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Home , Aphthous stomatitis, Morphea, Pyostomatitis vegetans

2017 Oregon Dental Conference® Course Handout

Nasser Said-Al-Naief, DDS, MS Course 8125: “The as The Body’s Mirror: Oral, Maxillofacial, and Head and Neck Manifestations of ” Thursday, April 6 2 pm - 3:30 pm 2/28/2017

The Mouth as The Body’s Mirror

Oral Maxillofacial and Head and Neck Manifestation of Ulcerative Conditions of Allergic & Immunological Systemic Disease the Oro-Maxillofacial Diseases Region Nasser Said-Al-Naief, DDS, MS Professor & Chair, Oral Pathology and Radiology Director, OMFP Laboratory Oral manifestations of Office 503-494-8904// Direct: 503-494-0041 systemic diseases Oral Manifestations of Fax: 503-494-8905 Dermatological Diseases

Cell: 1-205-215-5699 Common Oral [email protected] Conditions [email protected] OHSU School of Dentistry OHSU School of Medicine 2730 SW Moody Ave, CLSB 5N008 Portland, Oregon 97201

Recurrent aphthous (RAS) Recurrent (RAS)

• Aphthous" comes from the Greek word "aphtha”- • Recurrence of one or more painful oral , in periods of days months. = • Usually begins in childhood or , • The most common oral mucosal disease in North • May decrease in frequency and severity by age America. (30+). • Affect 5% to 66% of the North American • Ulcers are confined to the lining (non-keratinized) population. mucosa: • * 60% of those affected are members of the • Buccal/labial mucosa, lateral/ventral /floor of professional class. the mouth, soft /oropharyngeal mucosa • Etiopathogenesis:

1 2/28/2017

Etiology of RAU Recurrent Aphthous Stomatitis (RAS): Types:  Minor; small size, shallow, regular, preceeded by , heal in 7-10 days Bacteria ( S. Sanguis) Systemic diseases Immune component) with no scarring. (HLA B12, B51, CW7) - Usually start in childhood and may persist to adulthood - Lining mucosa. (T4/T8 decrease) HSV  Major (Sutton’s diseses) ; Larger, deeper, irregular, Pain+, less defined Smokers= no ulcers prodrome, can persist weeks to years+ (pain may not be for full duration), may VZV heal with scarring. Mucosal Barrier; - Usually start > puberty RAU Adenovirus & CMV RAU - Keratinized and non-keratinized mucosa - Aphthous stomatitis and systemic disease. Sensitivity to foods : e.g., to preservatives and agents • Iron, , B12, Zinc such as or •Menstruation / leuteal phase of =  Herpetiform; numerous, small size, shallow, regular, preceeded by prodrome, cinnamon, chocolates, peanuts Thicker lining = less ulceration heal in 7-10 days with no scarring, > in ♀. • Pregnancy = No ulcers - Keratinized and non-keratinized mucosa (+ in posterior oropharynx)

RAU

Traumatic Ulcer on , with Frictional

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RAU RECURRENT APHTHOUS STOMATITIS (RAS)

• Management/preventive measures: • Rx:______• Rx:______• Amelexanox oral paste 5% • (Decadron) elixir 0.5 mg/5 ml 1) Plaque reduction, manual • Disp: 5 gram tube • Disp: 320 ml • Sig: Dab on affected area qid until healed. 2) Antimicrobial /: •Sig: • Rx:______• 1. For 3 days, rinse with 1 tablespoonful (15 ml)  1% gel t.i.d. after meals x 35 days • Orabase Soothe-N-Seal Protective Barrier (OTC) • Disp: 1 package • qid and swallow. Then,  0.1% hexetidine mouth rinse 15 mL for 1 min t.i.d. after meals x • Sig: Apply as per the package directions • For 3 days, rinse with 1 teaspoonful (5 ml) every • qid and swallow. Then, 6 wk • Six hours when necessary. • For 3 days, rinse with 1 teaspoonful (5 ml) • qid and swallow every other time, Then  0.2% chlorhexidine 10 mL for 1 min t.i.d. x 6 wk • Rx:______• acetonide (Kenalog) in Orabase • Rinse with 1 teaspoonful (5 ml) qid and spit  Listerine mouth rinse (unspecified volume) for 30 sec b.i.d. x 6 •0.1% • out Discontinue medication when mouth • Disp: 5 gm tube • becomes comfortable mo • Sig: Coat the with a thin film after each • Meal and at bedtime  0.5% chlortetracycline 50 mL held in mouth 1 min q.i.d. • Rx:______• Rx:______• tablets 10 mg  2.5% chlortetracycline 10 mL held in mouth 1 min q.i.d. • Prednisone tablets 5 mg • Disp: 40 tablets • Disp: 26 tablets  5% 1 tsp held in mouth 1 min q.i.d. • Sig: Take 5 tablets in the morning for five • Sig: Take 4 tablets in the morning for • Days, then 5 tablets in the morning every other day five days until gone • Then decrease by 1 tablet on each successive day.

RAU TX of (CANDIDOSIS) Management • Rx:______• Rx:______5) Other agents (advanced) ; • Nystatin (Mycostatin, Nilstat) oral suspension • Nystatin vaginal suppositories 100,000 u • 100,000 units/ml • Disp: 40 • Disp: 240 ml • Sig: Let 1 suppository dissolve in the mouth • Thalomid, • Sig: 5 ml qid. Rinse for two minutes and swallow. • qid. Do not rinse for 30 minutes.

• Acyclovir, • Rx:______• Rx:______• Nystatin ointment • *Clotrimazole (Gyne-Lotrimin, Mycelex-G vaginal • , • Disp: 15 gm tube • Cream 1% (OTC) • Sig: Apply thin coat to inner surface of denture • Disp: One tube • and to affected area after meals. • Sig: Apply a think layer to tissue side of denture • Interferon alfa, • and/or to infected qid. • Rx:______• prostaglandin E 2 gel, • Ketoconazole (Nizoral) cream 2% • Rx:______• Disp: 15 gm tube • *Miconazole (Monistat 7) nitrate vaginal • Sig: Apply tin coat to inner surface of denture • Cream 2% (OTC) • , , and cyclosporine. • and to affected area after meals. • Disp: One tube • Sig: apply thin layer to tissue side of denture • Trental (pentoxyfylene). • Rx:______• and/or to infected oral mucosa qid • Mycostatin pastilles 2000,000 u • Glycyrrhiza extract (GX or DGL) in an oral topical time-release • Dis;p: 70 pastilles • Rx:______• Sig: Let 1 pastille dissolve in mouth five times • Ketoconazole (Nizoral) tablets 200 mg • a day. Do not chew. • Disp: 14 tabs patch held in constant or frequent contact with a new aphthous • Sig: Take 1 tablet daily with a meal or orange ulcer for at least 16 hours per day shortens healing time to 1-3 • Rx:______• juice. Do not take together with buffered • Clotrimazole (Mycelex) torches 10 mg • Medications or with gastric acid blockers days and relieves pain while in place. • Disp: 70 troches • Sig: Let 1 troche dissolve in mouth five times • Rx:______• a day. Do not chew. • Fluconazole (Diflucan) tablets 100 mg • Topical • Disp: 15 tablets • Sig: Take 2 tablets stat, then 1 tablet daily until • gone.

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Systemic Disorders Associated with RAU Celiac disease (Sprue) • Celiac Disease / gluten enteropathy. • Immune-mediated enteropathy • Behcet’s syndrome • (& immune deficiency including HIV) • Over 99% of people with celiac disease are positive for • Nutritional deficiency human leukocyte (HLA)-DQ2 or DQ8) • IgA deficiency • Inflammatory bowel disease & RAU • In up to 1% of the population. • Magic syndrome (mouth & genital ulcers with inflamed cartilage) (Behcet’s syndrome + Polychondritis) • FAPA syndrome (Periodic , aphthous stomatitis, , • Permanent sensitivity to the gliadin protein (fraction of cervical adenitis) gluten) found in cereal grains including wheat, rye, and • Reiter’s disease : Immune mediated arthritis + Nongonococcal barley Urethritis + Conjunctivitis • Sweet’s syndrome • Occurs in genetically susceptible individuals and a family • Ulcus vulvae acutum history of celiac disease (a key indicator for diagnostic testing) in young children with gastrointestinal(GI) symptoms.

Celiac disease (Sprue) Behcet’s disease (syndrome) • A complex, multisystem, inflammatory disease • A higher incidence in children with (Juvenile-type 1 • Classically characterized by diabetes, IgA deficiency, Down syndrome, auto immune  Recurrent oral ulceration thyroiditis, and rheumatoid arthritis, SLE), & Dermatitis  Genital ulceration Herpetiformis/10% = very itchy on the extremities,  Ophthalmologic inflammation. buttocks, trunk, and and neck • First described by Hulusi Behcet's, a Turkish dermatologist, in 1937 Symptoms include: , and abdominal cramping • Long-term; celiac Sprue: • Most frequently in the Middle East  Growth retardation, iron deficiency, osteoporosis, oral • Also endemic among populations clustered along the historic (eastern ulcers, coagulopathies, and infertility. Asia to the Mediterranean basin) • In the Middle East, Europe, and the United States: Prevalence for young ♂  Patients with refractory disease; increased risk for non- • Japan and Korea: Slight ♀ + Hodgkin's and significant gastrointestinal ulcerations. • The diverse range of clinical findings seems to stem from an underlying ; however, the ultimate etiologic agent remains unknown.

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Behcet’s disease Behcet’s disease Etiology • Clinical Features • Remains unknown • Mucosal/cutaneous finding: • Genetic and environmental factors (familial Behcet's has been reported); • The most common ; oral aphthous ulcerations at least three times  Middle East; 0 to 15 % in one year  The remainder of the world; 5% . Abnormal function; . Pyoderma-gangrenosum-like , -nodosum-like . Alterations in lymphocytes peripheral CD4+/CD8+ T cells IL 2 lesions, vasculitis, and , interferon- α TNF-α, IL-8, IL-4, IL-10, and IL-13 levels . pathergy . Infectious agents; virus type I, parvovirus B19, hepatitis C, and . One of the diagnostic criterions for Behcet's / small pustule species develop within 24 to 48 hours after the skin has been pricked by a ------sterile needle) • Histocompatibility association; • Genital lesions; typically resemble oral aphthous with irregular • HLA B5 – ocular form – Japan and middle east borders. • HLA B12 – Mucocutaneous form - N American & Europe  In ♂: Painful lesions on scrotum and penis, may heal with • HLAB27 – Arthritic form – no specific population - Neurological form- no specific population scarring.  In ♀: Lesions may be asymptomatic , on the vulva & vagina and/or cervix.

Behcet’s disease Behcet’s disease • Clinical Features . Ocular disease (The most serious clinical aspect) • Neurological symptoms:  Blurred vision, eye pain, loss of vision, and/or floaters. • Range from benign headaches serious findings  70 to 85 % of patients • Silent neurological disease may occur  Pathology vary (ranges from posterior , conjunctivitis, and corneal ulceration, to papilledema and arteritis) • Vascular abnormalities:  Glaucoma & cataracts are known complications • Common and involve blood vessels of all sizes • Arthritis • Both arterial and venous systems involved. • Most often a none-erosive mono- or oligoarthritis of the knees, • Cutaneous vasculitis, superficial thrombophlebitis, intracardiac ankles, wrists, and elbows thrombus or vasculitis of the coronary arteries, aortic aneurysm, • 50 % of patients. pulmonary artery thrombosis, glomerulonephritis, and portal hypertension, among others. • Gastrointestinal diseases • Ulcerations occurring at any point along the gastrointestinal tract: most common at the junction of the small and large bowels. • , diarrhea, melena, and perforation. • Differentiation from inflammatory bowel disease may be difficult

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Behcet’s disease • Management; • Colchicine (decrease genital lesions, arthritis, and , especially in women). • : 50 to 100mg per day (antineutrophilic effects) • Azathioprine (maintain eye health) • Cyclophosphamide • 7.5 to 20mg per week (watch for liver toxicity)  For refractory mucocutaneous disease, much success has been reported with .  Must be tailored to individual clinical presentation. • TX Aphthous ulcers and mucocutaneous disease:  Topical & systemic steroids (especially for ophthalmologic and neurological expression of disease)  Intralesional triamcinolone 5mg/mL  Topical , such a viscous 2-5%  Chlorhexidine oral rinses  Tetracycline mouthwash (250mg tetracycline in 5mL glycerin)

Pathergy Diagnostic Criteria of Behcet's Disease Summary

• Recurrent oral ulceration plus two of the following: • Recurrent genital ulceration • Eye lesions • Skin lesions • Pathergy test

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Neutropenia

• Most common reason is infectious process (viral), followed by iatrogenic Neutropenia • Etiology; • Decreased production • Agranulocytosis  Drugs (cytotoxic, methotrexate, antibiotics, anticonvulsants, antipsychotic, etc.) • Inadequate # of neutrophils (neutropenia (most common)  Hematologic dis. (cyclic neutropenia, aplastic , malignant infiltration of • Inadequate # of eosinophils (esosinopenia) (uncommon) bone marrow) • Inadequate # of basophils (very rare)  Nutritional def. (vit B12, folate)  Infection (TB, IM, AIDS, viral hepatitis) • Cyclic Neutropenia • Peripheral distraction • Inadequate # of neutrophils (neutropenia) Antineutrophil antibodies • Occurs in cycles Splenic/ lung trapping Autoimmune () Wegener’s Granulomatosis Drugs (transient neutropenia in hemodialysis

Agranulocytosis Cyclic Neutropenia • Most common etiology; Cancer Chemotherapy • Rare condition • Seen with leukemia • that occurs in phases • Idiopathic form; Neutrophils fail to mature at physiological rate. • Episodic fluctuation in the # of circulating neutrophils due to bone • With MDS; an early form of leukemia marrow maturation arrest (occurs Clinical; every 30 days and lasts 4 – 5 days • Severe bacterial infections (pneumonia & others). total) • Oral ulcerations & others; may resemble Aphthous stomatitis but seen anywhere Clinical ; within oral mucous membranes. • Frequent recurrent respiratory tract • Ulcers continue to enlarge and become deeper Osteomyelitis/ Sequestrum infections (bacterial+) • Deeper ulcers = guarded prognosis (life threatening infections). • Frequent (spontaneously • Treatment; Antibiotics , G-MCS factor resolve when counts stabilize)

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Cyclic Neutropenia Lipschu¨ tz ulcers (LU) • RAU like ulceration ulcus vulvae acutum develop anywhere, within • Acute vulvar ulcers, primary Aphthous ulcers or reactive non- sexually related acute genital ulcers 2-3 days • First described in 1913 • Premature PDD, alveolar • Systemic symptoms, such as fever, , headache, bone loss & PD pockets. diarrhea, oral aphthae, enlarged lymph nodes, tonsillitis or respiratory symptoms can be present. • Healing occurs spontaneously, often with scarring • More frequent in virgin girls or young women • A diagnosis of exclusion, after ruling out STD, idiopathic aphthosis, Behcet’s syndrome, extra-genital Crohn’s disease. • Age ranges = babies to 79 y.o

Lipschu¨ tz ulcers (LU) Sweet’s syndrome (acute febrile neutrophilic dermatosis). ulcus vulvae acutum • First described in 1964 by Sweet, • Characterized by 4 cardinal features: • Pedro Vieira-Baptista et al , 2016, European Journal of Obstetrics & Gynecology and Reproductive Biology 1) fever, 2) a relative increase of peripheral neutrophils  Investigated 11 women 3 tender erythematous plaques, nodules, vesicles, and cutaneous  May be found at any age and also sexually active. pustules on the face and extremities  In most cases the lesions are preceded by non-gynecological 4) : a dense dermal infiltrate with mature neutrophils symptoms  Viruses (EBV and CMV) are frequently found agents but  Etiology: a reaction (to non-specific infective Mycoplasma pneumoniae serology should be considered. I agents or other diseases?)  PVB19 also found  Preceding infections, such as upper respiratory infection, tonsillitis,  STD in up to a third of cases. or bronchitis.  Rare; occur in patients who received recombinant GCSF treatment

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Reiter Syndrome Sweet’s syndrome (acute febrile neutrophilic dermatosis) • Arthritis, redness of the eyes, and urinary tract signs. • Etiology • Clinical: Buccal ulceration, recurrent Aphthous- like ulcerations & ulcerative stomatitis • Infectious agents; appears > 1 to 3 weeks after bacterial infection with Chlamydia trachomatis (STD) & GI • TX: Systemic prednisone bacterial infections with Salmonella, Shigella, Yersinia, and Campylobacter. • Genetic; persons with HLA-B27 have higher susceptibility • ♂ 20 – 40 yo >>> ♀ • 3% of all men with a STD develop Reiter's syndrome

Reiter Syndrome Aphthous stomatitis • Symptoms; Arthritis and spondylitis • Conjunctivitis + Vs • Men: Increase frequency of urination with burning in men (inflammation in prostate, urethra and penis) HSV infection • Females: Salpingitis, Cervicitis, Urethritis • Skin: “keratosis blenorrhagica’” type lesions: Keratosis of palms and soles which may spread to scrotum, scalp and trunk and resemble • Nails: subungual fibrosis and • Oral: Aphthous like ulcers & -type lesions • Erythematous lesions with rough surfaces • Treatment; bed rest, NSAID, steroids, Antibiotics

9 2/28/2017

Erythema migrans

• A common benign condition • Primarily affect the tongue • 1-3% of the population • Unknown etiology • Patients with psoriasis; higher prevalence • Treatment: None/ reassurance unless symptomatic • Other mimickers+

GEOGRAPHIC TONGUE (BENIGN MIGRATORY ; ERYTHEMA Oral lesions mimicking Geographic tongue MIGRANS)

• Rx:______• Nystatin- (Mycolog II, • Reiter syndrome • Mytrex) ointment • Disp: 15 gm tube • LP (annular lesions) • Sig: Apply to affected area after each mean and • at bedtime.

•SLE • Rx:______• Clotrimazole-betamethasone dipropionate • Lyme disease • (Lotrisone) cream • Disp: 15 gm tube • Sig: Apply to affected area after each meal and • at bedtime.

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GEOGRAPHIC TONGUE (BENIGN MIGRATORY GLOSSITIS; )

• Rx:______• Betamethasone Valerate Ointment, 0.1%, Disp: 15 gm tube • Sig: Apply to affected areas after meals and at • bedtime. • Rx:______• Nystatin ointment • Disp: 15 gm tube • Sig: Apply to affected areas after meals and at • bedtime.

Vesiculobullous diseases vulgaris

• A desquamative condition of the oral mucosa & skin where are directed against the desmosomes. • In 50% of patients: Oral lesions are first to show, last to go Vesiculobullous Diseases • ♀ > ♂ (2:1)/ 4th –6th decade. • Jewish & Mediterranean descend • Skin = Flaccid vesicles and bullae • Oral = Vesicles rupture soon, erosion and ulcerations ( generalized). • + Nikolsky sign • Variants:  P. Vulgaris Oral  P. Vegetans  P. Erythematosus  P Foliaceus . Characteristic histology

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Vesiculobullous diseases • Immunofluorescent studies: • Diagnosis: 1) Direct:  ( Routine and immunofluorescence) • Antibodies (with fluorescent light) directed to  Serology (IgG & C3 & others) the patients in the lab • Treatment: • Frozen tissue / special fixed tissue *****  Immunosuppressive agents  Systemic steroids  Azathioprine 2) Indirect:  Cyclophosphamide ++ • Patients serum ( contains circulating  Other antibodies) reacted with monkey's esophageal epithelium / rat bladder etc --- observe changes

IgG Desmosomes.In.( DG 1 & III) Acantholysis

Spinous layer

Basal layer

Basement membrane

Hemi-desmosomes PV

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• Pemphigus vulgaris – Additional abdominal punch biopsy with desmoglein 3 ELISA that revealed significantly elevated value – Started initial 70 mg prednisone with slow taper with goal of changing over to steroid- sparing medication • Ocular inflammation was suggestive of episcleritis – Ruled out systemic causes

Vesiculobullous diseases • Paraneoplastic Pemphigus: • Occurs exclusively in the presence of an occult neoplasm ( B cell lymphoproliferative disorders, Non Hodgkin’s lymphoma, Castelman’s disease, thymoma, spindle cell sarcoma, Waldenstrom's gammaglobulinemia and others) • ♀ = ♂ / 6th –7th decades. • Autoantibodies to DG I & III/ desmosomes and hemidesmosomal proteins • IL-6 levels are elevated ( important in the pathogenenesis and treatment/ (Anti IL-6 therapy & cyclophosphamide) • Histo: Subepithelial and suprabasilar

13 2/28/2017

Vesiculobullous diseases BMMP Case (Cicatricial ) • A desquamative condition of the oral mucosa & skin • 66 year old female with history of MALT • Autoantibodies are directed against the basement membrane lymphoma • Affects the gingiva, prior to extending to other mucosal locations. • Generalized mouth sores for several months • ♀ > ♂ 4th –6th decade. • Oral, , vagina, laryngeal, esophageal, nasal, mucosa • Better chance to identify intact vesicles and bullae her as compared to pemphigus. • Ocular manifestation: Most significant; Conjunctiva fibrosis • Symblepharons: Bulbar/ palpebral adhesions & scarring ( Inner eyelid lining-globe)

Pathogenesis Of Pemphigoid

Spinous layer IgG

BPAG1

Basal ( Plactin plaque) layer

Plasma Transmembrane membrane proteins (¤6ß4 Basal lamina Integrin( BPA2) Laminin 5 •epiligrin

Anchoring fibrils (collagen 8) E acadherins

Subepithelial separation Collagen 4/ anchoring plaque

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IgG linear basement membrane zone (20x) and C3 linear basement membrane zone (40x) Pemphigoid

Vesiculobullous diseases BMMP (Cicatricial Pemphigoid)

• Diagnosis: • Biopsy ( Routine and immunofluorescent) • Serology ( not as effective as pemphigus) • Management: - Ophthalmological & GyN referrals - Topical & systemic steroids - Dapsone (be aware of restrictions) - Tetracycline

15 2/28/2017

Angina Bullosa hemorrhagica 54-year-old woman presented for routine • A benign and generally subepithelial oral mucosal filled dental care including “check-up” and with blood “cleaning”. At initial evaluation generalized erythema of • Not attributable to a systemic disorder or hemostatic defect. the gingiva was noted • Predominantly affect middle-aged or elderly people

• Medical history: • ♂ = ♀.  No significant medical history and no medications • Lesions may be confused with other more serious VB disorders  to penicillin (eg, pemphigoid, epidermolysis bullosa, linear IgA, ); • Social history: · Cigarette smoking 1ppd/20 years • Isolated nature, rapid healing, rare recurrence + hx of trauma help to make accurate diagnosis • Blisters last only few minutes and then spontaneously rupture, leaving a shallow ulcer that heals without scarring, discomfort, or pain.

16 2/28/2017

Angina Bullosa hemorrhagica • Some patients describe a stinging pain or burning sensation immediately before the appearance of the . • Patients do not report a tendency to bleed at other sites. • Treatment : None Exclude the presence of any rapidly enlarging bulla of the posterior or epiglottis.

Vesiculobullous Diseases Vesiculobullous Diseases • : • Histology & Immunofluorescent studies may be • Most common autoimmune blistering disease. identical to BMMP • Resembles cicatricial pemphigoid but differ in few • Management: aspects especially with limited clinical course, (vs. cicatricial pemphigoid which is progressive and Immunosuppressants protracted Dapsone • Primarily skin involvement (friction areas) Tetracycline • Oral lesions in 8-39% of cases Cyclophosphamide Diagnosis: • Biopsy ( Routine and immunofluorescent) • Serology (Circulating IgG & C3 against BP 1 &2 (230 & 180) in 90-100% of patients)

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B_P Vesiculobullous diseases (Epidermolysis Bullosa) • A generalized desquamating condition of the skin and mucosa • Associated scarring, contracture, and dental defects • Etiology; A wild spread hypersensitivity reaction that occurs in mild and severe forms t • Tissue reactions, centered around the superficial vessels of the skin & mucous membranes • Usually results from an inciting agent • 4 types:  3 main hereditary forms in children •EB simplex • Junctional EB • Dystrophic EB

 Acquired form in adults ( the only form believed to be autoimmune origin).

Vesiculobullous diseases (Epidermolysis Bullosa

EB simplex Junctional EB Dystrophic EB ( EB Letalis old name) • Mild form • Severe form • AD & AR (severe) • AD inheritance • AR inheritance Defect in 5 & • Blisters develop in site of • Large blisters on face, trunk, • Bullae, rupture, heal wit deep 14 friction & trauma; hands, feet, extremities, Fragile palatal and ,/ Contracture/Mitten-Claw neck, knees and elbows. perioral-perinasal blister. deformity Defect in Laminin 5 •Blisters heal without scarring • Loss of nails • Loss of nails

• Blisters heal with scarring • Severe oral involvement; Defect in , decrease opening, Collagen VII • Oral involvement uncommon •Oral involvement is common

• Teeth are not affected with •Teeth are affected with • Teeth are affected with hypoplasia hypoplasia/severe pitting and hypoplasia/severe pitting and * Epidermolysis Bullosa Acquisita = Anti- rapid caries rapid caries, delayed eruption Collagen VII Antibodies •Appear at birth, site of pressure, may not survive past • Appear during infancy, • Appear at birth, some infants early adulthood improve significantly with die in the first few months of •Cutaneous and oral lingual Pathogenesis of EB puberty life, sloughing at birth

18 2/28/2017

Epidermolysis Bullosa Acquisita: EB simplex • Adulthood • Association with multiple myeloma, diabetes, Amyloidosis, tuberculosis, IBD, EB, Junctional • Autoantibodies against type IV collagen • Oral lesion in 50% of cases (uncommon in the absence of Cutaneous lesions). • Blistering at area of trauma in skin and oral cavity

EB, Dystrophic • Similar to a milder junctional EB • Salt split studies (with IgG deposited at the floor of the bullae), as compared to cicatricial pemphigoid where deposition is seen at the roof).

Epidermolysis Vesiculobullous diseases Bullosa Acquisita (Epidermolysis Bullosa

• Management: • Non specific, meticulous wound care techniques • Dilantin (collagenase activity inhibition) • Acquired form: No much benefit from immune Anti-Collagen VII Antibodies suppression

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Vesiculobullous diseases EM • ; (EM) • Is a term first used by von Hebrain 1866 to describe a disease characterized by - Symmetrically distributed, pleomorphic, evolving cutaneous lesions, located primarily on the extremities - A proclivity for recurrence. - in 1922, Stevens and Johnson described two boys with febrile illnesses associated with cutaneous lesions similar to those of EM - They also had stomatitis and severe conjunctivitis that resulted in visual impairment. - The disease that they described became known as Stevens-Johnson syndrome

Lichen planus LP • Clinical: • An inflammatory dermatosis of unknown etiology • 3 distinct clinical presentations: • A skin disease with common oral involvement  Reticular : • occurring in 0.5%-1% of the population . Wickham’s striae • Described in 1869 . Rarely symptomatic . BM, vestibules, tongue, gingiva. • Mediated by cells and triggered by antigen alterations on . Commonly bilateral the cell surface of the basal layer of the epithelium.  Erosive LP - Oral & Cutaneous = 40% . Erythema & white pseudomembranous areas - Cutaneous alone = 35% . May mimic Candidiasis & other VB diseases - Oral alone , ♀ > ♂, 3rd to 7th decades, . BM & vestibules. children/adolescents rarely affected  Plaque LP - Etiology; . • Current trend; consider OLP as an auto-immune process  Atrophic LP = 25% . Buccal mucosa & gingiva, transitional stage from reticular to erosive

20 2/28/2017

LP LP • Management: Topical Retinoids • Topical : • Results with isotretinoin 0.1% gel were considered good • Lidex (fluocinolone acetonide), Temovate ( propionate) • Local irritation; easily controlled by decreasing the frequency of applications. • Recurrence is frequent after the interruption and the response is slow in cases of • Dexamethasone elixir at 0.5 mg/5mL, swish with 5 mL for 3 erosive LP. minutes t.i.d then expectorate. • Topical tazarotene has been used with good results in hyperkeratotic OLP. • Steroids inhalants: reserved for esophageal disease Cyclosporine • Systemic steroids: Erosive OLP and other disseminated forms. • Its effect in LP is explained by the action in the T lymphocytes. • Despite good results described by some, it should be considered as a last resort • The initial dose should not be less than 20 mg. due to its side effects and the need of high dosages (3-5 mg/kg/d) for control of • The recommended dosage is 30-40 mg/d for 4-6 weeks or until the disease. improvement of the symptoms, reducing slowly to 20 mg, which • Some report the use of cyclosporine 500 mg in the form of a daily mouth swirl should be maintained until complete remission (with this scheme, with good results and without side effects/Other studies do not show advantages recurrence is less frequent) of topic cyclosporine when compared with topic corticoids. Azathioprine • Intralesional Injections. Injections are seldom used because of the • Azathioprine may be used in association with steroids in cases of bullous LP associated pain. The recommended dose is 10 mg/mL and in severe forms of the disease as a corticoid-sparing drug. triamcinolone acetonide for cases of erosive OLP. • and pigmentation may occur, and in those cases treatment should be discontinued

Plaquenil: Dapsone - Great medication if tolerated • Doses of 100-150 mg/d Dapsone are indicated for bullous LP, but up to 200 mg may be administered Surgery and Laser Antibiotics • An options in symptomatic and hypertrophic cases that are unresponsive to other treatments. • Many antibiotics have been used without good response. • Excision with closing, electrosurgery, or cryosurgery may be used. • Tetracycline is described as efficient in cases of bullous • Carbon dioxide laser has been used in cases of OLP in plaque, but LP. recurrence is high. Extra-Body Phototherapy • It may be used topically in the form of mouth swirls • This therapeutic modality has been used more recently, twice a using 250 mg in 100 mL water 2-3 times a day for week during 3 weeks, especially for erosive LP erosive LP. Immunomodulation Treatment • Immunomodulators, like and interferon-α,, is indicated by some authors as an adjuvant therapy to prednisone in patients with symptomatic and difficult-to-treat LP.

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LICHEN PLANUS, TX • Rx:______• Rx:______• * (Lidex) gel 0.05% • Dexamethasone (Decadron) elixir 0.5% mg/5 ml • Disp: 30 gm tube • Disp: 320 ml • Sig: Coat the lesion with a thin film after each •Sig: • Meal and at bedtime. • Immunomodulation Treatment (Cont’d) • 1. For 3 days, rinse with 1 tablespoonful (15 ml) • Rx:______• qid and swallow. Then • *Dexamethasone (Decadron) elixir 0.5 mg/5 ml • Tacrolimus is a drug with powerful immunosuppressant • 2. For 3 days, rinse with 1 teaspoonful (5 ml) • Disp: 100 ml • qid and swallow. Then, • Sig: Rinse with 1 teaspoonful for two minutes effects used initially for patients receiving organ transplants. It • 3. For 3 days, rinse with 1 teaspoonful (5 ml) • qid and spit out. Discontinue when lesions become • qid and swallow every other time. Then, has been used in cases of symptomatic LP, especially for the • asymptomatic. • 4. Rinse with 1 teaspoonful (5 ml) qid and erosive form, with good results in symptom relief, despite • expectorate. frequent recurrences. • Rx:______• Prednisone tablets 10 mg • ?Capsules Immunosuppressant. • Disp: 26 tablets • Sig: Take 4 tablets in the morning for five Initial: 0.15-0.3 mg/kg/day administered in two divided doses • days, then decrease by 1 tablet on each successive day. • Rx:______q 12 h • Prednisone tablets 5 mg • Disp: 40 tablets Metronidazole • Sig: Take 5 tablets in the morning for five • days, then 5 tablets in the morning every other day until • 500 mg metronidazole twice a day for 20-60 days in patients gone. with generalized idiopathic LP show satisfactory results in 78.9% of cases. • Acts as an immunomodulator and antimicrobial agent.

Chronic ulcerative stomatitis LP • Ulcerative oral condition • Appear as desquamative or buccal • The relationship to plaque control mucosa ulcers • The relationship to stress • Histology = LP / lichenoid features. • Relationship to hepatitis C • Immunofluorescent staining = Diagnostic / • Relationship to Diabetes? against nuclei of epithelium • Chloroquine rather than steroids to manage

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Lichen Planus

Diagnosis: • Biopsy for routine and Immunofluorescent studies • Histological pitfalls: 1) Lichen planus & lichenoid dysplasia 2) The controversy with lichen planus 3) The need for follow -up

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Desquamative gingivitis

• A term used to describe gingival epithelium that sloughs spontaneously with manipulation • Represents a vesiculobullous diseases with different differential diagnosis; • LP & Pemphigoid > others • Pemphigus, DH, Linear IgA diseases, Epidermolysis Bullosa Acquisita, SLE, and paraneoplastic pemphigus and others

Lichen Planus & Malignancy • There is no increased risk of skin malignancy in patients with cutaneous LP, • There is a higher risk of developing squamous cell carcinoma in OLP, especially in men. • The probability of malignant change of OLP lesions = 0.4% - 2% (especially if lesions persist for 5 or more years). • The concept of lichenoid dysplasia: • Lateral tongue lesions; high prevalence; related to the OLP itself or to the risk factors involved in pathology or even the presence of oncogenic viruses? • The atrophic and erosive forms have the greatest potential of malignancy, however, all OLP forms can potentially become malignant. • The clinical red flag that an OLP lesion may be evolving into SCC is the presence of ulcerated or infiltrated lesions. • Homogeneous

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Case Presentation & History • 37YOWF with history of Acute Myelomonocytic Leukemia (AML- M4) , diagnosed in February 2006 with normal cytogenetics What else can look like • Received induction chemotherapy, LP??????? followed by HLA-matched sibling donor BMT in July 2006

• Achieved remission/ had GVHD limited to upper GI, managed with photopheresis Said-Al-Naief, 2010

AB

• Relapsed in summer of 2007; underwent re- induction with clofarabine and high dose Ara-C

• September 2007; consolidation high dose D C Ara-C and idarubicin

• November 2007; match unrelated stem cell transplant/fludarabine and TBI conditioning Said-Al-Naief, 2010 Said-Al-Naief, 2010

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The three phases of GVHD Immunobiology Lichenoid drug reaction Reconditioning of host /tissue damage with high dose chemo and radiation Patient • Erosive lichen planus like lesions Cytokines, chemokines Tissue & adhesion molecules • Antihypertensive medications ++ others & host cell LPS production activation • Diuretics Infused immunocompetent T cells + Macroph. • Gold compounds • Antimalarials CD4 Host APC + CD8+ + TNF- α, IL1, •NSAID Activated NO • Antibiotics CytotoxicTC INF- α, IL2 Host target, Liver GI • Identical to erosive LP histologically Fas-L Said-Al-Naief, 2010 Skin, Oral etc NKC

Lichenoid eruptions to • Cinnamon • Amalgam • Gold • Partial denture material • OTC compounds/ herbal Medication and other • Cocaine

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Oral Allergic Reactions (Allergic )

• Only 1-2% of population is actually allergic to mercury amalgam  Drugs and medications: • Acute reaction ------symptoms appear 2-24 hours • A wide spectrum of drugs can sometimes give rise to after placement of filling numerous adverse oral manifestations, particularly • Symptoms disappear 10-14 days after the removal of the dry mouth, taste disturbances, oral mucosal • Filling ulceration, and/or swelling. • 50 % patients show + skin reaction to mercury (compared to only 5% of normal population and those with conventional LP) • LP like features

Allergic mucosal reaction to systemic drugs TABLE 6 Drug-related Oral Ulceration ( Stomatitis Medicamentosa) • Numerous types: Alendronate Emepromium Molgramostim Phenytoin

Classic: EM & lichenoid drug reaction Allopurinol Flunisolide Naproxen Potassium chloride LE like eruptions Aurothiomalate Gold Nicorandil Proguanil Anaphylactic stomatitis Aztreonam Indomethacin NSAIDs Sertraline Captopril Interferons Olanzapine Sulindac Intraoral fixed drug Carbamazepine -2 Pancreatin Vancomycin Pemphigus like drug reaction Clarithromycin Isoprenaline Non specific vesiculoulcerative lesions Ketorolac Phenindione

Dideoxycytidine Losartan Phenylbutazone

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TABLE 7 Drug-related Pemphigoid-like Reactions TABLE 8 Drug-related Pemphigus-like Reactions

Ampicillin Cephalexin Oxyphenbutazone Probenecid Amoxicillin Ibuprofen Penicillin v Arsenic Diclofenac Penicillamine Procaine penicillin Azapropazone Isoniazid Penicillamine Sulphasalazine Benzylpenicillin Gold Phenobarbital Rifampicin Clonidine Mefenamic acid Phenacetin Sulphonamides

Captopril Interferon-beta Phenylbutazone Furosemide Nadolol Practolol

Cephadroxil Interleukin-2 Piroxicam

TABLE 9 Drug-related Erythema Multiforme (and Stevens-Johnson syndrome and toxic epidermal necrolysis) TABLE 10 Drug-related Lupoid Reactions

Acetylsalicylic acid Digitalis Mesterolone Streptomycin Allopurinol Diltiazem Minoxidil Sulindac

Amlodipine Ethambutol Nifedipine Sulphasalazine

Arsenic Ethyl alcohol Omeprazole Tenoxicam Ethosuximide Isoniazid Phenytoin Sulphonamides

Atropine Fluconazole Oxyphenbutazone Gold Methyldopa Phenothiazines Tetracyclines

Busulphan Fluorouracil Penicillin derivatives Theophylline

Carbamazepine Furosemide Phenolphthalein Tocainide Griseofulvin Para-aminosalicylate Procainamide

Chloral hydrate Gold Phenylbutazone Tolbutamide

Chloramphenicol Griseofulvin Phenytoin Trimethadione Hydralazine Penicillin Streptomycin

Chlorpropamide Hydantoin Piroxicam Vancomycin

Clindamycin Hydrochlorothiazide Progesterone Verapamil

Codeine Indapamide Pyrazolone derivatives Zidovudine

Co-trimoxazole Measles//rubella Quinine

Diclofenac Meclofenamic acid Retinol

Diflunisal Mercury Rifampicin

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TABLE 11 Drug-related Lichenoid Reactions

ACE inhibitors Dapsone Mepacrine Piroxicam

Allopurinol Dipyridamole Mercury (amalgam) Practolol • A chronic inflammatory condition of the skin, and internal organs Amiphenazole Ethionamide Metformin Prazosin • Circulating autoantibodies to DNA and other nuclear and RNA proteins Antimalarials Flunarizine Methyldopa Procainamide

Barbiturates Gaunoclor Metronidazole Propranolol • Occur in one of 3 forms

BCG vaccine Gold Niridazole Propylthiouracil  Discoid (DLE)

Captopril Griseofulvin NSAIDs Protease inhibitors  Subacute Cutaneous (SCLE)

Carbamazepine Hepatitis B vaccine Oral contraceptives Prothionamide  Systemic (SLE)

Carbimazole Hydroxychloroquine Oxprenolol Quinidine

Chloral hydrate Interferon-alpha Para-aminosalicylate Quinine Immune system changes Chloroquine Ketoconazole Penicillamine Rifampicin Deletions in basal cell, collagen, & vascular tissue Chlorpropamide Labetalol Penicillins Streptomycin Viruses Autoantibodies to DNA and other nuclear and Cholera vaccine Levamisole Phenindione Sulphonamides Sun light Cinnarizine Lincomycin Phenothiazines Tetracycline ribonuclear protein antigens are generated in the blood/circulating autoantibodies to multiple tissues Clofibrate Lithium Phenylbutazone Tocainide Colchicine Lorazepam Phenytoin Tolbutamide Increase in B cell function / decrease in Triprolidine suppressor T cells

LE Type Clinical features LE • Oral lesion: DLE • Cutaneous (sun exposed) & oral mucosal lesions and the most prominent features - May appear as non specific annular leukoplakia or • Alopecia/ scalp lesions/ scarring with hypo or hyper pigmentation erythematous ulcers and erosions • Oral lesions = 24% of patients ( lichen planus like, but skin always pres.) - Most often symptomatic

SCLE Intermediate form - Lesion may mimic LP • Skin of the upper parts of the body with mild systemic & - RAU like musculoskeletal involvement ( fever fatigue, malaise etc) - Leukoplakia • Skin present for a long time and eventually heal • ANA, Anti Sjogren’s antibodies - Migratory glossitis-like • Oral = rare SLE Most common with highest morbidity • Systemic problems (Kidneys+++) • Anemia, Arthritis, Arthralgias, Lung, heart, skin rashes, CNS •More in ♀ of child bearing ages, Oral lesions = 21% of patients

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LE . Serology: - Circulating ANA, anti double stranded DNA (70% of cases, Kidney involvement++), - Anti-SM protein antibodies, RF, Anticentromere, antiphospholipid, anticardiolipin etc - + lupus band test (DIF of IgG, IgM, or C3 on lesion and normal skin) . Management: - Immunosuppressant Meds +++. - DIF : + in lesional skin in both SLE and DLE - DIF: + Lupus band test in SLE in 25 – 60% of cases / 0 % in DLE. - ANA: Sensitive not Specific for SLE, not a good tool to distinguish from DLE. - Anti double stranded DNA & Anti-Sm antibodies; specific for SLE

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Systemic sclerosis/Crest Syndrome () • A generalized condition characterized by replacement of the normal connective tissue, with dense collagen bundles resulting in fibrosis, loss of mobility an altered function of organs. • Pathogenesis remains unknown; Endothelial cells

Circulating immune complexes BV Anti centromere antibodies ( in Crest syndrome)

Peri-capillary fibroblasts

Collagen

Systemic sclerosis/Crest Syndrome • 3 presentations: (scleroderma) Systemic sclerosis/Crest Syndrome (scleroderma) Diagnosis: 1) Classic/ diffuse form: 2) CREST syndrome • Biopsy • Generalized involvement of both body surfaces and visceral Calcinosis organs ( , intestines, kidneys heart, lungs • Anti Scl-70 (topoisomerase II) (anti centromere antibodies) Raynaud's • Skin: Firm immovable, loss of adnexa, • Endothelial cell autoantibodies levels elevated Esophageal stricture • /restricted mouth opening + loss ala of nose + mask like facies = mouse facies Management: • Xerostomia • Challenging • Sclerodactyly: tight skin around fingers • Steroids; little help • ♀3X > ♂ •Acro-osteolysis/claw deformity; loss of terminal phalanges. • ACE inhibitors to control HT • Widened PDL/ loss of condyle • OHI enforcement 3) Localized form ( skin only no visceral component) Prognosis: a) Linear • Generally poor for diffuse, better for limited b) • 80% will survive 2 years after the diagnosis c) en coup de sabre • Death is mostly to lung involvement

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Orofacial Granulomatosis • Group of conditions all characterized histologically by the presence of granulomatous inflammation. • A diagnosis of exclusion ; Melkersson-Rosenthal syndrome (MRS) ( facial palsy + lingual plicata + Macrochelia), Miescher's (an oligosymptomatic form of MRS), Crohn's disease Sarcoidosis Other

Sciubba & Said-Al-Naief, J.Oral Pathology & Medicine. 2003

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Pyostomatitis Vegetans

•Rare • Unusual presentation of IBD (UC + Crohns’s) • Oral lesions of PV can be seen without skin lesions but it is rare for them to be present in the absence of gastrointestinal disturbances • Young and middle-aged adults, • Male; female ratio = of 3 : 1 • Snail track distribution++++ • labial and buccal mucosae, hard and , gingivae and sulci >>>> tongue and floor of mouth. • Immune mediated and inflammatory related etiology • A mucosal variant of pyodermatitis vegetans or a variant of pemphigus vulgaris.

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Sarcoidosis Establishing The Diagnosis:

• Sarcoidosis is an idiopathic chronic granulomatous disease • Characterized by the accumulation of T-lymphocytes, * Clinical features * Laboratory tests mononuclear phagocytes, and non caseating epithelioid *Bx * The presence of tuberculin in the involved organ anergy * Chest x-ray • Can practically involve any organ including * Elevated serum angiotensin- mediastinal LN, peripheral LN, lung, liver, spleen, eyes, bones, * Demonstration of converting enzyme levels nasal and oral mucosa, larynx, salivary glands, kidneys, nervous accumulation of gallium * + Kveim - Siltzbach skin test system, heart, endocrine system, and GIT 67 isotope in the * Elevated 24 hour urine • A relatively common disease involved organ(s). calcium level • Affects both genders (slightly more common in females), all races, geographic locations and ages (with prevalence between ages 20 - 40 years)

SARCOIDOSIS The constitutional respiratory symptoms Sarcoidosis • Lungs: Majority / 90 % symptoms of acute • cough sarcoidosis • Lymph nodes: Majority / 90 % • dyspnea • Eyes: 25 – 50% • fever • vague retrosternal chest • Nervous system : 5% • fatigue discomfort +/or • Renal & Endocrine system : Less common • malaise • polyarthritis • Liver & spleen : 40 – 80% • anorexia • Parotid gland : 4 – 6 % • • Bone / BM: 1- 13% (up to 40% in some studies) • Skin & Oral/ peri-oral area: 25% +

PATHOGENESIS • A cell-mediated to an unidentified antigen

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Sarcoidosis of Bone: • Hands & Feet • Skull • Nasal bones • Long bones • Vertebrae •Ribs • Jaw lesions;  More common in anterior & posterior  Slight female predilection  No racial predilection  Age range = 16 – 49 ( mean = 44 y.o)  S&S: Pain / swelling in or around area, swelling, nasal obstruction, tooth mobility Suresh et al, J Periodntol, 2000

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Acquired Hereditary Angioedema Minor • In lymphoproliferative • A recurring rapid swelling of the and adjacent structures Disorders (patient develop Type 1 AD form (85%) • Occurs in susceptible patients after contact with an allergin , autoimmunity and prevent activation of complement binding of C1/ C1 INH pathway • Reduction of quantity of anti-inflammatory medication, or exposure to elements C1 INH • In lymphoproliferative C1 X C1 esterase • Rapid painless swelling of lips, anterior cheek, or tongue Disorders;T the lymphoid X • Airway compromised if more posterior region is involved. infiltrateh increases consumptione of C1 INH • Reaction stops once contact with an allergin stops/ subsides in Cleaves C4 and C2 24 -48 hour

• 2 forms recognized: Type 2 AD form • Acquired: • Normal levels of C1 – INH but dysfunctional Angioedema • Hereditary • LE • Viral bacterial infection • Marked peripheral blood Ag/ Ab complexes eosinophilia

Angioedema • Acquired: Hereditary  Most common • Majority of patient; Angioedema within hours  No respiratory or GI involvement • 30% of patients; delayed ( months to years)  Recent medication intake (Captopril, elalapril, lisinopril) (0.1-0.2% of pop.)  IgE immune mediated ( especially penicillin related)  NSAIDS, aspirin, indomethacin Destabilization of Ace inhibitors (eg; Captopril) membranes

Non-immune mediated Degranulation angioedema by enhancing activity of bradykinin Chemical mediators ( including bradykinin) Cold, sun or Inflammation/vascular dilatation and edema exercise

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Angioedema Wagner’s Granulomatosis

Management: • A systemic disorder characterized by vasculitis & granulomas, • Antihistamines involving upper and lower respiratory tract, accompanied by focal necrotizing glomerulonephritis • Often associated with ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCAs) • Unknown cause • All ages (+ in 4rth – 5th decade) Classic form • Upper and lower respiratory tract involvement • Rapid renal involvement if no treatment Limited form: • Lung lesions predominate • No rapid renal involvement  Superficial diseases : Primarily skin & mucosa :

Diagnosis: • Creatinine elevation • Indirect immunofluorescence for serum antibodies directed against cytoplasmic components of neutrophils • P ANCA ( perinuclear) • C ANCA ( cytoplasmic) 90 – 95% • Management: • Combination of Cyclophosphamide and glucocorticoids

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Midline Lethal Angiocentric (NK) lymphoma

•M> F, 6th decade + • Destructive Midfacial, nasal septum & palate perforation • Mostly localized to nasal area, may disseminate • ANCA -, no serological correlation • CD56+, CD2+, cytoplasmic CD3e +, CD43 & UCHL-1 + • Treatment: RT for localized diseases, chemo for disseminated cases • 30-50% overall survival • Local recurrence, relapse, and systemic failure common • EBV+ strong association

Photo: Dr. Richard Hart, West Virginia University, Morgantown, WV

• Invasive Aspergillosis is an increasingly common • The most common site for invasive Aspergillosis in Leukemic patients is the lung >>> liver, spleen, brain, heart, pericardium and other sites and a major concern in patients with Garson et al, 1984; Denning, 1998 sever immune deficiency. • The more common species associated with invasive Aspergillosis are A. fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans but A. • Leukemic patients; the largest overall group of patients at fumigatus accounts for ~ 90% of cases Denning & Stevens, 1999;Pagano et al, 1996; risk for developing invasive Aspergillosis. Denning, 1996;1998, Iwen et al, 1997; Walmsley et al, 1993 • Oral disease is considered rare; can be primary or secondary in origin • Leukemia and lymphoma; the predisposing condition in • The majority of oral cases reported were secondary (to extension form 42% of case as compared to BM (25.8%) and solid organ rhinosinus infection extension. Dreizen et al, 1985; Schubert et al; 1986; transplantation (13.0%) {total n = 1,941 patients reviewed Talbot et al, 1991; Chamber et al, 1995 by Lin et al, 2001}. • The 2nd most common oral fungal infection in neutropenic patients (to Candida) Dreizen et al, 1992; Myoken et al, 2001

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Acknowledgment

• Mrs. Lauren Malone • Mr. Conor McNulty • ODA Staff • Attendees • OHSU Biopsy Contributors

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