7/21/2017. Drug-induced Gastrointestinal Disease Belfast Pathology 2017 Wednesday, June 21st, Pattern of injury & mimics

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1 Drug-induced Gastrointestinal Disease Belfast Pathology 2017 Wednesday, June 21st, 2017 Professor Kieran Sheahan Pathology Dept. & Centre for Colorectal Disease St Vincent s University Hospital University College Dublin Ireland Geboes K, De Hertogh G, Ectors N. Drug-induced pathology in the large intestine. Current Diagnostic Pathology. 2006; 12, Parfitt JR, Driman DK. Pathological effects of drugs on the gastrointestinal tract: a review. Human Pathology. 2007;38: Price AB. Pathology of drug-associated gastrointestinal disease. Br J Clinical Pharmacology. 2003;56: Iatrogenic gut injury is common: 5% of patients receiving drugs experience an adverse reaction GI side-effects: diarrhoea, constipation, nausea & vomiting Entire gut can be affected Various patterns of injury (rarely specific) - Erosions / ulceration / necrosis / fibrosis & stenosis - Hyperplastic / reactive changes - Inflammatory infiltrate (lymphocytes/eosinophils) - Apoptosis / mitotic arrest / abnormal mitoses - Crystal deposition Generic injury patterns Specific injury patterns Drugs Inflammation active colitis (FAC) Focal NSAIDs, NaPO4 Chronic colitis NSAIDs Microscopic colitis NSAIDs, lansoprazole, ranitidine, PPI, ticlopidine, simvastatin, paroxetine carbamazepine, penicillin, flutamide, cyclo 3 Fort, sertraline Hypereosinophilia NSAIDs, Gold, L-Tryptophan, Carbamazepine, Methotrexate, Tacrolimus, Azothioprine, Rifampicin, Clozapine Malakoplakia Corticosteroids Pseudomembranous colitis Antibiotics, PPI Diagnosis: temporal relationship / improvement with withdrawal. Fibrosis Diaphragms NSAIDs Strictures KCL, Pancreatic enzymes Most cases: index of suspicion / clinico-pathological exercise Architectural Dilated/damaged crypts Villous atrophy Sulindac, Mycophenolate, NSAIDs, azathioprine, Olmesartan Ischaemia Ischaemic colitis NSAIDs, kayexalate, cocaine, diuretics, sumatriptan, dopamine, methysergide, amphetamines, oestrogens, ergotamine, alostron, digitalis, interferon Apoptosis / IELs Apoptotic ileitis / colitis Mycophenolate, Ipilimubab, NSAIDs, NaPO4, 5-FU Melanosis coli NSAIDs; Laxatives Increased / abnormal mitosis Increased number, Mitotic arrest Colchicine/ Taxane Erosion / perforation NSAIDs, KCL, Iron, Kayexalate, Cochicine, Yttrium 90,corticosteroids Epithelial atypia IV cyclosporin Pattern of injury & mimics 1. Villous atrophy 2. Apoptotic / erosive 3. Abnormal mitoses 4. Ulcerative 5. Crystals Coeliac disease GVHD Neoplasia IBD Vegetable matter 1. Villous atrophy: Mimics of Enteropathies (e.g. coeliac disease) Various drugs can elicit intraepithelial lymphocytosis with or without causing epithelial damage: - Olmesartan, angiotensin II receptor antagonist (Benicar ) - CTLA-4 monoclonal antibody (ipilimumab ) (melanoma, RCC, ovarian Ca) 1

2 69 year old female Subtotal villous atrophy,? Coeliac Disease No improvement on GFD Repeat biopsy: subtotal villous atrophy,? Refractory Coeliac Disease Type 1 Courtesy of Prof. Gene Connolly, Galway University Hospital No improvement on GFD Repeat biopsy, June 2012: subtotal villous atrophy,? Refractory Coeliac Disease Type 1 IHC (CD8/CD3 ratio): normal pattern Noted to be on Olmersartan medication Off Olmesartan x 2/12: mild partial villous atrophy CD 8 CD 3 Back on Gluten-diet, Off Olmesartan x 7/12 Conclusion: Severe sprue-like enteropathy associated with Olmesartan Olmesartan Medoxomil An angiotensin receptor blocker (ARB) Approved for the treatment of hypertension since

3 22 patients; August 1 st August 1 st patients with chronic diarrhoea (> 4 weeks) while taking olmesartan Cause of enteropathy not established after diagnostic evaluation - very ill patients Importantly - Clinical improvement after discontinuation F/U duodenal biopsies: In 18 pts After a mean of 242 days (from date of stopping drug) Histological recovery in 17 pts Focal partial VA in 1 pt Clinical response observed in all patients Medication-related villous atrophy, n = 19: Olmesartan - 16 Mycophenolate - 2 Methotrexate - 1 Angiotensin II receptor blockers (ARBs) Human Path (2016) 50:127 New drug class for treatment of hypertension & cardiac failure & protection from diabetic nephropathy (since 2002) At least 8 clinically available (azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan) Michel MC et al: Pharmacol Rev. 65: ,

4 Take home message Olmesartan (& other ARBs) causes symptoms & signs of coeliac disease In 2012, over 10 million prescriptions for 2 million patients (USA) In this era of polypharmacy, be vigilant of drug adverse effects Clinical Details: Macroscopy: Diarrhoea, weight loss, nausea and vomiting One pot labelled with patient details and D2, duodenum. Four pieces, 3 7mm. A/E. 3/1. Standardised report Microscopy: Comment on orientation Villous/crypt ratio Normal (type 1) / Partial / Subtotal (type 2) / Total (type 3) IELs Normal / Increased (>25) Presence of neutrophils, eosinophils, subepithelial collagen (> micron) Comment: Correlation with clinical history, serology & medication history advised 2. Apoptotic & Erosive Pattern of Injury Immunosuppressive or anti-neoplastic agents (predominantly): - Mycophenolate (cellcept ) - Anti-metabolites (methotrexate; capecitabine) - TNF-α antagonists (infliximab) IMMUNE CHECKPOINT INHIBITORS - CTLA-4 monoclonal antibody (ipilimumab ) - Anti-PD1 antibodies (pembrolizumab, nivolumab) Mycophenolic Acid (MPA) Mycophenolate-associated injury to small intestine (enteropathy) Mycophenolate mofetil (CellCept ) Mycophenolate sodium (Myofortic ) Immunosuppressive agents (transplant patients) Gastrointestinal injuries in ~45% of pts: - GVHD-like alterations throughout the GIT - Active oesophagitis with ulceration. - Chemical gastropathy; focal active gastritis - Crohn s-like & coeliac-like damage in the duodenum - Cryptitis, crypt withering & distortion, & increased neuroendocrine cells in colon 4

5 Mycophenolate-associated injury - Active colitis with apoptosis - Apoptotic microabscesses with eosinophils Colon Iatrogenic injury Vs GVHD in BMT pts? Eosinophils more commonly associated with Mycophenolate Oesophageal mucosa involvement suggests GVHD Take home message Increased risk of CMV colitis; associated in 10% of pts Diarrhoea following OLT in patients on MPA therapy was a noteworthy entity 5% of D2 biopsies show coeliac-like changes with negative serology (ttg) Pathologists should be aware of MPA-associated duodenal injury, & look for coeliac-like changes in patients and an increase in apoptotic counts A discontinuation or a reduction in dosage of MPA therapy should be considered Consider concurrent CMV infection (IHC) APPROVED IMMUNE CHECKPOINT INHIBITORS CTLA-4 monoclonal antibody (ipilimumab ). Nivolumab (anti-pd1) Pembrolizumab (anti-pd1) Avelumab (anti-pd1) Atezolizumab (anti-pdl1) Ipilimumab(anti-CTLA-4) PRACTICE POINTS MSI CRC, Metastatic lung carcinoma MSI CRC and all MSI cancers (FDA) Metastatic lung carcinoma Metastatic lung carcinoma Metastatic melanoma & RCC Median time to onset of GI side effect = 8 weeks Extent of colitis may predict response therefore clinicians keen to manage colitis & not stop drug For severe toxicity (grade 3-4), therapy is discontinued. GI toxicity can be observed after cessation of treatment Can exacerbate known or unknown IBD or other auto-immune diseases Anti-PD1 & Anti-CTLA-4 may be combined & or given sequentially. A monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 Offers durable therapeutic responses in patients with metastatic malignant melanoma and renal cell carcinoma How does if works? - CTLA-4 is expressed on T cells & following antigenic stimulation, it inhibits T cell signalling - mab against CTLA-4 results in increased expansion of tumourspecific T cells & enhances tumour destruction. Numerous immune-mediated toxicities, including enterocolitis, dermatitis, hypophysitis, uveitis, hepatitis & nephritis Major toxicity has been reported to be most frequently seen in the GIT (in 30% of patients receiving ipilimumab) 5% mortality rate in patients who develop fulminant colitis with colonic perforation Enterocolitis Villous blunting of small bowel Cryptitis in colon Apoptotic enteritis/colitis lymphoid follicles mimicking diversion colitis (beware CMV re-activation) Colon- apoptotic colitis CTLA-4 monoclonal antibody (ipilimumab) small intestine - apoptotic ileitis ) CTLA-4 monoclonal antibody (ipilimumab ) 5

6 61 year old female Stage IV lung adenocarcinoma, PDL-1 positive. Anti-PD1 mab Pembrolizumab Paper 1 Bloody diarrhoea. Proctitis to 15cm Rectal biopsy Tx: steroids +/- Infliximab Anxious to stay on drug trial UC NSAIDs CC CD Paper Abnormal Mitosis & Mimics of Dysplasia Mitotic arrest & atypical mitotic figures Eosinophilic transformation +/- withering of glandular structures Nuclear pseudostratification Clue: Monster nuclei intermixed with normal nuclei Colchicine Toxicity Alkaloid that binds to tubulin with antimitotic ability (used in severe gout) Taxane Effect [Taxol (paclitaxel); taxotere (docetaxel] Patients with renal or hepatic insufficiency and cannot clear the drug [long ½ life] present with - cholera-like syndrome - bone marrow suppression - acute renal failure Histology similar to colchicine toxicity: - ring mitoses - Occurs 2-3 days after initiation or in toxicity Nuclear stratification & ring mitoses Daniels JA. Am J Surg Pathol. 2008;32:

7 Eribulin-induced gastric epithelial atypia - a diagnostic pitfall. Dr Sampada Gupta, Dr Alan Beausang, Prof. John Crown, & Prof. Kieran Sheahan St. Vincent s University Hospital Introduction A host of medication-associated injuries can be encountered in the gastrointestinal and hepatobiliary tract. Gastric epithelial atypia has long been recognised in association with hepatic arterial infusion therapy with mitomycin C and 5-flurouracil while association with taxane therapy has been recognised more recently. We report a case of epithelial atypia induced by Eribulin which is a relatively new anti-cancer drug for late-stage, chemotherapy-resistant breast cancer. Histological findings Low power view showing acutely inflamed and ulcerated gastric mucosa with foveolar hyperplasia, intestinal metaplasia and increased mitotic activity. Case Summary A 75 year old female with metastatic breast cancer had a suspicious prepyloric polyp biopsied Histology revealed polypoid fragments of acutely inflamed antral-type gastric mucosa with focal intestinal metaplasia and surface ulceration. Numerous ring mitoses were identified in the epithelium raising concern for dysplasia but these were limited to the proliferative zone and there was no nuclear hyperchromasia and pleomorphism. Discussion with the oncologist revealed that the patient had received Eribulin nine days before the biopsy. In the light of the history these changes were interpreted to be induced by Eribulin which is a microtubule inhibitor that induces apoptosis following irreversible mitotic blockade. Discussion Eribulin mesylate (Halaven) is a relatively new anti-cancer drug for late-stage, chemotherapy-resistant breast cancer. Halaven is a non-taxane microtubule inhibitor which works through an end-poisoning mechanism, resulting in the inhibition of microtubule growth but not of shortening. Tubulin is also sequestered into non-functional aggregates, resulting in irreversible G2 to M- phase arrest and apoptosis which results in mitotic arrest in metaphase, and would correspond to the ring form or sun-burst appearance on histology. Thus it is reasonable to assume that the findings of mitotic arrest reflect an intended effect of medication rather than toxicity. Chemotherapy induced gastric dysplasia-like epithelial changes can be distinguished from true gastric dysplasia by the patchy involvement of proliferative zones without surface involvement, lack of stratification, nuclear pleomorphism and nuclear hyperchromasia. Attention to clinical details and knowledge of recent intravenous injection of chemotherapeutic agents may help in interpreting the findings. Conclusion To the best of our knowledge, this is the first report of Erbulin-induced gastric epithelial atypia, & pathologists should be aware of the association to avoid misinterpretation. 4. Ulcerative & Chronic Ileitis / Microscopic Colitis Pattern of Injury NSAIDs & other drugs can present with an ulcerative & chronic patterns of mucosal injury NSAIDs block COX 1 & 2 (cyclo-oxygenases) - Incidence of adverse effects reported in 70% with long-term Rx - Major pathology: ulceration & hemorrhage, more likely with high doses High power view of gastric mucosa with numerous mitosis in Metaphase with ring forms (sun-burst appearance). POSTER ISSP 2014 Prevalence of NSAID-induced enteropathy (small intestine) is underestimated Diaphragmatic Disease - > 50% of patients have mucosal damage in the small bowel by Video capsule endoscopy: - Mucosal erythema - Erosions, ulcers, perforation - Diaphragm disease & strictures Courtesy of I.S. Brown NSAIDs and colonic damage - A long story NSAIDs-induced diaphragm disease circumferential narrowing caused by concentric submucosal fibrosis, likely a result of ulceration of the top of mucosal folds Increasing due to use of enteric-coated or sustained (slow) release formulations (higher concentrations in the proximal colon) Various types of Colitis: Focal active colitis & chronic colitis Collagenous colitis & lymphocytic colitis Pseudomembranous colitis (Diclofenac ) Eosinophilic colitis (Naproxen ) Ulcers (right colon) Diaphragm disease Exacerbation of pre-existing IBD or diverticular disease (or perforation) 7

8 Focal active colitis Right sided NSAIDs IBD-like olitis NSAIDS ulcer: can occur anywhere in colon, but more common on right side sharply circumscribed on endoscopy with ischaemictype histology Differential diagnoses Solitary caecal ulceration, Ulceration secondary to a diverticulum, Local ischaemia, Stercoral ulceration Solitary rectal ulcer syndrome Collagenous Colitis Microscopic Colitis Lymphocytic colitis Recent study - St. Vincent s University Hospital, Dublin 222 patients with microscopic colitis NSAIDs, Olmesartan, others NSAIDs, PPI, SSRI; herbal remedies, ticlopidine, carbamazepine patients taking a variety of medications at diagnosis thought to be associated with microscopic colitis, including: - NSAIDs (22%) - PPIs (19%) - aspirin (19%) - statins (15%) - SSRIs (selective serotonin receptor inhibitors) (10%) Recent case: CRC patient with diarrhoea & focal active colitis Eosinophilic colitis Ischaemic colitis 5-FU Colitis NSAIDs, Gold, L-Tryptophan, Carbamazepine, Methotrexate, Tacrolimus, Azothioprine, Rifampicin, Clozapine Aliment Pharmacol Ther 2009;29: NSAIDs, Digoxin, Cocaine, OCP/oestrogenic compounds Am J Gastroenterol 2004:1175 8

9 5. Drug Crystals New Entities/Drugs/Biologicals Various non-absorbable drugs can be associated with a wide spectrum of mucosal & mural alterations Sodium Polystyrene Sulfate Cholestyramine Sevelamer Shape Angulated Angulated Fragments of tree bark Appearance Fish scale Homogenous Tree bark Colour Purple Red Rusty/2 toned Trade name(s) Kayexalate (hyperkalaemia) Questran (bile acid) Renage(hyperphospataemia) Modified from De Petris, Int J Pathol 2014;22:120 Recap - Pattern of injury & mimics CONCLUSION Diagnosis of Drug-Induced Injury is Difficult 1. Villous atrophy 2. Apoptotic / erosive 3. Abnormal mitoses 4. Ulcerative 5. Crystals Coeliac disease GVHD Neoplasia IBD Vegetable matter Some compounds are associated with characteristic patterns of injury (many are not) Since the gut has a limited set of response patterns to injuries: - overlapping features with common primary GI diseases including coeliac disease & IBD is usual & to be expected - clinical correlation is always important.when little or no clinical information is usually provided! Always consider drugs if you see an atypical itis Histological pointers: - Apoptotic -itis - Withering crypts - Ring mitoses Acknowledgement: Dr Aoife McCarthy & Dr Greg Lauwers 9