by Monzur Ahmed

Here is an unusual case which most gastroenterologists won’t see too often. A 36 year old lady presented at the age of 16 with abdominal pain. She was noted to have oral pigmentation and a clinical diagnosis of Peutz-Jeghers syndrome was made. There was no family history of this condition. A small bowel enema showed 3 large ileal polyps causing intussusception and she underwent small bowel (SB) resection and polyp excision. At the age of 21, she had a right hemicolectomy, SB resection and SB polypectomy, again for intussusception.

Over the years, she had numerous surveillance OGDs, colonoscopies and gynaecological / breast screening. Two years ago, a video capsule endoscopy showed duodenal/ jejunal polyps. Hence a oral route double balloon enteroscopy (DBE) was performed and 3 upper SB polyps were resected. A year ago, a further video capsule endoscopy showed ileal polyps, including one measuring ~2cm. Therefore, she now attends for rectal route DBE to remove the ileal polyp (see video)...
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Peutz-Jeghers syndrome (PJS) is part of a heterogeneous group of disorders, known as hamartomatous polyposis syndromes that involve the growth of multiple polyps in the gastrointestinal tract of affected individuals. PJS first described in a pair of twin sisters with dark pigment spots on their lips and oral mucosa by J.T. Connor in 1895. These symptoms were attributed to a familial syndrome in 1921, when Jan Peutz described four affected siblings. The syndrome was then defined as a distinct entity by Harold Jeghers in 1949 when he described 10 cases and was subsequently named Peutz Jeghers syndrome in 1954. The gene causing PJS (STK-11/LKB1) was identified in 1998 and allows early detection of the disease and screening of family members.

PJS affects males and females in equal numbers and can occur in any racial or ethnic group. The birth prevalence of PJS is estimated to be between 1/50,000 and 1/200,000. PJS is characterised by multiple hamartomas on the mucous lining of the gastrointestinal system and spots of dark blue to dark brown skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers, oral mucosa and anus. These melanocytic macules can appear as early as the first year of life and are present in most affected children under five years of age. They tend to fade away with age and might completely disappear in puberty or adulthood, although they tend to persist in the oral mucosa. Polyps also begin to grow within the first years of life, but associated symptoms typically arise between 10 to 30 years of age. Around half of patients with PJS have to undergo surgery by age 18 because of polyps-related complication. Polyps most often tend to develop in the small intestine (60-90%), especially in the jejunum, but can also arise in the stomach and large intestine. Rarely, polyps can grow outside the gastrointestinal tract and affect the ureters, bladder, lungs, bronchi, and gallbladder. Gastrointestinal polyps can cause abdominal pain, vomiting, diarrhoea, intestinal obstruction and rectal bleeding, which can lead to anaemia. They can also provoke intussusception, which can lead to severe abdominal pain and emergency surgery.

Individuals with PJS are at a highly increased risk of developing gastrointestinal and other cancers including breast, cervical, uterine, pancreas, and lung. The lifetime risk of developing cancer in affected individuals can be as high as 93%. The cumulative risk of GI cancers (excluding pancreatic cancer) has been reported to be around 33% at the age of 60, increasing to 57 % at the age of 70 years. Individuals that develop cancer are usually affected around their fifth decade of life (age 40-49 years). Affected females have an increased risk for a benign ovarian tumour called SCTAT (sex cord tumours with annular tumours) for which symptoms may include irregular or heavy periods or early puberty. Usually before age 20, affected males can develop Sertoli cells carcinoma of the testes that secretes oestrogen and can lead to gynaecomastia.

PJS is an autosomal dominant condition caused by mutations in the STK11/LKB1 gene which is located at 19p13.3. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo) in the affected individual. Approximately 60-78% of individuals with PJS have an affected relative. Around 80-94% of PJS patients have an identified mutation in the STK11 gene, which means that other genes are possibly involved in the disease. The penetrance of the STK11 gene mutation is thought to be 100% (which means that someone with a pathogenic mutation has a 100% chance of developing the disease), so genetic testing can give a definite diagnosis before symptoms appear. The STK11 gene produces a protein that is involved in the regulation of cell division and apoptosis (programmed cell death). It also interacts with p53, a major tumour suppression protein. Pathogenic mutations in STK11 lead to either cessation or dysfunction of protein production by the gene and uncontrolled cell growth, which can in turn lead to the development of hamartomas and cancer.

The dark pigmented spots (melanocytic macules) are thought to be caused by inflammation and blockage of melanin migration from cells where it is produced (melanocytes) to cells forming the outermost layer of the skin (keratinocytes).

A clinical diagnosis of PJS can be made when any one of the following criteria is present:
1. Presence of at least 2 histologically confirmed PJS polyps
2. Any number of PJS polyps with a positive family history of PJS
3. Presence of characteristic mucocutaneous pigmentations with a positive family history of PJS
4. Any number of PJS polyps in an individual with characteristic mucocutaneous pigmentation

Surveillance of the GI tract in PJS patients has two purposes:
1. To detect GI polyps that may cause complications (bleeding, anaemia, intussusception) and should be removed (in particular small-bowel polyp-related complications are the predominant clinical problem);
2. To detect cancer (mainly occurring in adults) at an early stage.
After initial diagnosis, it is recommended that individuals older than 8 years or having symptoms undergo endoscopic and small bowel examination. The latter can be done with magnetic resonance imaging of the intestines (magnetic resonance enterography, MRE) or video capsule endoscopy, (VCE). Gynaecologic and breast examination are also recommended for women older than 18 years. Testicular examination is recommended for men.

The ESGE recommendations for PJS are:
1. Perform a baseline OGD and colonoscopy at the age of 8 years in asymptomatic individuals with PJS.
2. Start routine OGD and colonoscopy surveillance at the age of 18 if the baseline endoscopy is negative.
3. An interval of 1 – 3 years based on phenotype for OGD and colonoscopy.
4. Small-bowel surveillance from the age of 8 years in asymptomatic individuals with PJS.
5. An interval of 1 – 3 years based on phenotype for small-bowel surveillance.
6. Either MRI studies or video capsule enteroscopy for small-bowel surveillance.
7. Elective polypectomy should be performed for small-bowel polyps >15–20mm to prevent intussusception. In a symptomatic patient, smaller polyps causing obstructive symptoms should be removed.
8. Device-assisted enteroscopy for the removal of polyps. Based on phenotype, intraoperative enteroscopy could be considered.
These guidelines are similar to those of the BSG / ACPGBI/ UKCGG.

REFERENCES
1. Beggs AD, Latchford AR, Vasen HFA et al; Gut 2010 Jul;59(7):975-86.
Peutz-Jeghers syndrome: a systematic review and recommendations for management
https://pubmed.ncbi.nlm.nih.gov/20581245/

2.Peutz Jeghers Syndrome, NORD
https://rarediseases.org/rare.../peutz-jeghers-syndrome/

3.van Leerdam ME, Roos VH, van Hooft JE et al, Endoscopy 2019; 51
Endoscopic management of polyposis syndromes: European Society of Gastrointestinal Endoscopy (ESGE) guideline
https://www.esge.com/.../upl.../2019/07/2019_a_0965_0605.pdf

4.Monahan KJ, Bradshaw N, Dolwani S, Hereditary CRC guidelines eDelphi consensus group, et al. Gut 2020;69:411-444.
Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)
https://gut.bmj.com/content/69/3/411

by Monzur Ahmed

A 76 year old man was admitted with a 3 week history of painless jaundice, dark urine and one stone weight loss. Initial investigations were as follows:
- Bilirubin 181 umol/L, ALT 105, Alk Phosp 270 (NR<130)
- WBC 8.4 increasing to 16, Hb 14.2 g/dL, Platelets 370
- CT scan:
  - large calcified stone in low CBD
  - dilated CHD/ IHD
It was thought that he had cholangitis secondary to a CBD stone. An ERCP, performed 2 days ago by colleagues, showed a bulky papilla and despite a needle knife precut, it was not possible to enter the bile duct. He was therefore referred for a second ERCP 2 days later (see video)...
Cannulation again proved difficult and the needle knife was again used to perform a further precut and fistulotomy. The CBD was eventually accessed but the stone proved stubborn. A sphincterotomy and sphincteroplasty were necessary before we were able to extract the stone with a balloon (dilatation assisted stone extraction, DASE). Finally, a pigtail stent was inserted because there was an additional short stricture (??) in the mid bile duct. Despite the messy procedure, the patient did not have any complications and went home a couple of days later with a view to having another ERCP 6 weeks later to remove the stent and reassess the CBD.

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By Monzur Ahmed
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A 68 year old man was admitted with a 2 week history of painless jaundice, dark urine, 2-3 stone weight loss and poor appetite. Initial investigations were as follows:
- Bilirubin 330 umol/L, ALT 230, Alk Phosp 420 (NR < 130)
- Hb15.3 g/dL, WBC 14, platelets 210
A CT scan showed a 5cm tumour in head of the pancreas with a dilated pancreatic duct (14mm) and dilated common hepatic duct and intrahepatic ducts. There was no evidence of metastasis or vascular invasion. It was thought that the appearances were compatible with pancreatic adenocarcinoma. He was discussed with the local HPB unit. In view of the COVID-19 pandemic, surgery was deferred and the recommendation was an ERCP with biliary stenting with subsequent “downstaging” chemotherapy as a prelude to surgery once the COVID situation improves! Hence the patient attended for ERCP. There was a surprise finding (see video)...

Intraductal papillary mucinous neoplasms (IPMNs) result from the intraductal proliferation of mucin producing neoplastic epithelium, leading to hypercellular outgrowths that secrete frank, mucinous fluid. IPMNs were first described in 1982 by Ohhashi et al, who described four patients with successfully resected main duct IPMN (MD-IPMN) [1]. The 1996 World Health Organization (WHO) classification designated these tumours as intraductal papillary mucinous tumors [2] and this was revised to intraductal papillary mucinous neoplasm in the 2010 publication [3].

IPMNs are classified as main duct (MD-IPMN), branch duct (BD-IPMN) or mixed type according to the anatomic involvement of the pancreatic ductal system. MD-IPMN have a higher risk of malignant transformation; the risk of malignancy has been found to range from 19% to 30% in BD-IPMNs and as high as 40% to 60% in MD-IPMN [4-7].

Histologically, IPMNs can be classified into four subtypes based on morphological and immunohistochemical characteristics: gastric, intestinal, pancreatobiliary and oncocytic [8]. While not always the case, gastric type IPMNs typically displays low-grade dysplasia, intestinal type often displays moderate to high-grade dysplasia, while the less common pancreatobiliary type and oncocytic type often display high-grade dysplasia. The two main histopathological types of invasive IPMN are colloid carcinoma, which typically arises from intestinal type IPMN, and tubular carcinoma, which arises from pancreatobiliary type IPMN. Histologic subtypes are typically only determined following surgical resection and currently may not be used to dictate clinical management.

Endoscopic ultrasound (EUS) should be considered as a ‘second-level’ diagnostic modality after CT and MRI. EUS is an invasive, operator-dependent imaging technique with the possibility of performing fine-needle aspiration (FNA) for cyst fluid analysis. EUS is useful in differentiating IPMNs from other pancreatic cysts, including macrocystic serous cystadenomas (SCAs), mucinous cystic neoplasms (MCNs) or pseudocysts. By analysing CEA level, amylase/lipase, glucose as well as cytology in the cyst fluid, it may be possible to increase the diagnostic yield in their differential diagnosis. A cut-off ≥192 ng/ml of cyst fluid carcinoembryonic antigen (CEA) has been suggested for distinguishing mucinous from non-mucinous cysts, with a sensitivity of 38–78% and specificity of 63–99%, but it is not helpful in distinguishing between benign and malignant mucinous cysts. Similar results are reported for cytological examination. At ERCP, IPMNs are characterised by the "fish mouth papilla” which is said to be diagnostic.

The management of IPMNs is dependent on the accurate assessment of the risk of malignant transformation. Surgical resection remains the best treatment to avoid this unfavourable outcome. However, two major problems remain: first, many BD IPMN (75–82%) will never progress to malignancy; and second, pancreatic surgery inherent morbidity is not negligible. Therefore, it is crucial to identify the patients who will actually need surgical resection. Several guidelines have been established to define the surgery criteria, depending on the presence or not of “worrisome signs” and “high risk stigmata of malignancy” (i.e., high grade dysplasia and invasive carcinoma [4,5,6,7,9,10]. In these algorithms, the patient’s performance status is taken into account to determine the surgery benefit/risk ratio.

The Sendai and Fukuoka consensus conferences of 2006 and 2012 / 2017 respectively [9,4,5], established some baseline clinical and radiological criteria, especially in terms of tumour size and associated lesions (lymphadenopathy), to guide the decision concerning the patient management (surveillance or surgical treatment). This consensus separated criteria in “worrisome” and “high-risk stigmata” that allow or not the surgical option. The Sendai guidelines [9], recommended resection for all MD-IPMNs and mixed type IPMNs if patients are good surgical candidates. Resection was also recommended for symptomatic patients with BD-IPMNs, or BD-IPMNs with main duct dilatation > 6mm or the presence of mural nodules. It was also recommended that lesions > 3 cm be resected, with the caveat that more data was required to determine whether all BD-IPMNs > 3 cm should be resected immediately.

The revised Fukuoka guidelines of 2012 [4] decreased the threshold of main duct dilatation for characterisation of MD-IPMN to > 5 mm without other causes of obstruction. Resection was recommended for all surgically fit patients with MD-IPMN. Both “high risk stigmata” and “worrisome features” were defined, with surgical resection recommended for high-risk stigmata, namely obstructive jaundice in a patient with a cystic lesion in the head of the pancreas, enhancing mural nodules and main pancreatic duct diameter ≥ 10 mm.

The above Japanese guidelines are complemented by the European and American guidelines as important decision-making aids [6,7,10]. In the latest update of the European guidelines of 2018, recommendations include a conservative approach for asymptomatic IPMN measuring <40 mm without an enhancing nodule [10]. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter ≥40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule >5 mm, and MPD diameter >10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery.
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REFERENCES
1. Ohhashi K. Four cases of mucous secreting pancreatic cancer. Prog Digest Endosc. 1982;20:348–351.
2. Klöppel GSE, Longnecker DS, et al., editors. Histologic Typing of Tumours of the Exocrine Pancreas. 2. New York, NY: Springer-Verlag; 1996.
3. Bosman FTCF, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010. Tumours of the Pancreas.
4.Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M, Jang J-Y, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatol Off J Int Assoc Pancreatol IAP Al. 2012;12:183–97.
5. Tanaka M, Fernández-Del Castillo C, Kamisawa T, Jang JY, Levy P, Ohtsuka T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatol Off J Int Assoc Pancreatol IAP Al. 2017;17:738–53
6. Vege SS, Ziring B, Jain R, Moayyedi P. Clinical Guidelines Committee, American Gastroenterology Association. American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015;148:819–22
7. Elta GH, Enestvedt BK, Sauer BG, Lennon AM. ACG clinical guideline: diagnosis and Management of Pancreatic Cysts. Am J Gastroenterol. 2018;113:464–79.
8. Furukawa T, Klöppel G, Volkan Adsay N, et al. Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Archiv. 2005;447:794–799.
9. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17–32.
10. European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018;67:789–804.

By Monzur Ahmed

Pharyngeal pouches (diverticula) are a common cause of dysphagia; they are associated with various morbidities and a decreased quality of life. There are several types of diverticula which are classified according to the anatomical location of their origin relative to the cricopharyngeal muscle. These include Zenker's, Killian-Jamieson's, and Laimer's diverticula. By far the most common is Zenker's diverticula, characterised by a posterior outpouching originating from Killian's dehiscence of the inferior constrictor muscle, between the cricopharyngeal and thyropharyngeal muscles. The Killian-Jamieson diverticulum is much rarer and is a herniation through the anterolateral located superolateral to the longitudinal muscle of oesophagus and inferior to the cricopharyngeal muscle. The rarest variant of pharyngeal diverticulum is often referred to as Laimer's or Laimer-Haeckerman's diverticulum. Similar to the Killian-Jamieson diverticulum, it originates between cricopharyngeus and the longitudinal muscle of the oesophagus; however, it is located posteriorly and midline, from the area termed Laimer-Haeckerman's triangle, and is covered only by the circular muscles of the oesophagus. Pharyngeal pouches can make endoscopic intubation difficult and even hazardous, with a risk of perforation. Hence, if a pouch is suspected or proven, then it is important to appreciate the anatomy of the pharyngeo-oesophageal region in order to safely intubate the oesophagus. The video shows a recent case of an elderly co-morbid patient where previous attempts at intubation were unsuccessful (see video)…

by Monzur Ahmed

“He who controls the Spice, controls the Universe.” Baron Harkonnen, Dune

In the science fiction world of Frank Herbert’s “Dune,” the drug, Spice, was the most essential and valuable commodity in the universe. Found only on the desert planet Arrakis, the drug gave the user a longer life span, greater vitality, and heightened awareness; it could also unlock prescience in some humans, depending upon the dosage and the consumer's physiology. In real life, Spice or the “Zombie drug” seems to have similar importance in UK prisons. Here is a case from our hospital of a Spice smuggling prisoner who was admitted handcuffed and chained to a prison officer...

​A 28 year old male prisoner had a history of epilepsy, personality disorder and drug abuse. Eleven days ago he swallowed drug package containing “Spice” (synthetic cannabinoid) with a street value of £1000. The package did not pass through his system as he intended. So, 5 days ago, he swallowed an USB stick and one AA battery to push the package along! Unfortunately this strategy did not work and he presented to hospital one day ago because the package still had not come out the other end. The initial AXR and CXR showed a AA sized battery and a USB stick in the stomach. In addition there was an oval shaped outline of what could have been the drug package in the fundus of the stomach. An urgent out of hours OGD was performed by a colleague. A battery and a large oval package were visible in the stomach but it was not possible to extract the package with a snare because the package would not pass through the upper oesophageal sphincter. An overtube was then used, but again the procedure was unsuccessful. The next day, the surgeons were preparing to take him to theatre but asked me to have a last ditch attempt at endoscopic extraction (see video)… The procedure was performed with the prisoner still handcuffed and chained to one of the two accompanying prison officers!

by Monzur Ahmed

One of my favourite TV shows is the forensic crime drama “CSI: Crime Scene Investigation" (the original Las Vegas version, starring William Peterson as Gil Grissom, not the subsequent spin-offs). The show ran for 15 seasons. In one memorable episode entitled “Dog Eat Dog,” the body of a man is found in a dumpster; cause of death unknown [1]. What appears to be blood on his lips turns out to be cranberry sauce. Initially foul play is suspected but it transpires that the man died from asphyxia caused by gastric distention. The postmortem revealed vast amounts (and variety) of food in the stomach. After some detective work, Grissom diagnoses Prader-Willi syndrome, a condition associated with an insatiable appetite. The dead man literally ate himself to death having won a food-eating contest along the way! When I first watched this episode of CSI, I marvelled at the ingenuity of the script writers. A few days ago, I was reminded of “Dog Eat Dog" by a patient...

​A 22 year old man was admitted to my hospital with a one day history of severe abdominal pain, distention and nausea but no vomiting. He was still opening his bowels and passing wind. He had a history Prader-Willi syndrome and had spinal surgery for scoliosis at age 10 years. There was also a history of anxiety. For 3 years he had been living in a Residential Home where his meals were regulated. He was a vegetarian. On examination, he was not obese (BMI 20 kg/m^2) and had a distended, tender abdomen. Initial AXR showed a very distended stomach containing food material. A CT scan confirmed these findings and worryingly the report mentioned “imminent danger of perforation.” The surgeons were called in, presumably with a view to surgery, but instead they asked me to do an OGD to see if there was anything that could be done endoscopically. A large phytobezoar was found in the stomach which proved challenging to treat (see video)... ​

by Monzur Ahmed

A 25 year old female gave a 6 months history of high dysphagia and choking. The symptoms were worse with solids. She had lost one stone in weight. 3 weeks ago, an urgent (2 week wait) OGD was performed by one of our Nurse Endoscopists. This showed an impassable high oesophageal stricture (not biopsied). A subsequent barium swallow showed a short narrowing at the junction of the hypopharynx and oesophagus. Routine blood tests revealed iron deficiency anaemia (Hb 8.0 g/d, MCV 66). On direct questioning, the patient admitted to longstanding menorrhagia. There was no PR bleeding or haematuria and she was not a vegetarian. She was referred for a further OGD with a view to dilatation (see video…) ​