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CONTEMPORARY MANAGEMENT OF ODONTOGENIC TUMORS

RUI FERNANDES, DMD, MD,FACS, FRCS(ED)

PROFESSOR UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE- JACKSONVILLE

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Benign

th 4 Edition Odontogenic 2017 Tumors

Malignant

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BENIGN ODONTOGENIC TUMORS BENIGN ODONTOGENIC TUMORS

• EPITHELIAL • MESENCHYMAL • • • CALCIFYING EPITHELIAL • ODONTOGENIC FIBROMA • PINDBORG TUMOR • PERIPHERAL ODONTOGENIC FIBROMA • ADENOMATOID ODONTOGENIC TUMOR • • SQUAMOUS ODONTOGENIC TUMOR • ODONTOGENIC GHOST CELL TUMOR

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BENIGN ODONTOGENIC TUMORS MALIGNANT ODONTOGENIC TUMORS

• PRIMARY INTRAOSSEOUS CARCINOMA • MIXED TUMORS • CARCINOMA ARISING IN ODONTOGENIC • / FIBRO- • AMELOBLASTIC FIBROSARCOMA • ODONTOMA • AMELOBLASTIC • CLEAR CELL ODONTOGENIC CARCINOMA • ODONTOAMELOBLASTOMA • SCLEROSING ODONTOGENIC CARCINOMA New to the Classification • PRIMORDIAL ODONTOGENIC TUMOR New to the Classification • ODONTOGENIC CARCINOSARCOMA

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0.5 Cases per 100,000/year

Ameloblastomas 30%-35%

Myxoma AOT 3%-4% Each Ameloblastic fibroma

CEOT Ghost Cell Tumor 1% Each

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Courtesy of Professor Ademola Olaitan AMELOBLASTOMA

• 1% OF ALL CYSTS AND TUMORS

• 30%-60% OF ALL ODONTOGENIC TUMORS

• 3RD TO 4TH DECADES OF LIFE

• NO GENDER PREDILECTION

• 80%

• 20%

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AMELOBLASTOMA CLASSIFICATION AMELOBLASTOMA HISTOLOGICAL CRITERIA

• SOLID OR MULTI-CYSTIC Conventional 2017 • UNICYSTIC 1. PALISADING NUCLEI 2 • PERIPHERAL 2. REVERSE POLARITY 3. VACUOLIZATION OF THE CYTOPLASM

4. HYPERCHROMATISM OF BASAL CELL LAYER 1

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Ameloblastoma: Delineation of early histopathologic features of neoplasia Robert Vickers, Robert Gorlin, Cancer 26:699-710, 1970

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AMELOBLASTOMA CLASSIFICATION OF 3677 CASES AMELOBLASTOMA SLOW GROWTH – RADIOLOGICAL EVIDENCE

Unicystic Peripheral 6% 2%

Solid 92%

~3 years after enucleation of “dentigerous ”

P.A . Reichart, H.P. Philipsen and S. Sonner Eur J Cancer, Part B, Oral Oncol 31B:86-99, 1995

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AMELOBLASTOMA AGGRESSIVE /DESTRUCTIVE BEHAVIOR

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CASE# 1 19 YO WITH AMELOBLASTOMA AMELOBLASTOMA ASPIRATION

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19 YO WITH AMELOBLASTOMA TUMOR RESECTION

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POST-OPERATIVE APPEARANCE CASE #2

• 69 Y.O. MALE REFERRED WITH A PROVEN AMELOBLASTOMA OF THE MANDIBLE • HIS MEDICAL HISTORY AND SURGICAL HISTORY ARE NONE CONTRIBUTORY • OVERALL HEALTHY

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Q: How would you maintain the mandibular relationship ? (no VSP)

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Q: How would you reconstruct this defect?

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1 year post , removal of reconstruction plate

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Overall recurrence rates: Facial appearance prior to dentures, vertical collapse consistent 5 year: 9.3% 10 year: 17.6% 15 year: 24.4% with edentulous upper and lower arches Resection Only Independent Prognostic Factor

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AMELOBLASTOMA UNICYSTIC AMELOBLASTOMA AMELOBLASTOMA UNICYSTIC VARIANT

First Report • GENERALLY A UNILOCULAR • 20 PATIENTS RADIOLUCENCY ASSOCIATED WITH AN IMPACTED THAT IS DIFFICULT TO • PRESENTED WITH UNILOCULAR CYSTIC LESIONS DISTINGUISH FROM A DENTIGEROUS • LESIONS MIMICKED DENTIGEROUS CYSTS CYST. • SIMPLE ENUCLEATION • ROBINSON AND MARTINEZ, 1977 • LESS RECURRENCE I.E. LESS AGGRESSIVE BEHAVIOR ?

• ASSOCIATED WITH A LOW RATE OF “RECURRENCE” AFTER ENUCLEATION Robinson L, Martinez MG AND CURETTAGE Unicystic ameloblastoma: a prognostically distinct entity. Cancer. 1977 Nov;40(5):2278-85. • GARDNER AND CORIO, 1984

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UNICYSTIC AMELOBLASTOMA

Cyst lined by Intramural nodular ameloblastoma ameloblastoma

50 % to 80% associated with an impacted tooth most commonly: mandibular 3rd molar

Treatment: simple (luminal or intraluminal): enucleation mural or transmural: radical Intramural infiltrating Intraluminal resection ameloblastoma ameloblastoma

Ackermann GL, Altini M, Shear M. The unicystic ameloblastoma: a clinicopathologic study of 57 cases. Journal of Oral Pathology 1988;17:541±546. 37 38

14 Y.O. WITH MANDIBULAR AMELOBLASTOMA 14 Y.O. WITH MANDIBULAR AMELOBLASTOMA

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14 Y. O. WITH MANDIBULAR AMELOBLASTOMA 14 Y.O. WITH MANDIBULAR AMELOBLASTOMA

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14 Y.O . WITH MANDIBULAR AMELOBLASTOMA 14 Y.O. WITH MANDIBULAR AMELOBLASTOMA

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14 Y.O. WITH MANDIBULAR AMELOBLASTOMA

• U OF MARYLAND’S EXPERIENCE & WORLD LITERATURE • UNDER AGE 20 YEARS • MARYLAND EXPERIENCE 11PTS • 8 PRIMARY, 3 RECURRENT LESIONS • AVERAGE AGE 15.5 Y • 9 OF 11 UNICYSTIC • WESTERN POPULATION 85PTS • AVERAGE AGE 14.3 • UNICYSTIC AMELOBLASTOMAS 76.5% • AFRICAN POPULATION 77PTS • AVERAGE AGE 14.7 • UNICYSTIC AMELOBLASTOMAS 19.5%

• RECURRENCES AFTER ENUCLEATION OF UNICYSTIC AMELOBLASTOMAS • FOLLOWED FOR AT LEAST 5 YEARS OR UNTIL RECURRENCES SHOWED A RECURRENCE RATE OF 40%

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STAGED IMMEDIATE IMPLANT PLACEMENT…

BRAF and SMO negative

2 years post treatment

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CASE #2 CASE # 2 • 39 Y.O. FEMALE NURSE REFERRED WITH A BIOPSY PROVEN AMELOBLASTOMA OF THE MANDIBLE

• HIS MEDICAL HISTORY AND SURGICAL HISTORY ARE NONE CONTRIBUTORY • OVERALL HEALTHY • HIGH ESTHETIC DEMAND AND WISHES FOR A RAPID RETURN TO WORK AND DEFINITIVE SURGER

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Q: How would you reconstruct this defect?

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CALCIFYING EPITHELIA ODONTOGENIC TUMOR (PINDBORG TUMOR)

• ACCOUNTS FOR LESS THAN 1% OF ALL ODONTOGENIC TUMORS • FEWER THAN 200 REPORTED CASES • PATIENTS BETWEEN 30 AND 50 YEARS OLD • 2/3RDS OCCUR IN THE MANDIBLE • PRESENT AS A PAINLESS SLOW GROWING MASS

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CALCIFYING EPITHELIA ODONTOGENIC TUMOR ADENOMATOID ODONTOGENIC TUMOR (A.O.T.) (PINDBORG TUMOR)

• UNCOMMON TUMOR • ACCOUNTS FOR 3 TO 7% • DISCRETE ISLANDS OF • YOUNG PATIENTS POLYHEDRAL SHEETS • VERY UNCOMMON IN PTS OLDER • LARGE AREAS OF AMYLOID LIKE THAN 30 Y MATERIAL • ALSO KNOWN AS THE 2/3RDS • CONCENTRIC CALCIFICATIONS TUMOR KNOWN AS LIESENGANG RINGS • 2/3 FEMALES • 2/3 MAXILLA • 2/3 IMPACTED CANINE Treatment: Resection with a 1 cm bony linear margin 71 72

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A.O.T. HISTOLOGY A.O.T. TREATMENT

• WELL DEFINED Due to the thickness of the • THICK CAPSULE capsule, the tumor may be

• SPINDLE SHAPED CELLS treated by enucleation and curettage • WHORLED MASSES OF CELLS WITH SCANT FIBROUS STROMA Only one recurrence in the • ROSETTE-LIKE STRUCTURES literature WITH CENTRAL EMPTY SPACES

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A.O.T. CASE EXAMPLE A.O.T. CASE EXAMPLE

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A.O.T. CASE EXAMPLE

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MYXOMA MYXOMA HISTOLOGY

• UNCOMMON BENIGN • STELLATE, SPINDLE SHAPED OF THE JAWS CELLS • DEVELOPS FROM • LOOSELY MYXOID STROMA ECTOMESENCHYME • SLOW GROWING WITH POTENTIAL • RESEMBLES STELLATE FOR AGGRESSIVE BEHAVIOR RETICULUM • HIGH RECURRENCE RATE AFTER • FEW COLLAGEN FIBRILS INADEQUATE THERAPY

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MYXOMA RADIOGRAPHIC APPEARANCE 1 MYXOMA TREATMENT

• UNILOCULAR OR MULTILOCULAR IN APPEARANCE • MAY DISPLACE OR CAUSE ROOT RESORPTION • TRABECULAE OF RESIDUAL BONE ARRANGED AT RIGHT ANGLES TO ONE ANOTHER “STEPLADDER” Patient with an expanding mass on the right maxilla, diagnosis: myxoma

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MYXOMA TREATMENT 2

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26 cases

No statistical difference in recurrence between conservative vs radical treatment

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Overall recurrence 5/39(13%) X10y

Conservative tx 4/22(19%) X11y Resection 1/17(6%) x9y

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AMELOBLASTOMA

MALIGNANT AMELOBLASTOMA &

AMELOBLASTIC CARCINOMA

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MALIGNANT AMELOBLASTOMA VS. AMELOBLASTIC CARCINOMA WHO Classification 2005 • MALIGNANT (METASTASIZING) AMELOBLASTOMA • IS A NEOPLASM IN WHICH THE FEATURES OF AN AMELOBLASTOMA ARE SHOWN BY THE PRIMARY GROWTH IN THE JAWS AND BY ANY METASTATIC GROWTH. Malignant (Metastasising) Ameloblastoma

• AMELOBLASTIC CARCINOMA • IS A NEOPLASM IN WHICH THERE HAS BEEN HISTOLOGICALLY MALIGNANT TRANSFORMATION, WITH OR WITHOUT METASTATIC DEPOSITS. Ameloblastoma Type 1 Primary intraosseous carcinoma, ex (Malignant types) Type 2 Primary intraosseous carcinoma, ex ameloblastoma

Malignant ameloblastoma

Ameloblastic carcinoma arising de novo, ex ameloblastoma, or ex odontogenic cyst

Type 3 Primary intraosseous carcinoma arising de novo

Non-keratinizing Ameloblastic Carcinoma

Keratinizing

Slootweg PJ, Muller H: Malignant ameloblastoma or ameloblastic carcinoma Oral Surg 57:168-176; 1984 113 114

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WHO Classification 2017 AMELOBLASTIC CARCINOMA

• 8 CASES Malignant (Metastasising) Metastasizing Ameloblastoma Ameloblastoma • 7 CASES IN THE MANDIBLE, 1 CASE IN THE MAXILLA

Benign Category • A DIAGNOSIS OF BENIGN AMELOBLASTOMA WAS MADE FOR ALL CASES BASED ON INCISIONAL BIOPSY

Ameloblastoma • ONE CASE HAD CERVICAL AT THE TIME OF INITIAL (Malignant types) PRESENTATION • MOST COMMON PRESENTING SYMPTOMS INCLUDED RAPID GROWTH (6 CASES) AND PAIN (3 CASES) • 3 PATIENTS DEVELOPED RECURRENT DISEASE Ameloblastic Carcinoma

Corio RL, Goldblatt LI, Edwards PA, Hartman KS. Ameloblastic carcinoma: a clinicopathologic study and assessment of eight cases. Oral Surg Oral Med Oral Pathol. 64:570-6; 1987 115 116

AMELOBLASTIC CARCINOMA

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PT WITH METASTATIC DISEASE OR NON-RESECTABLE DX

TARGETED SYSTEMIC THERAPY �

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MOLECULAR MARKERS IN MELANOMA

• BRAF (B-RAF PROTO-ONCOGENE) MUTATIONS V600E • 50 – 70% BRAF • KIT (PROTO-ONCOGENE C-KIT) MUTATIONS

• 10 – 15% MUCOSAL (SINONASAL AND CHRONICALLY SUN EXPOSED SKIN) • NRAS (NRAS PROTO-ONCOGENE) MUTATIONS

• 15% SKIN WITH CHRONIC AND INTERMITTENT SUN EXPOSURE

Sensitivity to agents that inhibit the BRAF or MAPK pathway

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Timeline of treatment options for metastatic melanoma Timeline of treatment options for metastatic melanoma

1970 1998 2011 1970 1998 2011 2012 2012 2013 Dacarbazine IL-2 Ipulimumab Dacarbazine IL-2 Ipulimumab Dabrafenib Dabrafenib Trametenib Vemurafenib Vemurafenib

Trametenib: Dabrafenib: Dabrafenib side effects: Tramatenib side effects: Orally available small molecule Inhibits BRAF Cutaneous side effects Rash common (papulopustular) Selective inhibitor of MEK1 & MEK2 When compared to vemurafenib in a phase rash, hyperkeratosis, Diarrhoea Median progression free survival 4-8 months 3 trial papillomas, plantar-palmar Peripheral edema Overall survival at 6 months 81% Overall survival favored Dabrafenib erythrodysaesthesia Decreased ejection fraction 7% Cutaneous SCCA 6% NO SCCA

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BRAF MUTATION IN AMELOBLASTOMA ~60% TARGETED THERAPY FOR AMELOBLASTOMA

Case Report:

85 yo male with Mandibular Ameloblastoma Refused Surgery Tested for BRAF mutation: BRAF V600E

Treatment: Dabrafenib 150 mg PO every 12 hours

Side effects: Low energy, plaque like skin lesions (thought to be actinic keratoses) on , back, and scalp, voice changes

After 73 days opted out of therapy Image: Tumor size unchanged

Later composite resection of tumor Path: 90% response (alteration of ameloblastoma)

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