Pseudoepitheliomatous hyperplasia (PEH) in BRONJ Jerry Bouquot,* Douglas Gnepp,** Patricia Suarez,* Shaolei Lu * * University of Texas, Houston, USA ** Brown University, Providence, Rhode Island, USA Pseudoepitheliomatous hyperplasia (PEH) in BRONJ may mimic squamous cell carcinoma J. E. Bouquot, DDS, MSD, FICD, FACD, FADI, FRCM (London) Professor & Chair, Department of Diagnostic & Biomedical Sciences University of Texas School of Dentistry at Houston, Room 5460 7500 Cambridge Street, Houston, TX 77054 Jerry.Bouquot@uth.tmc.edu; bouquot@aol.com; 713-486-4420

Dr. Bouquot, Oral Cancer, Precancer J.E. Bouquot, DDS, MSD, FAAOMP, Diplomate-ABOMP, FICD, FADI, FACD, FRSM 1945 1946 1947 1949 1954 With brothers Dave, Randy, Den With father Elmer With sisters Jan, Marlene With mother Marion With brother Dave 1963 1967 1969 2000 2012 High school grad, Caldwell, New Jersey College grad. Northfield, Minnesota With mother Marion, at Univ. Minnesota Director of Research, MFCenter, WV University of Texas; this is what 45 years in dentistry will do to you

Dr. Bouquot, Oral Cancer, Precancer Fall, 2011

Most Popular Oral Pathology Presentations in the World The Bouquot-To-Go (BTG) disk An oral disease resource, developed by Dr. J. E. Bouquot, USA Most Popular Oral Pathology Presentations in the World This disk, first made available in 2002, has more than 3,000 clinical and microscopic photos in Power Point 2010 format, usually with hyperlinks. It is continuously updated and all photos are copyright free. The 53 Most Common Oral Lesions. Hyperlink handout; 500+ clinical photos; first version: 2002 The Must-Know Oral Lesions. Hyperlink handout in differential diagnosis; 720+ clinical photos; first version: 2009 The Beginnings of Oral Pathology/Oral Medicine, 1805- 1899. PP presentation depicting the earliest books, articles, drawings of oral lesions; 90+ photos; first version: 2002 The CD Johnson Collection – A potpourri of Oral Lesions from the Urgent Care Clinic. Hyperlink handout of various oral lesions, especially those related to drug use; 500+ clinical photos; first version: 2009 The Dreizen Collection – Oral Lesions from the University of Texas, Houston, 1978. One of the first popular collections of oral clinical lesions, from a previous University of Texas faculty member; 90+ clinical photos; first PP version: 2009 Ischemic Jawbone Disease. Hyperlink handout providing very detailed information about ischemic and inflammatory jaw disorders; 1,000+ photomics and clinical photos; first version: 2006 Review of NICO. PP of a popular lecture; 150+ photos; first version: 2003 The Little Book of Lists. Hyperlink handout of those important lists of oral lesions/ effects associated with drugs, syndromes, systemic disorders, etc.; first version: 2009

Pseudoepitheliomatous Hyperplasia in BRONJ The Problem

PEH in BRONJ The Problem: Alveolar Epithelium is Very Proliferative © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ The Problem: Alveolar Epithelium is Very Proliferative Odontogenic and alveolar/gingival epithelium has a very strong tendency to produce long rete processes which in other sites might be interpreted as “invasion” Inflamed mucosa at edge of BRONJ (Bisphosphonate Related Osteonecrosis of the Jaws) is often very proliferative This may be mistaken for carcinoma Gingivitis Gingivitis Oral pathologists are familiar with this phenomenon; not so for medical pathologists Proliferative Epithelium of Marginal Gingiva Periapical Cyst

PEH in BRONJ The Problem: Odontogenic Epithelium is Very Proliferative © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ The Problem: Odontogenic Epithelium is Very Proliferative Subacute Gingivitis Periapical Cyst

PEH in BRONJ The Problem: Alveolar Epithelium Entraps Bone © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ The Problem: Alveolar Epithelium Entraps Bone Chronic Gingivitis with Entrapped Bone Fragment v

PEH in BRONJ The Problem: Proliferative Epithelium Engulfs Bone © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ The Problem: Proliferative Epithelium Engulfs Bone v Chronic Gingivitis with Entrapped Bone Fragment

PEH in BRONJ The Problem: Proliferative Epithelium Near BRONJ Bone © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ The Problem: Proliferative Epithelium Near BRONJ Bone Proliferating, degenerated epithelium may look ominous because it is not expected in osteonecrosis; also, it is known that carcinoma can develop at openings of draining osteomyelitis in long bones

Pseudoepitheliomatous Hyperplasia in BRONJ Study Design

PEH in BRONJ Objective, Study Design: A Biopsy Service Series © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Objective, Study Design: A Biopsy Service Series Objective: To characterize pseudoepitheliomatous hyperplasia (PEH) in bisphosphonate-related osteonecrosis of the jaws (BRONJ) Study Design: A convenience sample -- Referral biases are unknown Cases were identified from 89 BRONJ biopsies in two surgical pathology services (4 cases were consults) Exclusion criteria: poor records BRONJ BRONJ (from above case)

Pseudoepitheliomatous Hyperplasia in BRONJ Results

PEH in BRONJ Results: 13 Examples of PEH Amongst 89 BRONJ Cases © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: 13 Examples of PEH Amongst 89 BRONJ Cases 13 cases (14.6%) identified from 89 BRONJ cases 9 (69.2%) used IV, 5 used oral bisphosphonates 8 (61.5%) were females Average age at diagnosis: 63 years (range: 54-79) 4 (30.8%) with actinomycosis 4 (30.8%) cases: prior suspicion of squamous cell carcinoma Exposed bone in BRONJ © Clinical photo: Dr. John Hellstein, University of Iowa

PEH in BRONJ Results: Histopathology of BRONJ © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of BRONJ All cases: subacute inflammation, bony sequestra with resorption lacunae, osteoclasts (maybe), bacterial colonies

PEH in BRONJ Results: Histopathology of BRONJ © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of BRONJ 13 (100%): inflammatory cells 13 (100%): granulation tissue 5 (38.5%): fibrous tissue 2 (15.4%) with osteocytes 1 (7.7%) with osteoclasts Osteoclasts Resorption lacunae with occasional osteocytes

PEH in BRONJ Results: Histopathology of Ulcer Margin © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of Ulcer Margin All cases: epithelial proliferation and subacute inflammation of mucosa at margin of exposed bone

PEH in BRONJ Results: Histopathology of Marginal Epithelium © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of Marginal Epithelium 8 (61.5%): very degenerated proliferating epithelium; much like lining of periapical cyst

PEH in BRONJ Results: Histopathology of Marginal Epithelium © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of Marginal Epithelium Proliferation of surface epithelium overlying bony sequestra

PEH in BRONJ Results: Histopathology of Proliferating Epithelium © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of Proliferating Epithelium 7 (53.9%): epithelium immediately adjacent to bony sequestra; no entrapment of bone

PEH in BRONJ Results: Histopathology of Proliferating Epithelium © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of Proliferating Epithelium Inflammation and proliferation epithelium adjacent to bony sequestra, maybe filling resorption lacunae

PEH in BRONJ Results: Histopathology of Entrapped Bone © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of Entrapped Bone Multiple sequestra entrapped by epithelium

PEH in BRONJ Results: Histopathology of Entrapped Bone © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of Entrapped Bone 5 (38.5%): bony sequestrum completely surrounded by epithelium, with occasional dark, somewhat enlarged nuclei in 2 (15.4%)

PEH in BRONJ Results: Histopathology of Proliferating Epithelium © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of Proliferating Epithelium 2 (15.4%): massive epithelial proliferation filling medullary spaces

PEH in BRONJ Results: Histopathology of Entrapped Bone © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Results: Histopathology of Entrapped Bone Degenerated epithelium filling medullary spaces and entrapping bone Resorption lacunae filled with epithelium mimics destruction by squamous cell carcinoma

Pseudoepitheliomatous Hyperplasia in BRONJ Discussion

PEH in BRONJ Discussion: PEH Reports with Jawbone Associations © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Discussion: PEH Reports with Jawbone Associations Potential look-alikes: Squamous odontogenic tumor Odontogenic hamartoma Squamous cell carcinoma, including primary intraosseous types Primary intraosseous mucoepid. carcinoma PEH with jawbone fragments has been reported previously: Chronic osteomyelitis with augmentation bone (n = 2; Warter, et al, 2000) 5 of 8 BRONJ cases (Hansen, et al, 2006) 7 of 10 osteoradionecrosis (ONJ) cases (Hansen, et al, 2006) 4 of 15 BRONJ cases (Bouquot, Gnepp, 2009, AAOMP abstract) Frequent in BRONJ and ONJ in rats (Hokugo, et al, 2010)

Conclusions Conclusions Pseudoepitheliomatous Hyperplasia in BRONJ Pseudoepitheliomatous Hyperplasia in BRONJ Conclusions Conclusions

PEH in BRONJ Conclusions: © J.E. Bouquot,, University of Texas; Houston, USA; presented at 16th Biennial IAOP Congress, São Pedro, SP, Brasil, 2012 PEH in BRONJ Conclusions: Pathologists should be aware of this proliferative phenomenon so as not to misdiagnose it as squamous cell carcinoma BRONJ-associated PEH must be ruled out before a carcinoma diagnosis can be applied to a BRONJ lesion © Right photo: Dr. K. Gundlach, University of Rostock, Germany

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