Diagnosis and Management of Chronic Oral Graft-Versus-Host ...

Department of Clinical Haematology

Oxford BMT Programme

B.2.7d of 14 April 2022 V1.2 Diagnosis And Management of Oral Chronic GVHD

Authorised by: Dr Andy Peniket

This is a controlled document and therefore must not be changed

Diagnosis and Management of Chronic Oral Graft-Versus-Host Disease (GVHD)

Background

The oral cavity is one of the most frequently affected sites in chronic graft versus host disease

(cGVHD). Oral symptoms can have a significant effect on quality of life post-HSCT.

Inability to maintain a normal diet due to oral discomfort is a risk factor for poor nutrition in

these patients. In addition there is a risk of second malignancy in the oral cavity and

appropriate education and screening is necessary.

Oral cGVHD may present as lichenoid-appearing hyperkeratotic lesions, hyperkeratotic

plaques, erythema and ulceration, atrophy of the oral mucosa, fibrosis and sclerodermoid

changes of the oral mucosa and perioral region, salivary gland dysfunction and taste

dysfunction.

Patients may report generalised or localised oral mucosal sensitivity and pain, dry mouth

symptoms, taste disturbance and difficulty eating. Superficial mucoceles are often described

by patients as “bubbles” developing on the lower lip or palate prior to or during mealtimes.

Patients who experienced long periods of mucositis during their transplant or who have severe

ulcerative cGVHD may have difficulties maintaining good oral hygiene. This can lead to the

development of periodontal disease and dental caries. Hyposalivation also increases the risk

of dental decay.

Whilst immunosuppressed patients are at greater risk of oral infections, including bacterial,

viral and fungal infections. Topical therapy for oral cGVHD may be complicated by

infection, usually fungal, due to local immunosuppression and appropriate prophylaxis is

usually required.

Assessment of severity

1. Mucosal disease

a. Patient reported






i. Lee symptom scale (mouth subset)

ii. Chronic oral mucosal diseases questionnaire (Appendix 1)

iii. Chronic cGVHD Activity Assessment – Patient Self Report (1)

b. Clinical assessment

i. NIH modified oral mucosa score (0-12) (1)

ii. NIH organ scoring (0-3) (2)

2. Salivary gland disease

a. Patient reported

i. Xerostomia questionnaire may be used






ii. Ask regarding modification of diet and symptoms during daytime

iii. Nocturnal dryness and dryness of the mouth on awakening is normal

however it may be more severe in these patients

b. Clinical assessment

i. Dry oral mucosa – mirror or gloved finger sticks to buccal mucosa

ii. No saliva pooling in floor of mouth

iii. Formal sialometry – less than 0.2ml/min resting salivary flow rate

1. Ask patient to expectorate saliva into a cup for 15 minutes

without stimulating flow, measure volume and calculate rate in

ml/min.

Investigations

1. Diagnosis of oral cGVHD (2,3)

a. This is primarily a clinical diagnosis, based on the presence of diagnostic

features:

i. Lichen-planus like changes (hyperkeratotic white lines and lacy

appearance)

b. Distinctive features include:

i. Xerostomia

ii. Mucoceles

iii. Mucosal atrophy

iv. Ulcers

v. Pseudomembranes

c. Biopsy is not usually necessary, but if performed the pathology is as follows:

i. Mucosa – lichenoid interface reaction, with lymphocyte exocytosis and

apoptosis

ii. Minor salivary glands – lymphocytic inflammation (periductal or

interlobular) with lymphocyte exocytosis and commonly periductal

fibrosis

2. Diagnosis of common infections

a. The majority of oral infections may be diagnosed clinically.

i. Dental infection – pain localised to a tooth, sensitivity to hot and cold

or biting, presence of a draining sinus, gingival abscess or swelling.

Dental radiographs may demonstrate bone loss around the apex or root

of the tooth due to infection.

ii. Candidal infection – presence of pseudomembranous deposits which

wipe off, erythematous areas associated with removable dentures,

erythematous areas on the dorsal tongue and hard palate. Swabs are

useful for assessing drug resistance but correlate poorly with active

infection (organism is a commensal).

iii. Viral infection – recrudescent herpetic infection presents with small

vesicles or ulcers clustered together or coalescing, unilateral and

limited to a nerve distribution. Primary herpetic gingivostomatitis






presents with generalised ulceration and inflammation of the gingivae

and labial mucosae.

1. Swabs for PCR and viral culture may be useful in identifying

the virus and any drug resistance.

3. Diagnosis of abnormal mucosal lesions

a. Some lesions may be easily diagnosed clinically (e.g. aphthous ulceration)

however the majority of abnormal mucosa lesions which are not consistent

with oral cGVHD will require biopsy for diagnosis, in view of the risk of

second malignancy/recurrence, post-transplant lymphoproliferative disease and

unusual infective or neoplastic processes in this patient population.

b. Patients with oral lesions requiring biopsy should be referred to an oral

medicine or oral surgery unit.

Important differential diagnoses

It is important to recognise that not all oral symptoms in this patient cohort are due to

cGVHD. Patients may have significant oral mucosal sensitivity and pain in the absence of

any clinical evidence of GVHD, and this is often due to a small fibre neuropathy of the oral

cavity (post-inflammatory hyperalgesia or oral dysaesthesia). This may occur following

significant mucosal inflammatory disease or may be idiopathic. The symptoms are worsened

by haematinic deficiency, psychological stress/mood disorders and ongoing medical illness.

Immunosuppressive treatment is unlikely to change these symptoms.

1. Infection

a. Bacterial infection

i. This is usually related to dental or periodontal structures and will

require appropriate broad spectrum coverage, including anaerobic

coverage. It is important that the source of the infection is also treated

ie. teeth are treated by root canal therapy or extracted, and abscesses

are drained. Antibiotics will control dental infection but it will recur if

the source is not eliminated.

b. Fungal infection

i. Candidal infection of the oral cavity is a significant problem in the

immunosuppressed patient. Candida is a normal commensal organism

in the majority of the population. Active infection should be diagnosed

clinically – swabs are not useful due to the organism being a

commensal. Positive swabs do not correlate well with active infection.

ii. Systemic antifungal treatment with fluconazole is usually

recommended, and the addition of a topical agent such as miconazole

or nystatin can be helpful in maintaining long term control.

iii. Some patients are particularly susceptible to recurrent fungal infection

and will require prophylactic treatment. This may range from second

daily chlorhexidine mouthwash to a course of nystatin or miconazole

for the first week of every month.






c. Viral infection

i. HSV reactivation is a possibility in these patients although the majority

are on prophylactic antiviral treatment.

ii. Viral ulceration has a distinct clinical appearance and should be

distinguished from cGVHD.

iii. Viral ulceration of the oral mucosa is extremely painful and should be

managed aggressively with topical anaesthesia and/or prescription of

drugs for neuropathic pain (such as amitriptyline or nortriptyline) if

symptoms persist after resolution of the ulceration.

iv. If unresponsive to standard antiviral therapy consider sending sample to

test for acyclovir resistance (liaise with Consultant Virolgist).

2. Inflammatory

a. Oral cGVHD is virtually indistinguishable clinically and histologically from

oral lichen planus (OLP). The principles of treatment are similar.

3. Neurological

a. Neuropathic pain due to chemotherapy effects, post-inflammatory hyperalgesia

or idiopathic oral dysaesthesia is a common cause of persistent oral sensitivity

and pain in the absence of clinical signs of active cGVHD or infection.

b. Symptoms reported include pain, burning, excessive sensitivity to food and

drinks (particularly spicy/hot temperatures), sensation of dryness in the

presence of good salivary flow, abnormal taste (often metallic) or loss of taste,

perception of abnormal sensations (e.g. pressure, pushing) or size of oral cavity

structures (e.g. tongue, teeth)

4. Neoplastic

a. Oral epithelial dysplasia is a potentially malignant disorder of the oral mucosa.

It is a histological diagnosis. The clinical appearance of dysplastic areas may

range from thick homogeneous white plaques, to mixed red and white speckled

lesions, to erythroplakia (deep red areas). If the mucosal appearance is not

consistent with lichenoid changes of cGVHD then biopsy is required to rule

out other pathologies, including dysplasia and malignancy.

5. Other

a. Calcineurin-inhibitor associated fibrovascular polyps

i. Well-defined, ulcerative, exophytic masses, often associated with

trauma

ii. Require biopsy / excision due to interference with function and to rule

out other pathology

b. Verruciform xanthoma

i. Yellow-white to red papillary surface, requires biopsy to rule out

carcinoma

ii. Managed by surgical excision






Treatment

Treatment consists of active treatment aimed at reducing the intensity of the inflammatory

response in the oral mucosa, and symptom control treatment, which should run in parallel

with active therapy.

Active treatment

The intensity of treatment depends on severity and chronicity of symptoms. The treatment

ladder, in order of increasing intensity of treatment, is as follows:

1. Topical corticosteroids

a. Betamethasone mouthwash

i. Betamethasone 500mcg soluble tablets – dissolve in 20ml water, rinse

and hold in mouth for 3-5 mins then spit out, 2-3 times daily

b. Fluticasone propionate mouthwash or spray (mouthwash for widespread

disease, spray for localised areas of disease)

i. Flixonase 400mcg nasules – open one nasule into 10-15ml water, rinse

and hold in mouth for 3-5 mins then spit out, up to three times daily

ii. Flixonase 50mcg nasal spray – 2 puffs to painful area twice daily

c. Elocon (Mometasone) 0.1% ointment

i. Apply a small amount directly to the ulcerated area twice daily

d. Budesonide mouthwash (second line therapy)

i. Budesonide 1mg respules (Pulmicort) – open one respule into 20 ml

water, rinse and hold in mouth for 3-5 mins then spit out, twice daily

2. Topical immunomodulators

a. Tacrolimus 0.1% ointment

i. Apply a small amount directly to the ulcerated area twice daily

ii. Use for up 3-4 weeks at a time with 2-4 week window

3. Intralesional corticosteroids

a. These are indicated for localised persistent areas of ulceration which have not

responded to a combination of topical therapies as above

b. Up to 20mg of triamcinolone acetonide injected directly underneath the

ulcerated area, may be repeated after a 4 week period (use 40mg/ml

concentration)

4. Systemic therapy

a. If topical therapy has failed to control symptoms, systemic therapy including

oral prednisolone and/or immunosuppression should be initiated according to

local guidelines

5. Extracorporeal photophoresis

a. There is some evidence that ECP can be an effective means of managing

severe oral GVHD which is poorly responsive to topical and systemic

therapies.(4)

Symptom control






1. Pain relief

a. Topical anaesthetic

i. Difflam (benzydamine hydrochloride)

1. Available as a spray or mouthwash, may be used 2 hourly as

required for relief of symptoms

2. Some patients may experience stinging with this formulation

ii. Lidocaine 5% ointment

1. May be applied up to four times daily to painful or ulcerated

lesions in the oral cavity

iii. Lidocaine 10% spray

1. 2 sprays to oral mucosa every 3 hours as required, maximum 20

sprays per day

2. Barrier treatment

a. Gelclair

i. Forms a film over the oral mucosa and can effectively control

symptoms in atrophic, erosive or ulcerative disease

3. Dry mouth symptom control

a. Simple measures

i. Water sipping and maintaining hydration

ii. Stimulation of salivary flow – sugar-free sweets or chewing gum,

massage of parotid glands (apply firm pressure from pre-auricular area

forwards across cheek)

iii. Comfort – bicarbonate of soda mouthwash (1 teaspoon of bicarb soda

to 1 litre of water), olive oil applied to the oral mucosa at night

b. Salivary replacement

i. Bioextra or Biotene (OUH 1st line) saliva replacement gels

ii. Xerotin, Saliva Orthana (OUH 1st line) or Glandosane saliva

replacement sprays (NB Orthana contains porcine products)

c. Salivary stimulation

i. Pilocarpine

1. Parasympathomimetic drug – avoid in uncontrolled asthma or

COPD, decompensated cardiac failure; caution in controlled

asthma/COPD/cardiac disease, biliary tract disease, urinary

obstruction, angle-closure glaucoma

2. Side effects – sweating, visual disturbance (blurring),

abdominal upset, urinary frequency

3. Prescribe Salagen 5mg 4 times daily with meals and at bedtime

4. Discontinue if side effects not tolerated or ineffective after 3

months

4. Oral hygiene

a. If toothpaste causes pain, switch to Kingfisher toothpaste (SLS free) or

Sensodyne Pro-Enamel






b. Recommend liaison with hygienist to ensure that oral hygiene is optimised

whilst mouth is painful

i. Aim to reduce bacterial flora due to plaque as this can delay resolution

of ulcerative cGVHD due to secondary infection

c. If toothbrushing is too difficult due to pain, use chlorhexidine-soaked swabs or

cotton tips to gently disrupt plaque around gingival margins

5. Prevention of infection

a. If patients are not receiving systemic antifungal prophylaxis and are using

potent topical corticosteroids in the oral cavity, they should be prescribed

chlorhexidine mouthwash to use second daily as antifungal prophylaxis

Monitoring and prevention

1. Review of oral symptoms/clinical appearance

a. At each follow-up visit, or at least 3 monthly during systemic

immunosuppressive therapy (5)

2. Dental review

a. Recommend 6 monthly dental check-up and professional hygiene(5,6)

b. More frequently if high caries rate or periodontal disease is present

3. Oral mucosal soft tissue screening

a. Recommend 6 monthly soft tissue examination by general dental practitioner

and immediate referral to oral medicine or maxillofacial surgery if any

abnormalities noted(6)

b. Patients should be educated regarding the risk of oral mucosal malignancy

following HSCT. One study reports the median time to diagnosis of oral

squamous cell carcinoma after transplant to be 8 years, with a range of 1-14

years.(7) It is important that patients are aware of the need to continue

screening for this significant late effect.

Resources

For useful clinical photos and a comprehensive discussion of management, see Treister et al

2012 (8)

References

1. Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. Biology of Blood and

Marrow Transplantation. Biology of Blood and Marrow Transplantation. Elsevier Inc;

2015 Jun 1;21(6):984–99.

2. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. Biology

of Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation.

Elsevier Inc; 2015 Mar 1;21(3):389–401.e1.

3. Shulman HM, Cardona DM, Greenson JK, Hingorani S, Horn T, Huber E, et al. Biology

of Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation.

Elsevier Inc; 2015 Apr 1;21(4):589–603.






4. Flowers MED, Apperley JF, van Besien K, Elmaagacli A, Grigg A, Reddy V, et al. A

multicenter prospective phase 2 randomized study of extracorporeal photopheresis for

treatment of chronic graft-versus-host disease. Blood. 2008 Sep 22;112(7):2667–74.

5. Carpenter PA, Kitko CL, Elad S, Flowers MED, Gea-Banacloche JC, Halter JP, et al.

Biology of Blood and Marrow Transplantation. Biology of Blood and Marrow

Transplantation. Elsevier Inc; 2015 Jul 1;21(7):1167–87.

6. Dignan FL, Scarisbrick JJ, Cornish J, Clark A, Amrolia P, Jackson G, et al. Organ-

specific management and supportive care in chronic graft-versus-host disease. British

Journal of Haematology. 2012 Apr 26;158(1):62–78.

7. Mawardi H, Elad S, Correa ME, Stevenson K, Woo S-B, Almazrooa S, et al. Oral

epithelial dysplasia and squamous cell carcinoma following allogeneic hematopoietic

stem cell transplantation: clinical presentation and treatment outcomes. Bone Marrow

Transplantation. Nature Publishing Group; 2011 Apr 4;46(6):884–91.

8. Treister N, Duncan C, Cutler C, Lehmann L. How we treat oral chronic graft-versus-host

disease. Blood. 2012 Oct 25;120(17):3407–18.

Appendix 1 Chronic Oral Mucosal Disease Questionnaire

Author(s)

Dr Rubeta Matin, Consultant Dermatologist

Dr Martina Shephard, Consultant Oral Physician

Audit

These processes are subject to the OxBMT audit programme

Circulation

NSSG Haematology Website

Review

Name Revision Date Version Review date

Diagnosis & Management of Oral

Chronic GVHD

New document Feb 2017 1.0 Feb 2018

Dr Rubeta N Matin, Consultant

Dermatologist,

Cristina Ovas, BMT Quality and

Data Manager

Minor formatting

changes

July 2019 1.1 July 2021

Dr Rubeta N Matin, Consultant

Dermatologist

Minor changes April

2022

1.2 April 2024






Appendix 1- Chronic Oral Mucosal Disease Questionnaire

Pain and functional limitation

1. How much do certain types of food/drink cause you

discomfort (spicy food, acidic food)?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

2. How much does your oral condition cause you to limit the

types of food/ drinks you consume?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

3. How much do certain food textures cause you discomfort

(rough food, crusty food)?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

4. How much does your oral condition cause you to limit the

textures of the food you consume?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

5. How much does the temperature of certain foods/drinks

cause you discomfort?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

6. How much does you oral condition cause you to limit the

temperature of the foods/drinks you consume?

Not at all 0

Slightly 1

Moderately 2

Considerably 3






Extremely 4

7. How much does your oral condition lead to discomfort

when carrying out your daily oral hygiene routine

(brushing, flossing, mouthwash usage)?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

8. How much does your oral condition cause you to limit

your daily oral hygiene routine (brushing, flossing,

mouthwash usage)?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

9. How much does your oral condition lead to discomfort

when wearing a denture (false teeth)?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

Medication and treatment (including mouthwashes, gels, creams, ointments, injections,

tablets, infusions)

1. How much do you feel you need medication to help you

with activities of daily life (talking, eating etc.)?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

2. How satisfied are you with the medication being used to

treat your oral condition?

Not at all 4

Slightly 3

Moderately 2

Considerably 1

Extremely 0

3. How concerned are you about the possible side effects of

the medications used to treat your oral condition?

Not at all 0

Slightly 1

Moderately 2






Considerably 3

Extremely 4

4. How much does it frustrate you that there is no single

standard medication to be used in your oral condition?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

5. How much does the use of the medication limit you in your

every day life (routine / the way you apply or take your

medications)?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

6. How much does it bother you that there is no cure for your

oral condition?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

Social and emotional

1. How much does your oral condition get you down? Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

2. How much does your oral condition cause you anxiety? Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

3. How much does your oral condition cause you stress? Not at all 0

Slightly 1






Moderately 2

Considerably 3

Extremely 4

4. How much does the unpredictability of your oral condition

bother you?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

5. How much does your oral condition cause you to worry

about the future (spread of the condition, possible cancer

risk)?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

6. How much does your oral condition make you pessimistic

about the future?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

7. How much does your oral condition disrupt social

activities in your life (social gatherings, eating out parties)?

Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

Patient Support

1. How satisfactory do you consider the information available

to you regarding your oral condition?

Not at all 4

Slightly 3

Moderately 2

Considerably 1

Extremely 0

2. How satisfied are you with the level of support and Not at all 4






understanding shown to you by family regarding this oral

condition?

Slightly 3

Moderately 2

Considerably 1

Extremely 0

3. How satisfied are you with the level of support and

understanding shown to you by friends/work colleagues

regarding your oral condition?

Not at all 4

Slightly 3

Moderately 2

Considerably 1

Extremely 0

4. How isolated do you feel as a result of this oral condition? Not at all 0

Slightly 1

Moderately 2

Considerably 3

Extremely 4

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