S Muller Oral Dysplasia 4/6/2019

Review the grading of oral epithelial dysplasia using the 2017 WHO criteria

HPV and oral dysplasia Diagnostic Challenges of Oral Epithelial Dysplasia and Precursor Lesions Goals Review atypical verrucous keratosis Susan Muller, DMD, MS including proliferative verrucous Professor Emeritus Emory University School of Medicine Discuss the pitfalls in the diagnosis of oral dysplasia

1 2

2017 WHO: Three Tiered vs Binary

It is a truth universally acknowledged that grading of oral dysplasia suffers from both intra- and inter- observer variability

Müller S. Oral epithelial dysplasia, atypical verrucous lesions and oral potentially malignant disorders: focus on histopathology. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018 Jun;125(6):591-602. 3 4

Epithelial Dysplasia – Diagnostic Criteria Epithelial Dysplasia – Diagnostic Criteria Architectural Features Architectural Features • ↑mitoc • Irregular epithelial figures/superficial stratification mitoses • Loss of basal cell • Dyskeratosis polarity • Keratin pearls within rete • Drop-shaped rete ridges • Loss of epithelial cohesion

5 6

1 S Muller Oral Dysplasia 4/6/2019

Epithelial Dysplasia Epithelial Dysplasia – Diagnostic Criteria Diagnostic Criteria OR What Really Matters

Cytologic Features • Drop-shaped rete • Abnormal variation in nuclear size • ↑mitoc and shape figures/superficial • Abnormal variation is cell size and mitoses/atypical shape mitoses • ↑ nuclear:cytoplasmic ratio • Nuclear and cellular • Atypical mitoses pleomorphism • ↑ number & size of nucleoli • Loss of basal cell • hyperchromasia polarity

7 8

9 10

11 12

2 S Muller Oral Dysplasia 4/6/2019

13 14

15 16

P16 High risk HPV RNA ISH

17 18

3 S Muller Oral Dysplasia 4/6/2019

HPV-associated Oral Epithelial Dysplasia

P16 in the oral cavity The risk of cannot be used alone transformation has yet as a surrogate marker to be determined. for HPV infection in OED

19 20

High risk HPV RNA ISH 21 22

Oral

23 24

4 S Muller Oral Dysplasia 4/6/2019

25 26

27 28

Dysplasia should NOT be present in lichen planus

Lichen Planus is a bilateral and/or multifocal disease!

29 30

5 S Muller Oral Dysplasia 4/6/2019

Low-power microscopic features of a band- Should we make the diagnosis like inflammatory cell infiltrate can mimic of lichenoid dysplasia? lichen planus Oral Dysplasia • The term may cause With Budding of the epithelial rete and cytologic confusion “Lichenoid” atypia can be seen • May result in inadequate patient management Inflammation Oral lichenoid lesions that do not have the typical clinical and histologic features of oral lichen planus have a higher malignant transformation rate than lichen planus

31 32

33 34

Tongue

35 36

6 S Muller Oral Dysplasia 4/6/2019

38F with no tobacco hx

25 M with tongue cancer

37 38

Why?

15 year old ….is the tongue becoming the most female frequent site of OSCC?

….is the tongue the overwhelming site of OSCC in young patients?

39 40

A 72 year old A 72 year old female with female with multiple white multiple white areas on the areas on the gingiva and gingiva and lateral tongue lateral tongue

41 42

7 S Muller Oral Dysplasia 4/6/2019

Band-like lymphocytic infiltrate?

YES

43 44

Subepithelial separation?

a. Oral Lichen Planus Dyskeratotic cells? b. Oral Lichenoid Contact Reaction What is your c. Mucous Membrane diagnosis? d. Lichenoid Dysplasia e. None of the above

45 46

Proliferative Verrucous Proliferative Verrucous Leukoplakia Leukoplakia

• First described in 1985, it is a clinical mimic of OLP • Patients are often older females with no Relentless progression to EtOH or tobacco history malignancy – • Multifocal lesions with a propensity for • the gingiva, , tongue, and buccal • Squamous cell carcinoma mucosa

47 48

8 S Muller Oral Dysplasia 4/6/2019

PVL Histology

• Verruciform epithelial hyperkeratosis with a focal area of interface mucositis is noted in an early stage PVL

49 50

A 56M – biopsy submitted as rule out lichen planus

Atypical Epithelial Hyperplasia

51 52

A 56M – biopsy submitted as rule out lichen planus Proliferative Verrucous Leukoplakia

53 54

9 S Muller Oral Dysplasia 4/6/2019

? Atypical Verrucous Keratosis vs Verrucous CA ? 5 weeks later…..

55 56

• Both inflamed epithelia and regenerative epithelia, a common occurrence in the oral cavity, can show reactive epithelial changes. • In the milieu of an active ulcer such as an aphthous ulcer or traumatic ulcerative granuloma distinguishing • Histologic features of Candida colonization reactive atypia from true are epithelial hyperplasia with parakeratosis dysplasia may be difficult. and superficial neutrophilic microabscesses • Nuclear hyperchromatism • Variable inflammation in the connective and pleomorphism is usually tissue can be incited by the organism and less severe in regenerating interface mucositis may be prominent and epithelium and generally a normal to near normal mistaken for an oral dysplasia nuclear:cytoplasmic ratio is Pitfalls in the diagnosis of maintained oral dysplasia

57 58

Smokeless Tobacco Keratosis

• Early lesions the epithelium shows marked parakeratosis with a focal wavy or chevron keratinization • Intracellular edema with ballooned cells • Epithelial dysplasia is generally absent although increased basal cell hyperchromasia is often present Smokeless Tobacco Keratosis

59 60

10 S Muller Oral Dysplasia 4/6/2019

Smokeless Tobacco Keratosis

Smokeless Tobacco Keratosis

61 62

Smokeless Tobacco Keratosis Smokeless Tobacco Keratosis

63 64

Oral Submucous Fibrosis

• Chronic, irreversible disease associated with the use of betel nut, quid, nass, paan and other substances commonly used in India and other South-Central Asian countries • Early signs include blanching of the mucosa • Trismus • About 7% malignant transformation rate

Isaac U, Issac JS, Ahmed Khoso N. Histopathologic features of : a study of 35 biopsy specimens. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008 Oct;106(4):556-60.

65 66

11 S Muller Oral Dysplasia 4/6/2019

Blanching of the Mucosa Oral Submucous Fibrosis Atrophic epithelium with juxtaepithelial hyalinization and collagen of varying density Diffuse nonspecific chronic inflammation

Source: Dr. Susan Muller 67 68

• Marked shaggy parakeratosis, epithelial hyperplasia and ballooned cells with intracellular edema • Shredding of the superficial keratin consistent with biting is apparent & often bacteria is noted on the keratin surface, particularly in the tongue • No dysplasia is present & unless ulcerated, inflammation is not Frictional Keratosis Frictional Keratosis significant.

69 70

 Despite shortcomings, histologic grading based on morphology remains the accepted method for the diagnosis of oral dysplasia.  Oral lichenoid lesions can be a diagnostic challenge for the pathologist due to the tremendous overlap in the clinical and pathologic presentation of many inflammatory, reactive, and immune-mediated disorders than commonly involve the . Conclusions  Ideally good clinical information will accompany the biopsy specimen including site, presentation and other relevant information as an accurate diagnosis cannot be made in a vacuum.  Oral epithelial dysplasia grading is not a predictive tool Beware of an abrupt transition for progression to malignancy. Active surveillance of clinically suspicious lesions remains a mainstay of from para- to orthokeratosis patient management.

71 72

12 S Muller Oral Dysplasia 4/6/2019

References 1: Müller S. Frictional Keratosis, Contact Keratosis and Smokeless Tobacco Keratosis: Features of Reactive White Lesions of the Oral Mucosa. Head Neck Pathol. 2019 Mar;13(1):16-24.

2: Müller S. Oral epithelial dysplasia, atypical verrucous lesions and oral Final Thought potentially malignant disorders: focus on histopathology. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018 Jun;125(6):591-602.

Never diagnose an isolated oral 3: Müller S. Oral lichenoid lesions: distinguishing the benign from the deadly. lesion as lichen planus Mod Pathol. 2017 Jan;30(s1):S54-S67.

4: Cheng YS, Gould A, Kurago Z, Fantasia J, Muller S. Diagnosis of oral lichen planus: a position paper of the American Academy of Oral and Maxillofacial Pathology. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Sep;122(3):332-54.

5: Müller S. Oral manifestations of dermatologic disease: a focus on lichenoid lesions. Head Neck Pathol. 2011 Mar;5(1):36-40.

6: Müller S. The Lichenoid Tissue Reactions of the Oral Mucosa: Oral Lichen Planus and Other Lichenoid Lesions. Surg Pathol Clin. 2011 Dec;4(4):1005-26.

73 74

13