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Drug-induced Gastrointestinal Disease‘Belfast Pathology 2017’Wednesday, June 21st, 2017

Professor Kieran SheahanPathology Dept. & Centre for Colorectal Disease

St Vincent’s University HospitalUniversity College Dublin

IrelandPrice AB. Pathology of drug-associated gastrointestinal disease. Br J Clinical Pharmacology. 2003;56:477-82

Parfitt JR, Driman DK. Pathological effects of drugs on the gastrointestinal tract: a review. Human Pathology. 2007;38:527-36.

Geboes K, De Hertogh G, Ectors N. Drug-induced pathology in the large intestine. Current Diagnostic Pathology. 2006; 12 , 239-247.

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 Focal active colitis (FAC) 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

Fibrosis Diaphragms NSAIDs

Strictures KCL, Pancreatic enzymes

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

Diagnosis: temporal relationship / improvement with withdrawal.Most cases: index of suspicion / clinico-pathological exercise

Pattern of injury & mimics

1. Villous atrophy2. Apoptotic / erosive3. Abnormal mitoses4. Ulcerative5. 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)

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69 year old female –Subtotal villous atrophy,

? Coeliac Disease

Courtesy of Prof. Gene Connolly, Galway University Hospital

No improvement on GFDRepeat biopsy: subtotal villous atrophy,

? Refractory Coeliac Disease Type 1

No improvement on GFDRepeat biopsy, June 2012: subtotal villous

atrophy,? Refractory Coeliac Disease Type 1IHC (CD8/CD3 ratio): normal pattern

Noted to be on Olmersartan medication

CD 8

CD 3

Off Olmesartan x 2/12: mild partial villous atrophy

Back on Gluten-diet, Off Olmesartan x 7/12

• An angiotensin receptor blocker (ARB)• Approved for the treatment of hypertension since 2002

Conclusion: Severe sprue-like enteropathy associated with Olmesartan

Olmesartan Medoxomil

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22 patients; August 1st 2008 - August 1st 2011

• 22 patients with chronic diarrhoea (> 4 weeks) while taking olmesartan

• Cause of enteropathy not established after diagnosticevaluation - very ill patients

• Importantly - Clinical improvement after discontinuation

F/U duodenal biopsies:In 18 ptsAfter a mean of 242 days(from date of stopping drug)

Histological recovery in 17 ptsFocal partial VA in 1 pt

Clinical response observed in all patients

Medication-related villous atrophy, n = 19:Olmesartan - 16

Mycophenolate - 2Methotrexate - 1

Angiotensin II receptor blockers (ARBs)

• 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: 809-48, 2013

Human Path (2016) 50:127

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Take home messageOlmesartan (& other ARBs) causes symptoms & signs of

coeliac disease

• In 2012, over 10 millionprescriptions for 2 million patients (USA)

• In this era of poly-pharmacy, be vigilant of drug adverse effects

Clinical Details: Diarrhoea, weight loss, nausea and vomiting

Macroscopy: One pot labelled with patient details and ‘D2, duodenum’.

Four pieces, 3 – 7mm. A/E. 3/1.

Microscopy:Comment on orientationVillous/crypt ratio – Normal (type 1) / Partial / Subtotal (type 2) / Total (type 3)IELs – Normal / Increased (>25)Presence of neutrophils, eosinophils, subepithelial collagen (> 10-20 micron)

Comment: Correlation with clinical history, serology & medication history advised

Standardised report2. 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)

• 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

Mycophenolic Acid (MPA)Mycophenolic Acid (MPA)Mycophenolate-associated injury to small intestine (enteropathy)

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Iatrogenic injury Vs GVHD in BMT pts? •Eosinophils more commonly associated with Mycophenolate•Oesophageal mucosa involvement suggests GVHD

Mycophenolate-associated injury- Active colitis with apoptosis

- Apoptotic microabscesses with eosinophils

Increased risk of CMV colitis; associated in 10% of pts

Colon

• 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)

Take home message

APPROVED IMMUNE CHECKPOINT INHIBITORSAPPROVED IMMUNE CHECKPOINT INHIBITORS

• Nivolumab (anti-PD1)

• Pembrolizumab (anti-PD1)

• Avelumab (anti-PD1)

• Atezolizumab (anti-PDL1)

• Ipilimumab(anti-CTLA-4)

• .

• MSI CRC, Metastatic lung carcinoma

• MSI CRC and all MSI cancers (FDA)

• Metastatic lung carcinoma

• Metastatic lung carcinoma

• Metastatic melanoma & RCC

PRACTICE POINTS

•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.

CTLA-4 monoclonal antibody(ipilimumab®)

CTLA-4 monoclonal antibody(ipilimumab®)

• 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 tumour-specific 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)

CTLA-4 monoclonal antibody (ipilimumab)small intestine - apoptotic ileitis®)

CTLA-4 monoclonal antibody (ipilimumab)small intestine - apoptotic ileitis®) CTLA-4 monoclonal antibody (ipilimumab®)

Colon- apoptoticcolitis

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Anti-PD1 mab Pembrolizumab®

• 61 year old female

• Stage IV lung adenocarcinoma, PDL-1 positive.

• Bloody diarrhoea.• Proctitis to 15cm• Rectal biopsy

Tx: steroids +/- InfliximabAnxious to stay on drug trial

UC

CC CD

NSAIDs

Paper 1

Paper 2 2

3. 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 ToxicityAlkaloid that binds to tubulin with antimitotic ability (used in severe gout)

• 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

Nuclear stratification & ring mitoses

Taxane Effect[Taxol (paclitaxel); taxotere (docetaxel]

• Histology similar to colchicine toxicity:

- ring mitoses

- Occurs 2-3 days afterinitiation or in toxicity

Daniels JA. Am J Surg Pathol. 2008;32:473-7

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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

Conclusion

Histological findings

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.

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.

Case SummaryA 75 year old female with metastatic breast cancer had a suspicious pre-pyloric 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.

High power view of gastric mucosa with numerous mitosis in Metaphase with ring forms (sun-burst appearance).

Low power view showing acutely inflamed and ulcerated gastric mucosa with foveolar hyperplasia, intestinal metaplasia and increased mitotic activity.

DiscussionEribulin 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.

POSTER ISSP 2014

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 withhigh doses

Prevalence of NSAID-induced enteropathy (small intestine) is underestimated

- > 50% of patients havemucosal damage in the small bowel by Video capsule endoscopy:- Mucosal erythema- Erosions, ulcers,

perforation- Diaphragm disease &

strictures

Courtesy of I.S. Brown

Diaphragmatic Disease

NSAIDs-induced diaphragm disease—circumferential narrowing caused by

concentric submucosal fibrosis, likely a result of ulceration of the top of mucosal

folds

NSAIDs and colonic damage - ‘A long story’

• 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)

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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 ischaemic-type histology

Differential diagnoses Solitary caecal ulceration,

Ulceration secondary to a diverticulum, Local ischaemia,

Stercoral ulceration Solitary rectal ulcer syndrome

Collagenous Colitis Lymphocytic colitis

NSAIDs, PPI, SSRI; herbal remedies, ticlopidine, carbamazepine

NSAIDs, Olmesartan, others

Microscopic Colitis Recent study - St. Vincent’s University Hospital, Dublin

• 222 patients with microscopic colitis• 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

5-FU Colitis

NSAIDs, Digoxin, Cocaine, OCP/oestrogenic

compounds

Eosinophilic colitis Ischaemic colitis

Am J Gastroenterol 2004:1175Aliment Pharmacol Ther 2009;29:535-541

NSAIDs, Gold, L-Tryptophan, Carbamazepine, Methotrexate,

Tacrolimus, Azothioprine, Rifampicin, Clozapine

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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

• Various non-absorbable drugs can be associated with a wide spectrum of mucosal & mural alterations

5. Drug Crystals New Entities/Drugs/Biologicals

Recap - Pattern of injury & mimics

1. Villous atrophy2. Apoptotic / erosive3. Abnormal mitoses4. Ulcerative5. Crystals

• Coeliac disease• GVHD• Neoplasia• IBD• Vegetable matter

CONCLUSIONDiagnosis of Drug-Induced Injury is Difficult

CONCLUSIONDiagnosis of Drug-Induced Injury is Difficult

• 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