Finally, we found that capsaicin compromised the health and lifespan of flies through intestinal dysplasia and oxidative innate immunity. Overall, our study suggests that egg-laying sensation converts capsaicin into an aversive behavior for female Drosophila, mirroring an adaptation to facilitate the survival and fitness of both parents and offspring.

It is believed that sessile serrated adenomas/polyps lead to the development of microsatellite unstable cancer via a dysplasia-carcinoma sequence. Little is known regarding the morphologic and biologic features, and outcome of sessile serrated adenomas/polyps with dysplasia, or of its specific dysplasia subtypes (intestinal versus serrated). The aims of this study were to analyze and compare the clinical, pathologic, and outcome characteristics of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia. The study included 86 patients with sessile serrated adenomas/polyps with dysplasia (50 serrated dysplasia, 22 intestinal dysplasia, 14 mixed serrated and intestinal dysplasia). The clinical and pathologic features, and the prevalence rate of prior, concurrent, and future neoplastic lesions, were compared between sessile serrated adenomas/polyps with intestinal versus serrated dysplasia and with matched control patients with ≥1 conventional adenoma. The mean age of the patients, polyp size, and prevalence of adenocarcinoma within the polyps were significantly higher in sessile serrated adenomas/polyps with high versus low-grade dysplasia. Sessile serrated adenomas/polyps with intestinal dysplasia showed a significantly higher rate of adenocarcinoma (23%) compared with those with serrated dysplasia (6%, P=0.05), and the high-grade lesions occurred at a significantly younger age in the former compared with the latter (65 versus 76 years, P=0.05). Compared with patients with conventional adenomas, patients with sessile serrated adenomas/polyps with dysplasia showed a significantly higher rate of invasive carcinoma within the polyps (12 versus 0%, P=0.01) and a significantly lower association with prior or future conventional adenomas. Sessile serrated adenomas/polyps with dysplasia should be considered high-risk neoplastic precursor lesions, particularly those with intestinal dysplasia. Cancer may develop from sessile serrated adenomas/polyps with either type of dysplasia.

Oral sodium phosphate-based laxatives are frequently used for bowel preparation or relief of constipation in some countries. However, these agents are not without risk. Small and clinical insignificant increments on serum phosphorus levels are observed in almost all individuals after use of oral sodium phosphate. Some patients are prone to severe hyperphosphatemia such as elders, those with chronic or acute renal disease and those with poor bowel motility. Severe hyperphosphatemia accompanied with hypocalcemia may be life-threatening in these patients. We present an 18-year-old woman with neuronal intestinal dysplasia who developed symptomatic and severe hyperphosphatemia after bowel preparation with oral sodium phosphate enema. Urgent hemodialysis was performed two times for severe hyperphosphatemia.

Aim: Cryptosporidiosis causes colon dysplasia. This research aimed to evaluate the effect of a novel combination between artesunate and nitazoxanide on intensity of infection and the resulting intestinal dysplasia. Materials & methods: Subjects were divided into five groups. Artesunate was used alone, then combined with nitazoxanide. Results: The highest efficacy in reducing oocyst shedding obtained from the combined therapy (68.5, 75.9, 99%) after 7, 14 and 21 days. The histopathology of infected colonic mucosa showed marked improvement and low-grade of dysplasia in the infected and treated group with the combined therapy. The immunohistochemistry of the same group revealed mild dysplastic changes in colonic epithelium without nuclear expression for cyclin D1. Conclusion: These results give hope for treatment of Cryptosporidium and improving intestinal dysplasia.

Children with spina bifida, high anorectal anomalies, or neuronal intestinal dysplasia who are treated with a laparoscopic antegrade continence enema to achieve a socially acceptable level of fecal continence sometimes have problems with the stoma and its catheterization. The goal of this study was to determine the nature and incidence of these problems, and their relationship to the underlying condition.A retrospective review of the hospital case notes of 74 consecutive patients who had a laparoscopic antegrade continence enema was undertaken.The laparoscopic antegrade continence enema procedure is well tolerated but is associated with a variety of usually minor complications including stomal stenosis, leakage, peristomal infection, granulation tissue overgrowth, mucosal prolapse, abdominal discomfort during irrigation, appendiceal false passage, and ineffective irrigation. Surgical revision of the stoma was required in 19% of the cases in this study, usually because of stenosis and skin overgrowth. Ongoing problems achieving colonic emptying were most likely to occur in patients with an anorectal malformation.Overall, the laparoscopic antegrade continence enema provides an effective method of facilitating emptying of the bowel. However, it has a high incidence of minor troublesome problems, with stenosis and skin overgrowth of the stoma being the most common. Younger children tend to have more complications and difficulty performing effective irrigation. Children with anorectal malformations were more likely to require surgical revision of the stoma, and often needed ongoing manual evacuation and bowel washouts despite the laparoscopic antegrade continence enema.

The authors present the case of a newborn girl who had cystic fibrosis associated with neuronal intestinal dysplasia type B (NID-B). The association is rare but must be considered in the differential diagnosis of gastrointestinal problems in patients with cystic fibrosis. The present case elucidates the intestinal problems that can arise with this combination of diseases. Although the unusual association found in this patient could have been a random occurrence, the possiblity of an NID-B determining gene localized on chromosome 7q should be considered.

Neuronal intestinal dysplasia (NID) is wellknown, but its definition is a topic of debate. The histopathological diagnosis of NID is based on traditional enzyme-histochemical methods such as the acetylcholinesterase and dehydrogenase reaction on native cryosections. In this study, we have investigated the enteric nervous system in whole mount preparations of resected intestinal segments affected by NID of the plexus submucosus (type B). The plexuses of the tunica mucosa and tunica submucosa were visualized by immunohistochemical methods using a polyclonal antibody to protein gene produce 9.5 (PGP 9.5). PGP 9.5 is a novel general cytoplasmatic marker specific for the nervous system. The morphology of the plexuses is revealed in full, making possible changes easily discernible. Known pathological findings of the NID can be identified and judged more precisely with this method. Numerous enlarged nerve trunks run within the tunica submucosa and tunica mucosa. Hyperplastic ganglia with an unusually high nerve cell number in the tunica submucosa can be demonstrated as well as heterotopic nerve cells in the tunica mucosa.

Prostatic neoplasms are rare in childhood. We report a case of primary prostatic carcinoid in a 7-year-old boy who was subsequently diagnosed with multiple endocrine neoplasia IIb. To our knowledge this is the first report of either pediatric carcinoid of the prostate or of prostatic carcinoid in conjunction with neuronal intestinal dysplasia and medullary thyroid carcinoma suggestive of multiple endocrine neoplasia IIb. Management and histogenesis regarding this prostatic tumor are discussed as is a possible association with other neuroendocrine tumors. Neoplastic disease of the prostate, benign or malignant, infrequently occurs in children and carcinoid of the prostate, either primary or secondary, has not been described at this age, although distribution is widespread. Carcinoid has been isolated from gastrointestinal, biliary, respiratory and genitourinary tracts. Genitourinary sites include the testis, kidney, bladder, urethra, prostate, ovary, cervix and vagina. In regard to prostatic carcinoid recent histopathological findings reveal the presence of enterochromafh cells in the neoplastic and nonneoplastic prostate.1*2 Speculation as to a functional or divergent differentiation from the usual histomorphological type to a carcinoid or carcinoid-like tumor through neoplastic transformation has been made? The majority of reported cases have been associated with adenocarcinoma and as such they have been observed in older men.3*4 We report a unique case of carcinoid of the prostate in a 7-year-old boy without adenocarcinoma, the incidental finding of neuronal intestinal dysplasia in the appendix and the detection of medullary thyroid carcinoma based on investigation of a persistently elevated calcitonin. CASE HISTORY A 7-year-old boy presented with a 3-year history of burning micturition associated in the last year with 2 episodes of gross hematuria. Evaluation was negative for incontinence, frequency, urgency, abdominal pain and systemic symptoms. History included toxic hip synovitis, proximal right leg weakness, distant circumcision and meatotomy. Vital signs were normal, and height and weight were below the 10th percentile. Abdominal and genitourinary examination was unremarkable. Digital rectal examination revealed an asymmetrically enlarged prostate with a prominent right lobe. Urine microscopy and culture, inclusive for tuberculosis and fungi, serum multiple analysis, including calcium and phosphate, and complete blood count were normal. Abdominal and pelvic ultrasound, computerized tomography (CT) and magnetic resonance imaging identified an enlarged inhomogeneous prostate, with elevation of the bladder base and displacement of the urethra to the left side (fig. 1). No other abnormalities, including adenopathy, were noted. Cystoscopic examination confirmed the clinical and radiological picture. A pediatric resectoscope could not be passed, and transrectal ultrasound guided biopsy was performed, which provided a tissue diagnosis of carcinoid. Further clinical staging, including bone scan, CT of the chest and scrota1 ultrasound, was unremarkable. Oncofetal, pheochromocytoma

Neuronal intestinal dysplasia (NID) usually mimies Hirschsprung's disease, but rarely presents as neonatal neterocolitis. The authors report a case of colonic hyperganglionosis, which is a form of NID, presenting with postenterocolitis intestinal strictures. NID should be considered as a possible (although rare) cause of neonatal enterocolitis and may present with intestinal strictures.

The rate of Hirschsprung-associated neuronal intestinal dysplasia (HANID) is reported to be as high as 20-75% but no report deals with its sequelae. The aim of our study was to evaluate the influence of the retained neuronal dysplastic segment in patients with Hirschsprung's disease (HD). We report on 47 patients with HD including 11 cases with HANID (23%). All 47 children had a Duhamel procedure subsequent to colostomy and in none of the 11 cases with HANID was the neuronal dysplastic segment resected. There was no significant difference of early and late complications in both groups and the results of the mean follow-up of 5 years after the Duhamel procedure show that the patients with HANID did as well as the patients with isolated HD. It is suggested therefore that HANID may be a distinct disease compared to isolated NID and that the NID attained segment may be retained without increased risks or morbidity.

During infancy at least six intestinal motility syndromes are known to occur. These are: (1) aganglionosis (Hirschsprung’s disease); (2) meconium plug syndrome (also known as neonatal small left colon); (3) microcolon of prematurity; (4) CPAP belly syndrome (found in infants treated on a ventilator with continuous positive airways pressure); (5) megacystis microcolon intestinal hypoperistalsis (neonatal hollow viscus myopathy); and, (6) neuronal intestinal dysplasia.

The association of megacolon in adults and Hirschsprung’s disease was re-evaluated by the morphological assessment of the enteric nervous system. Whole-mount preparations of the resected colonic segments and an immunohistochemical treatment with the pan-neuronal marker protein gene product 9.5 allowed an optimal visualization of the entire intramural nervous plexus layers. The findings included different forms of intestinal neuronal malformations (hypoganglionosis, neuronal intestinal dysplasia, and heterotopic ganglia) apart from classic aganglionosis, thus indicating their ethiologic relevance to the development of megacolon in adults.

The complex of malformations of neuronal dysplasia of the colon and small bowel was designated "neuronal intestinal dysplasia" (NID) by Meier-Ruge in 1971 (1). In recent years, particularly in the English literature, the term IND (intestinal neuronal dysplasia) has taken precedence. Since the abbreviation NID has already been adopted in international terminology for normal-weight, insulin-dependent diabetes, its use in other contexts can lead to misunderstandings.

Nous avons pratique une manometrie anorectale chez 8 enfants ayant une dysplasie intestinale neuronale soit suspectee soit confirmee par les examens histo-chimiques. Ces resultats furent compares a un score electromanometrique theorique prepare auparavant. Les symptomes cliniques ainsi que les resultats histologiques et manometriques furent compares dans le but d'etudier la fiabilite de ce score electromanometrique dans le diagnostic d'une dysplasie intestinale neuronale. Une etude statistique fut impossible vu le petit nombre de malades examines. Par contre il apparait a prime abord que certains parametres electromanometriques sont regulierement presents lors d'une dysplasie intestinale neuronale

In order to identify possible underlying ganglion-cell disorders, specimens have been taken in neonates and infants with intestinal obstruction treated between January 1988 and June 1992. NID was confirmed in 3 patients with intestinal malformation, 2 patients with neonatal intestinal obstruction, 3 patients with meconium peritonitis, 1 patient with persistent constipation after Duhamel's pullthrough for Hirschsprung's disease and 1 patient with rectal stricture after conservative treatment for necrotising enterocolitis. Additionally, NID was found in 1 patient with recurrent prolapse of an ileostomy. Associated Hirschsprung's disease has been ruled out by additional rectal suction biopsies in patients where specimens have been collected at laparotomy first. Development of NID in previous normal bowel, the association of NID with intestinal malformations as well as the clinical heterogenity of patients with NID of the present series suggest that NID is a reaction of the neural intestinal system caused by congenital obstructive factors or inflammatory diseases. © 1993, Georg Thieme Verlag KG Stuttgart, New York. All rights reserved.

A familial occurrence of Hirschsprung's disease and neuronal intestinal dysplasia (NID) is reported. Familial occurrence of NID in a parent and long-segment Hirschsprung's disease in two children in a family as well as a further report of NID in monozygotic twins is described. The linkage of these neurodevelopmental conditions is explored and a common etiologic mechanism for the two conditions is postulated.

Six children with isolated neuronal intestinal dysplasia (NID) and unusual complications are presented. Three had meconium peritonitis, one of them in association with a solid pyloric atresia, one midgut volvulus, one rectal stenosis, and one jejunojejunal intussusception. These cases show that patients with isolated NID may present with a heterologous pattern of symptoms very different from those generally reported, indicating that NID may not be a distinct clinical entity. The symptomatology of NID seems to be directly correlated with the degree of functional defect of gut motility. NID should be suspected in any case of functional small-bowel obstruction.

The diagnosis of neuronal intestinal dysplasia (NID) is currently established by histochemical procedures. From October 1, 1981, until July 31,1990, we submitted a total number of 737 patients under 15 years of age with several distinct colonic and anorectal disorders, to clinical, radiological, electromanometrical, histochemical and histological evaluation. 573 had a clinical diagnosis of chronic constipation, and in 38 of these NID could be demonstrated by histochemical examination. Motivated by our own findings with the anorectal electromanometry in these patients we performed a double-blind prospective study to find out if there are any particular and pathognomonic manometric parameters of NID in childhood. 80 % of our patients with NID diagnosed prospectively since April 1st, 1986, had a relaxation of the internal anal sphincter which was not proportional to the volume of rectal distention. Anorectal hyperexcitability was also present in these patients, whereas a statistically highly significant (p

Neuronal intestinal dysplasia in pediatric patients has similar clinical symptoms and often similar radiologic findings to those of Hirschsprung's disease. Yet neuronal intestinal dysplasia shows hyperplasia of the myenteric plexus for the pathology, and it requires different treatment compared with Hirschsprung disease. This disease has been reported many times in Europe but, to date, only one case has been reported in the radiologic literatures in Korea. We report here on a case of neuronal intestinal dysplasia that involved the entire colon in a two-month-old boy, and we include the radiographic findings.

This study presents the case of a patient with neurofibromatosis and megacolon. A diffuse, but patchy abnormality of neural tissue was present throughout the colon, especially in the myenteric plexus, but also in the submucosal plexus, smooth muscles, and lamina propria. This consisted of (a) a marked decrease in the number of argyrophilic neurons within the myenteric plexus, enlargement and deformity of those neurons present, and a marked increase of nerve fibers and nerve tract size in the myenteric plexus; (b) a proliferation of neurons and nerve fibers within the smooth muscle and submucosa; and (c) a proliferation of nerve fibers within focal areas of the lamina propria. The relationship of this case to previously reported cases of neuronal intestinal dysplasia and plexiform neurofibromatosis is discussed. Surgical treatment may be necessary and the surgical options are reviewed.

Over a period of 10 years we have treated 10 patients with neuronal intestinal dysplasia (NID), including 3 in whom the entire intestinal tract was affected by NID, and one in whom small intestinal NID coexisted with total colonic aganglionosis. Three of these 4 patients have died and the one survivor requires parenteral feeding. The six patients with less extensive NID have all been treated successfully; three have required surgery (Duhamel procedure in 2 and colostomy in 1), but 3 responded to conservative measures. We have made detailed histologic studies, including acetylcholinesterase activity in all cases, silver impregnation studies in 4, and immunohistochemical investigation of the peptidergic innervation of the bowel in one case. Follow-up rectal biopsies have not shown any significant morphological changes with time, but functional improvement does occur and we suggest that the myenteric ganglia in NID may have the capacity for functional maturation.

Summary Objectives There is an association between chronic inflammation and cancer, including colon cancer. Cryptosporidium parvum is a protozoan parasite that infects the gastrointestinal epithelial cells causing several parasitological and pathological changes. It is incriminated in the development of colorectal cancer in immunosuppressed individuals. Cyclin D1 expression is essential for cell cycle progression and its overexpression has been reported in colorectal cancer. This work aimed to study the gastrointestinal changes, including parasitological and pathological changes, induced by C. parvum infection in both immunocompetent and in chemically immunosuppressed mice, together with immunohistochemical assessment of cyclin D1 expression in infected tissues. In addition, the effectiveness of nitazoxanide (NTZ) in the treatment of cryptosporidiosis was evaluated. Methods This study included six groups of mice: group I, infected; group II, infected and immunosuppressed; group III, infected and treated with NTZ; group IV, infected, immunosuppressed, and treated with NTZ; and groups V and VI representing non-infected controls. Mice were subjected to stool examination for oocyst counts and were later sacrificed for intestinal dissection and routine histopathological examination of pathological changes; the endogenous developmental stages of the parasite were counted and immunohistochemical staining was carried out for the determination of cyclin D1. Results Group II showed the highest numbers of oocysts shed and endogenous developmental stages compared to the other groups. Intestinal dysplastic changes were seen only in groups I and II, where these changes were in favor of group II compared to group I. High-grade dysplasia was seen in four out of 20 mice in group II and was significantly associated with the number of endogenous developmental stages of C. parvum . NTZ was effective in the treatment of Cryptosporidium infection, with a greater effect in group III than in group IV. Conclusions C. parvum is one of the infectious agents that may induce intestinal dysplasia, including the high-grade category, which occurs particularly in the presence of immune suppression states and elevated endogenous parasite loads. Cyclin D1 is a good and useful marker for the detection of intestinal dysplasia. The effectiveness of NTZ is dependent on the immune status of the infected host.

A series of 21 patients with NID is presented. A histologic and histochemical picture of NID was seen in an heterogenous group of patients. NID was associated with bowel obstruction and/or Perforation in six neonates and infants. One neonate died. During follow-up the bowel histology gradually normalized in four of the five patients.

Findings in 23 children with neuronal intestinal dysplasia (NID) are presented. Twelve children had Hirschsprung's disease that masked the existence of proximal NID. In all cases the diagnosis was established by histological-histochemical examination. Amelioration of symptoms by conservative treatment alone was achieved in 4 children; in 13 cases colostomy was necessary. In 6 patients colon resection was performed: 2 suffered from both colitis and obstruction; the other 4 were treated for obstruction, multiple perforations, persistant adynamia of the left colon, and fistulation. In 9 patients the colostomy was closed. Four of 6 children who did not have sonographic confirmation of motility had complications due to colon dysmotility after closure of their normally functioning colostomy. Therapeutic measures are based exclusively on clinical and functional parameters. The clinical picture dictates the emergency measures (colostomy, colon resection, and colectomy). Normal colostomy function is not a sufficient criterion of normal colon motility. Functional sonography of the colon is included in the planning of further therapy. Indications, timing, and extent of colon resection can be reliably determined using the sonographic method.

We report a patient with an unusual cause of chronic intestinal pseudoobstruction, i.e., neuronal intestinal dysplasia. This disorder is characterized by hyperplasia of the nerve plexuses of the intestine or colon, or both. Detailed morphologic and manometric studies are provided. The discussion emphasizes the various motor abnormalities that may be found in chronic intestinal pseudoobstruction. We propose that rectal biopsy may be of value in the diagnosis of this unusual form of pseudoobstruction.

Three types of neuronal intestinal dysplasia (type A, type B, and combination with Hirschsprung’s disease) can be distinguished. Functional assessment of the affected bowel segments can be achieved by functional colonic ultrasonography, thus providing exact parameters for further therapeutical procedure. The technique is described. Ten children with neuronal intestinal dysplasia in whom functional colonic ultrasonography was employed and results of their follow-up examinations are reported.

Neuronal intestinal dysplasia is characterized by structural changes consisting of hyperplasia of the myenteric plexus, an increase of the acetyl cholinesterase activity and the formation of giant ganglia. The condition gives rise to signs and symptoms similar to Hirschsprung's disease. Neuronal intestinal dysplasia can occur as a clinical entity itself in a localized or disseminated form. It may also accompany Hirschsprung's disease either as a localized defect or as a disseminated disorder of the entire intestinal tract. In localized forms, resection of the entire diseased segment is curative. Disseminated forms often have a fatal outcome despite ileostomy and colectomy. It is conceivable that differences in the severity of symptoms depend upon the development or absence of sympathetic innervation.

Neuronal intestinal dysplasia is histologically and histochemically well defined. The resection of the neuronal dysplastic segment is usually recommended in the literature as being curative. Whether a resection is necessary in every case remains to be debated. The case history of a male patient with Hirschsprung's disease and proximal intestinal neuronal dysplasia of the entire colon is presented. After manometrical, radiological and functional examination the aganglionic portion of the gut only has been resected and the neuronal dysplastic part has been left in situ. Several months later the patient is well. It seems possible to avoid in some selected cases a subtotal or total colectomy.