J Oral Maxillofac Surg

68:2962-2974, 2010

Metastasizing (Malignant) Ameloblastoma:

Review of a Unique Histopathologic
Entity and Report of
Mayo Clinic Experience
Scott D. Van Dam, DDS, MD,* Krishnan K. Unni, MB, BS,† and
Eugene E. Keller, DDS, MSD‡

Purpose: To provide a comprehensive review of metastasizing (malignant) ameloblastoma, establish a

new baseline of valid cases using histologic criteria and minimum documentation, and report 3 cases
from the Mayo Clinic files.
Patients and Methods: Ninety-eight original reports of “metastasizing,” “malignant,” or “atypical”
ameloblastoma were reviewed. The following data were gathered for reports that demonstrated well-
differentiated ameloblastoma at the metastatic site: gender, ethnicity, age at time of primary tumor
diagnosis, histologic pattern of primary tumor, anatomic sites of primary and metastatic tumors, interval from
diagnosis of primary to diagnosis of metastasis, number of recurrences preceding metastasis, treatment re-
sponses to radiation and/or chemotherapy, presence of hypercalcemia, and length of survival after metastasis.
Results: Twenty-seven valid reports of metastasizing (malignant) ameloblastoma were identified; 81%
originated in the mandible, recurring on average 4 times before metastasis. Lungs were the initial site of
metastasis in 78% of reports, of which 71% were bilateral. The average time from diagnosis of primary
to metastasis was 18 years. Over half of the patients were alive and had survived an average of 10 years
since diagnosis of metastasis. Those patients who had succumbed to their disease had an average survival
time of 3 years after diagnosis of metastasis.
Conclusions: Metastasis of well-differentiated ameloblastoma occurs more rarely than previously believed.
Metastasis to the lungs bilaterally, by the hematogenous route, usually follows multiple failed attempts at
primary tumor control. The absence of malignant cytologic transformation correlates with relatively indolent
metastatic site growth. Treatment of metastasizing (malignant) ameloblastoma should include close observa-
tion, thoracotomy with wedge resections, or experimental chemotherapeutic combinations.
© 2010 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 68:2962-2974, 2010

Ameloblastoma is a slowly growing, locally invasive On rare occasion, a well-differentiated ameloblas-

tumor of odontogenic epithelial origin. It is a unique
jawbone tumor found exclusively in the maxillofacial
region.1 Because of complex biologic behavior, the
ameloblastoma continues to be a subject of intense in-
terest and some controversy.2,3 It has a high propensity
for local recurrence if not adequately removed. In its
histopathologic appearance and biologic behavior,
ameloblastoma bears some resemblance to basal cell
carcinoma of the skin.
toma has been documented to give rise to distant
metastasis.4 In 1984, Slootweg and Muller5 proposed
the term malignant ameloblastoma for a well-differ-
entiated ameloblastoma that metastasizes but main-
tains the characteristic cytologic features of the origi-
nal tumor. In addition, Slootweg and Muller recommended
the term ameloblastic carcinoma for an ameloblastic
tumor that undergoes malignant cytologic transforma-
tion.

*Private practice, Black Hills Oral and Maxillofacial Surgery,
Rapid City, SD.
†Consultant Emeritus, Department of Laboratory Medicine and
Pathology, and Professor Emeritus of Pathology, Mayo Clinic Col-
lege of Medicine, Rochester, MN.
‡Consultant, Department of Surgery, Division of Oral and Maxil-
lofacial Surgery, and Professor of Surgery, Mayo Clinic College of
Medicine, Rochester, MN.
Address correspondence and reprint requests to Dr Van Dam:
Black Hills Oral and Maxillofacial Surgery, 3415 5th St, Rapid City,
SD 57701; e-mail: sdvandam@gmail.com
© 2010 American Association of Oral and Maxillofacial Surgeons
0278-2391/10/6812-0006$36.00/0
doi:10.1016/j.joms.2010.05.084

2962
VAN DAM, UNNI, AND KELLER 2963

The World Health Organization (WHO)6 has recog-
nized the important histologic distinction between the
well-differentiated “metastasizing (malignant) ameloblas-
toma” and “ameloblastic carcinoma,” which behaves
more aggressively and demonstrates distinct cytologic
atypia in its primary and/or metastatic locations.
Reviews of metastasizing (malignant) ameloblas-
toma (MA) have been conducted by Carr and Hal-
perin,7 Herceg and Harding,8 Ikemura et al,9 Sehdev
et al,10 Gall and Shreiner,11 Buff and Ravin,12 Madiedo
et al,13 Kunze et al,14 Ameeraly et al,15 Laughlin,16
Ueda et al,17 Henderson et al,18 Reichart and Phil-
ipsen,19 and Cardoso et al.20
The intent of this article is to provide a comprehen-
sive review of MA, to establish a new baseline of valid
cases based on histologic criteria, and to report the
Mayo Clinic experience of 3 previously unpublished
cases.
A tumor that closely resembles ameloblastoma his-
topathologically, called adamantinoma, is found al-
most exclusively in the tibia (34 of 40 in the Mayo
Clinic files).21 Adamantinoma is not to be confused
with MA. However, the term adamantinoma has
been applied in the past to ameloblastomas of the
jaw, including several cases with reported metastasis,
and therefore several early reports of metastasizing
adamantinoma are included in this review.
Analysis of World Literature
A review of the world literature beginning in 1923
and extending through 2009 identified 101 reports
of possible MA (reports of “metastatic” or “metas-
tasizing” ameloblastoma, “malignant ameloblas-
toma,” “atypical ameloblastoma,” or “adamantinoma”
in which the investigators also provide a history of
jaw tumor metastasis). These 101 reports were mostly
individual patient reports, with several small series.
We were able to obtain the original journal articles for
98 of these reports. The histopathologic images pre-
sented in these reports were reviewed by an author
(K.K.U.). Other reports identified as “ameloblastic
carcinoma” were not reviewed, because we assumed
this term was applied correctly since its introduction
in 1984, thus representing tumors of ameloblastic
cellular origin that display unmistakable cytologic
atypia.
Twenty-four patient reports were classified as MA
based on convincing photomicrographic documenta-
tion of “well-differentiated” ameloblastoma at the
metastatic site and similar innocent/typical histology
(presumed or documented) of the primary maxillary
or mandibular tumor. To these 24 patient reports we
add 3 previously unreported cases from the Mayo
Clinic files. The resultant 27 patient reports (Table 1)
represent the subject of this review.
Forty-two patient reports were classified according
to histopathology as “poorly differentiated” at the
metastatic site. We did not attempt in this review to
further characterize the histologically atypical tumors
according to their cell of origin, which was signifi-
cantly heterogeneous (various types of metastatic car-
cinoma). These 42 patient reports (Table 2) did not
meet our inclusion criteria for further review.
Thirty-five patient reports were classified as inde-
terminate. These included 31 patient reports with
inadequate or absent histopathology of the metastatic
tumor in the original article, 3 reports that were
unavailable for review, and 1 patient report that was
classified as “surgically implanted” rather than meta-
static. These 35 patient reports (Table 3) did not meet
inclusion criteria for further review.
For all patient reports reviewed and authenticated
as MA, the following data were gathered where avail-
able (Table 4): patient’s gender, ethnicity, age at
which the primary tumor was diagnosed, histologic
pattern of the primary tumor, anatomic site of the
primary tumor, initial surgical treatment of the pri-
mary tumor, number of primary tumor recurrences
preceding metastasis, anatomic site(s) of metastasis,
interval from diagnosis of primary tumor to diagnosis
of metastasis, response to adjunctive chemotherapy
or radiation therapy, development of hypercalcemia

Table 1. WELL-DIFFERENTIATED HISTOPATHOLOGY—PATIENT REPORTS CONSISTENT WITH METASTASIZING

(MALIGNANT) AMELOBLASTOMA

1. Lee et al,4 1959 10. Kunze et al,14 1985 19. Ciment and Ciment,37 2002
2. Tsukada et al,23 1965 11. Takahashi et al,30 1985 20. Zwahlen et al,38 2003
3. Pennisi et al,24 1966 12. White and Patterson,31 1986; Laughlin,16 1989 21. Gilijamse et al,39 2007
4. Hoke and Harrelson,25 1967 13. Cranin et al,32 1987 22. Hasim et al,40 2007
5. Suzuki et al,26 1970 14. Inoue et al,33 1988 23. Cardoso et al,20 2009
6. Spiessl and Prein,27 1972 15. Houston et al,34 1993 24. Dao et al,41 2009
7. Eda et al,28 1972 16. Newman et al,35 1995 25. Mayo patient 1
8. Buff and Ravin,12 1980 17. Henderson et al,18 1999 26. Mayo patient 2
9. Jephcote,29 1981 18. Onerci et al,36 2001 27. Mayo patient 3
Van Dam, Unni, and Keller. Metastasizing (Malignant) Ameloblastoma. J Oral Maxillofac Surg 2010.
2964 METASTASIZING (MALIGNANT) AMELOBLASTOMA

Table 2. POORLY DIFFERENTIATED HISTOPATHOLOGY (AT PRIMARY AND/OR METASTATIC SITES)—PATIENT

REPORTS NOT CONSISTENT WITH METASTASIZING (MALIGNANT) AMELOBLASTOMA

1. Simmons,42 1928 (1/2) 15. Ikemura et al,9 1972 29. Eliasson et al,67 1989
2. Hanamura,43 1931; Ohinoue,44 1934 16. Steinhaeuser,56 1972 30. Harada et al,68 1989
3. Vorzimer and Perla,45 1932 17. Hartman,57 1974 31. Ueda et al,17 1989
4. Havens,46 1939 18. Byrne et al,58 1974 32. Ramadas et al,69 1990
5. Schweitzer and Barnfield,47 1943 19. Sehdev et al,10 1974 (1/7) 33. Phillips et al,70 1992
6. Grimes and Stephens,48 1948 20. Gall and Shreiner,11 1975 34. Duffey et al,71 1995
7. Villa,49 1958 21. Seward et al,59 1975 35. Moster et al,72 1996
8. Masson et al,50 1959 22. Teshima et al,60 1977 36. Witterick et al,73 1996
9. Lash and McCoy,51 1969 23. El-Mofty,61 1978 37. Weir et al,74 1998
10. Sugimura et al,52 1969 24. Krempien et al,62 1979 38. Schmidt et al,75 1999
11. Harrer and Patschefsky,53 1970 25. Azumi et al,63 1981; Takeuchi et al,64 1981 39. Sugiyama et al,76 1999
12. Dahlgren et al,54 1971 26. Levine et al,65 1981 40. Grunwald et al,77 2001
13. Herceg and Harding,8 1972 27. Madiedo et al,13 1981 41. Zarbo et al,78 2003
14. Hopson and Littlewood,55 1972 28. Hyvernat et al,66 1985 42. Campbell et al,79 2003
Van Dam, Unni, and Keller. Metastasizing (Malignant) Ameloblastoma. J Oral Maxillofac Surg 2010.

after metastasis, and length of survival after diagnosis 1975—A 26-year-old female patient undergoes
of metastasis. segmental resection of the right mandibular ra-
mus with immediate bone graft (Fig 1).
1987—Recurrent ameloblastoma occurs in same
Review of Mayo Clinic Cases
anatomic site.
A review of the Mayo Clinic ameloblastoma files, 1987—Referral to Mayo Clinic. Patient under-
which included a previous review by Mehlisch22 ex- goes block resection and 4 months later autog-
tending back to 1941, revealed 3 adequately docu- enous iliac bone graft of the surgical defect.
mented patients with MA. 2008 (May)—Panorex radiograph and clinical
examination negative for local recurrence ac-
PATIENT 1
cording to local dentist (Panorex reviewed by
author, E.E.K.).
A. Primary tumor history (ameloblastoma)
B. History of metastasizing lesion
1995—Patient is 46 years of age. Multiple bilat-
eral pulmonary nodules noted on routine chest
Table 3. INDETERMINATE PATIENT film. Computed tomographic (CT) scans docu-
REPORTS—INADEQUATE OR ABSENT ment multiple nodules (right perihilar, right and
HISTOPATHOLOGY OF METASTASIS
left multiple parenchymal nodules, 4 to 12 mm;
1. Simmons,42 1928 (1/2) 20. Sheppard et al,90 1993 Fig 2). Lung biopsy at local hospital is “negative”
2. Vorzimer and Perla,45 1932 21. Ameerally et al,91 for malignancy and diagnosed as “benign nodu-
3. Ishikawa and Shimada,80 1996 (1/3), case 2 larity/granulomatous disease.”
1954 22. Tada et al,92 1998
4. Yonemoto et al,81 1959 23. Ullah and Yousaf,93
1999 —Follow-up CT scan shows that the right
5. Carr and Halperin,7 1968 2001 midlung nodule had increased to 2 cm and other
6. Pandya and Stuteville,82 24. Verneuil et al,94 2002 nodules are unchanged.
1972 25–28. Goldenberg et al,95 2000 —Fine-needle aspiration of right lung nod-
7. Jacobs and Selle,83 1974 2004 (4/4) ule; final core biopsy demonstrates “plexiform
8 –13. Sehdev et al,10 29. Abada et al,96 2005
1974 (6/7) 30. Milles et al,97 2005 pattern of epithelial islands lined by columnar
14. Brandenburg et al,84 1976 31. Nguyen,98 2005 cells with focal squamous metaplasia, stellate
15. Tsaknis and Nelson,85 32. Emura,99 1923* reticulum identified” (Fig 3).
1980 33. Ito et al,100 1962* 2000 —Referral to Mayo Clinic. Multiple wedge
16. Lanham,86 1987 34. Narozny et al,101
17. Clay et al,87 1989 1999* resections of pulmonary nodules are accom-
18. Pradham et al,88 1989 35. Martin-Oliva et al,102 plished by open thoracotomy. Pathology con-
19. Ueda et al,89 1992 (1/2) 1994† firms “metastatic ameloblastoma.”
*Other indeterminate cases: unavailable for review. 2007—Lung CT scan shows multiple bilateral
†Other indeterminate cases: implantation at graft site. lung nodules all stable in size.
Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo- 2008 —No clinical or radiographic evidence of
blastoma. J Oral Maxillofac Surg 2010. progressive pulmonary disease 13 years after
 VAN DAM, UNNI, AND KELLER
Table 4. CLINICAL DATA—VALID REPORTS OF METASTASIZING (MALIGNANT) AMELOBLASTOMA
Interval Between
Diagnosis of Survival after
Age at Time of Site of Initial Number of Primary and Adjunctive Chemotherapy or Diagnosis of
Report Number, Primary Tumor Histology of Primary Treatment of Primary Tumor Diagnosis of Radiation Therapy/Development Metastasis
Reference Gender Ethnicity Diagnosis (yr) Primary Tumor Tumor Primary Tumor Recurrences Site of Metastasis Metastasis (yr) of Hypercalcemia (yr)

1. Mayo patient 1 F Caucasian 26 Plexiform R mand Resection 1 Bilateral lungs 20 None 14⫹
2. Mayo patient 2 F Caucasian 61 Follicular R mand Resection 4 Bilateral lungs 7 Chemotherapy 5
3. Mayo patient 3 M Caucasian 42 Follicular L max Resection 2 Bilateral lungs, chest wall, diaphragm, 10 Chemotherapy, hypercalcemia 7
mediastinum, perihiatal lymph node,
liver, retroperitoneum
4. Lee et al4 F Caucasian 18 Plexiform, follicular L mand U 11 Bilateral lungs (pleura, diaphragm, liver) 8 Radiation to primary and 6
secondary tumors
5. Tsukada t al23 F African- 28 Plexiform (with L mand Curettage 6 Bilateral lungs 31 Radiation to primary tumor 2
American granular cells)
6. Pennisi et al24 M Chinese 8 Plexiform, follicular L mand Curettage 4 Bilateral lungs ⫹ ribs, spleen, kidney 27 Radiation to primary tumor 9
7. Hoke and Harrelson25 F African- 44 Plexiform, L mand Curettage 8 Cervical vertebrae 18 None 20⫹
American follicular, (with
granular cells)
8. Suzuki et al26 U U U U U U U Lung 24 U U
9. Spiessl and Prein27 M U 34 Follicular L mand Curettage 11 L lung 12 None ⬍1
10. Eda et al28 F U 44 Follicular L max Curettage 6 Bilateral lungs, thoracic vertebrae, 10 Radiation to primary tumor ⬍1
submandibular lymph node
11. Buff and Ravin12 M Caucasian 6 Plexiform R mand Resection 3 Bilateral lungs 15 None U
12. Jephcote29 F U 31 Plexiform R mand U 4 Bilateral lungs 16 None 8⫹
13. Kunze et al14 M U 40 Plexiform, follicular L mand Resection 4 R lung 5 None 4⫹
14. Takahashi et al30 F U 24 U (with granular R mand Curettage 4 Thoracic vertebrae 38 None ⬍1
cells)
15. White and Patterson,31 M Caucasian 35 Follicular L mand Resection 1 Bilateral lungs, pleura, skin, brain, 11 Hypercalcemia 25⫹
Laughlin16 femur, gluteus
16. Cranin et al32 F African- 14 U (with granular L mand Curettage 7 Bilateral lungs 45 None 0 (autopsy)
American cells)
17. Inoue et al33 F Japanese 52 Follicular L max Resection 1 Bilateral lung 14 Hypercalcemia 1
18. Houston et al34 M African- 19 Plexiform L mand Curettage 0 Cervical lymph node 17 None 5⫹
American
19. Newman et al35 F Sri Lankan 24 Plexiform R mand Curettage 2 Bilateral lungs 22 None 3⫹
20. Henderson et al18 F U 15 Acanthomatous L mand Marsupialization, 3 R lung 33 None 4⫹
enucleation
21. Onerci et al36 M U 37 U R max Curettage 6 Bilateral lungs 12 None 3⫹
22. Ciment and Ciment37 M U 26 U mand Resection 0 Lung 29 None 1.5
23. Zwahlen et al38 M U 38 Follicular R max U 7 R lung, heart 19 Radiation to primary tumor ⬍1
24. Gilijamse et al39 M U 12 Plexiform mand Curettage 2 Submandibular lymph node 14 None 2⫹
25. Hasim et al40 F U 39 U L mand Curettage 3 Bilateral lungs 17 None 37⫹
26. Cardoso et al20 F U 24 Plexiform mand Resection 0 Submandibular lymph nodes 3 None 1⫹
27. Dao et al41 M African- 47 Plexiform Anterior Curettage with 0 R submandibular lymph node 10 None 3⫹
American mand peripheral
ostectomy

Abbreviations: ⫹, patient alive at time of report; F, female; L, left; M, male; mand, mandible; max, maxilla; R, right; U, unknown.
Van Dam, Unni, and Keller. Metastasizing (Malignant) Ameloblastoma. J Oral Maxillofac Surg 2010.

2965
2966
FIGURE 1. Mayo patient 1: histopathology of mandible (magnifi-
cation, ⫻40).
Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo-
blastoma. J Oral Maxillofac Surg 2010.
metastasis and 33 years after initial treatment of
primary mandibular ameloblastoma tumor.
PATIENT 2
A. Primary tumor history (ameloblastoma)
1995—A 59-year-old female patient has multiloc-
ular radiolucency/tumor of the mandibular right
ramus removed by enucleation and peripheral
ostectomy. Immediate grafting with freeze-dried
bone and primary closure follows. Histopathol-
ogy shows “follicular ameloblastoma” (Fig 4).
1998 —Recurrent tumor with biopsy-confirmed
ameloblastoma. Treatment is delayed 5 months
FIGURE 2. Mayo patient 1: chest computed tomogram shows
tumor (arrow).
Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo-
blastoma. J Oral Maxillofac Surg 2010.
METASTASIZING (MALIGNANT) AMELOBLASTOMA
FIGURE 3. Mayo patient 1: histopathology of lung (hematoxylin
and eosin; magnification, ⫻63).
Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo-
blastoma. J Oral Maxillofac Surg 2010.
because breast adenocarcinoma is diagnosed
and treated with localized surgery and tamox-
ifen. Surgery is reported as marginal block re-
section.
1999 —Referral to Mayo Clinic. Recurrent tumor
is treated by right hemimandibulectomy and
right partial posterior maxillary block resection.
2000 —Recurrent tumor in infratemporal fossa
is treated with block resection in combination
with right parotidectomy and upper modified
neck dissection (sphenoid sinus involvement
but no intracranial extension). Postoperative ad-
junctive irradiation therapy.
2002—Imaging of primary surgical site shows
“no local recurrence.”
FIGURE 4. Mayo patient 2: histopathology of maxilla (hematox-
ylin and eosin; magnification, ⫻63).
Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo-
blastoma. J Oral Maxillofac Surg 2010.
VAN DAM, UNNI, AND KELLER 2967

2003—Clinical examination of primary surgical

site is negative.
2004 —Clinical examination of primary surgical
site is negative.
B. History of metastasizing lesion
2002—Multiple bilateral pulmonary nodules are
identified on routine chest film (Fig 5).
2003—Multiple pulmonary nodules are noted to
have increased. CT guided needle biopsy of pul-
monary nodule identifies “ameloblastoma” (Fig 6).
2004 —Decreased bilateral breath sounds are re-
corded. Chemotherapy is started shortly after nee-
dle biopsy (phase I oncology study with epidermal
growth factor receptor tyrosine kinase inhibitor in
combination with hycamtin.). Oncology note of
FIGURE 6. Mayo patient 2: histopathology of lung (hematoxylin
December 22, 2004, states that the patient is off and eosin; magnification, ⫻63).
the study and has returned home.
Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo-
2007—Date of death, June 6, 2007 (age 71 blastoma. J Oral Maxillofac Surg 2010.
years); presumed expired from pulmonary met-
astatic disease progression (12 years after diag- 1990 —Recurrent tumor is treated by “curet-
nosis of mandibular ameloblastoma and 5 years tage.”
after identifying pulmonary metastasis). 1994 —Referral to Mayo Clinic. CT scans (1994
and 1997) show postoperative changes and no
PATIENT 3
evidence of local tumor recurrence (Fig 7).
B. History of metastasizing lesion
A. Primary tumor history (ameloblastoma)
1994 —Referral to Mayo Clinic for evaluation of
1984 —A 42-year-old male patient has a gingival
bilateral pulmonary nodules. CT scan confirms
mass on the left hard palate excised and diag-
lung lesions (large right lung base lesion ⫻2,
nosed as “ameloblastoma.”
large left midlung lesion, multiple small bilateral
1988 —Recurrent tumor is treated by left pos-
nodules in both lung fields, right paratracheal
terior segmental maxillectomy for recurrent
lymph nodes). Mediastinoscopy and multiple
ameloblastoma (is noted to extend into the
surgical wedges of the bilateral lung nodules and
maxillary antrum and pterygoid muscle).
mediastinal lymph nodes; pathology indicates
“metastatic ameloblastoma” (Fig 8).

FIGURE 5. Mayo patient 2: chest computed tomogram shows FIGURE 7. Mayo patient 3: chest computed tomogram shows
tumor (arrow). tumor (arrow).
Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo- Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo-
blastoma. J Oral Maxillofac Surg 2010. blastoma. J Oral Maxillofac Surg 2010.
2968
FIGURE 8. Mayo patient 3: histopathology of lung (hematoxylin
and eosin; magnification, ⫻63).
Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo-
blastoma. J Oral Maxillofac Surg 2010.
1997 (May)—New pulmonary nodules, mass
right cardiophrenic angle, mass anterior chest
wall lateral to sternum. Surgery consists of block
resection of the lower sternum and right chest
wall, including portions of 6 and 7 ribs and the
pericardium; pathology indicates “metastatic
ameloblastoma” (Fig 9).
1997 (July)—Further thoracic surgery of the
right lower lobe mediastinum and posterior
chest wall; pathology indicates “metastatic
ameloblastoma.” Adjuvant chemotherapy and
radiation treatment are considered but rejected.
1998 (December)—Pulmonary nodules are sta-
ble by imaging.
1999 (November)—Imaging shows enlarging
pulmonary nodules, with extension of metasta-
sis into the posterior abdomen, right pararenal
space, and liver. Hypercalcemia is noted and
treated.
2000 (February)—Chemotherapy (gemcitabine
and carboplatin) results in stabilization of bilat-
eral pulmonary metastasis and notable improve-
ment in performance status and quality of life
during first 12 months of administration.
2001 (June)—Patient expires from complica-
tions of metastatic disease (17 years after pri-
mary mandible ameloblastoma biopsy and 7
years after identification of metastasis).
Worldwide Literature Review
Table 1 lists patient reports consistent with
MA,4,12,14,16,18,20,23-41 Table 2 lists reports not con-
sistent with MA,8-11,13,42-79 Table 3 lists reports with
inadequate or absent histopathology of metasta-
METASTASIZING (MALIGNANT) AMELOBLASTOMA
sis,7,10,42,45,80-102 and Table 4 presents valid reports
of MA.4,12,14,16,18,20,23-41
Summary of Clinical Findings
Table 4 lists a summary of clinical findings.
1. Age when primary was detected: The average
age for detection of the primary tumor was 30
years (range, 6 to 61 years). Most primary tu-
mors (17 of 26, 65%, 1 unknown) were de-
tected between the third and fifth decades of
life. Seven of 26 primary tumors (27%) were
detected before age 20 years. Only 2 primary
tumors were detected after age 50 years.
2. Gender: The distribution between male and
female patients was nearly equal (14 women,
12 men, 1 unknown).
3. Ethnicity: Six Caucasian, 5 African American, 3
Asian, 13 unknown.
4. Histologic subtypes/patterns of primary tumor:
Nine plexiform, 7 follicular, 4 plexiform and
follicular, 1 acanthomatous, 6 unknown. The
presence of granular cells was noted in 4 of the
27 reports.
5. Anatomic site of primary: Twenty-one of 26
primary tumors (81%) originated in the mandi-
ble and 5 originated in the maxilla (19%). One
report of jaw tumor failed to specify the site of
origin.
6. Primary treatment: Fourteen of the 23 initial
tumors (61%) were treated by enucleation and
curettage. Nine (39%) tumors were treated ini-
tially by resection (block or segmental). The
primary treatment was unspecified in 4 re-
ports.
FIGURE 9. Mayo patient 3: histopathology of mediastinum (he-
matoxylin and eosin; magnification, ⫻63).
Van Dam, Unni, and Keller. Metastasizing (Malignant) Amelo-
blastoma. J Oral Maxillofac Surg 2010.
VAN DAM, UNNI, AND KELLER
7. Primary recurrences: The number of primary
recurrences per patient ranged from 0 to 11.
The average and median numbers of primary
tumor recurrences were 4.
8. Anatomic site of metastasis: The initial site of
metastasis was to the lungs in 21 of 27 cases
(78%). Of these 21 pulmonary metastases, 15
were specified as being bilateral (71%). In 4
patients (15%) the initial metastasis was to the
regional lymph nodes; in 2 patients the metas-
tasis was to the cervical or thoracic vertebrae.
9. Interval from diagnosis of primary to diagnosis
of metastasis: The average interval from diag-
nosis of the primary tumor to diagnosis of me-
tastasis was 18 years (range, 3 to 45 years).
10. Adjunctive therapy
a. Chemotherapy: Two of 27 patients received
chemotherapy for treatment of metastatic dis-
ease. Clinical information on response to che-
motherapy was available only for 1 patient
(Mayo patient 3). This patient showed marked
symptomatic improvement after starting che-
motherapy with gemcitabine and carboplatin
and did not report any noticeable side eff-
ects. Over a 1-year period, increased strength,
resolution of abdominal pain, and stable met-
astatic disease were attributed to the chemo-
therapy. However, the patient died of compli-
cations of metastatic disease within 15 months
of starting chemotherapy.
b. Radiation therapy: In 5 patients radiation
was delivered to the primary tumor before
detection of metastases. A sixth patient1 re-
ceived simultaneous treatment of primary
and secondary tumors with radiation. Over a
6-month period, this therapy was credited
with significant facial pain relief, decrease in
size of the primary tumor, and a mixed re-
sponse in size reduction of metastatic lung
nodules. This patient survived for 6 years
after detection of bilateral pulmonary metas-
tases.
c. Treatment for hypercalcemia: Hypercalce-
mia was documented and treated in 3 pa-
tients with pulmonary metastases.
11. Survival after diagnosis of metastasis: Of the 25
patient reports that provided details of survival,
death from any cause was reported in just un-
der half of patients (12 of 25). Average survival
time after diagnosis of metastases in these 12
patients was approximately 3 years. The re-
maining patients (13 of 22) were still alive at
the time their reports were made and had sur-
vived an average of 10 years since the diagnosis
of metastasis. Three patients were alive longer
2969
than 20 years after diagnosis of metastasis. One
patient40 was alive and reported to be doing
well longer than 37 years after detection of
bilateral pulmonary metastasis and longer than
50 years since diagnosis of her primary jaw
tumor.
Discussion
After a review of the world literature on this topic,
we agree with other investigators in recognizing a
rare, well-defined clinical pathologic entity character-
ized by metastasis of ameloblastoma, with mainte-
nance of the typical “well-differentiated” cellular fea-
tures of ameloblastoma at the metastatic site. We
reviewed the printed histopathology from 98 patient
reports of ameloblastoma claimed to metastasize and
identified only 24 cases in which “well-differentiated”
ameloblastoma was demonstrated convincingly at the
metastatic site. To these reports we add 3 previously
unpublished examples of MA from the Mayo Clinic
files, bringing the total number of well-documented
cases of MA to 27.
Investigators in the past observed that some MAs
maintain the histologic characteristics and clinical be-
havior of the parent jaw tumor, whereas other tumors
adopt a much more aggressive clinical behavior in the
metastatic site, “becoming truly malignant when they
advanced to the stage of metastasis.”23 Slootweg and
Muller5 and others have focused on clear histologic
differences that help to account for this varied clinical
behavior. The WHO also recognizes these 2 distinct
entities: metastasizing (malignant) ameloblastoma and
its histologically atypical counterpart, ameloblastic
carcinoma.
It was our hypothesis that a critical, histology-based
review of MA would further highlight key differences
in the clinical behavior between MA and ameloblastic
carcinoma. One limitation of this study was the need
to rely on the printed histology of the metastatic
tumor to select valid cases of MA, rather than having
access to the original pathology slides or tissue. Nev-
ertheless, this retrospective study shows that a more
homogenous clinical pathologic entity can be isolated
based on histologic criteria alone. These 27 patient
reports provide a valid new baseline for MA and an
opportunity to better understand the true incidence,
clinical behavior, and responses to therapy of this rare
histopathologic entity.
The literature on this topic has been plagued by
inadequate documentation of many presumed cases
and inconsistent application of terminology in others.
The 1992 WHO classification used the term malig-
nant ameloblastoma to describe a tumor that cur-
rently would most likely qualify as an ameloblastic
carcinoma.19,103 In more recent classifications, the
2970
terms malignant ameloblastoma and metastasizing
ameloblastoma have been combined to metastasizing
(malignant) ameloblastoma (ICD-9, code 9310/3), with a
clear emphasis on the benign histologic appearance of this
entity.
Because the term ameloblastic carcinoma is rela-
tively new and the name implies a poorly differenti-
ated odontogenic epithelial tumor, investigators who
are familiar with this term tend to use it appropriately
as defined by Slootweg and Muller5 and the WHO.6,103
In contrast, investigators must be careful not to apply
the term malignant ameloblastoma to an ameloblas-
toma that shows distinct “malignant” cytologic trans-
formation. Similar confusion may arise through the
use of the term atypical ameloblastoma15 to denote
lesions with fatal outcome for various reasons, such
as metastasis, cytologic atypia, or relentless local
spread.104
Most of the patient reports we reviewed repre-
sented disease other than MA. It was not within the
scope of this article to attempt to assign alternate
histologic diagnoses to these patient reports (our cy-
tologically “atypical” or “indeterminate” categories).
Although some of these certainly represent cytologi-
cally atypical ameloblastic tumors (eg, ameloblastic
carcinoma), others represent a wide variety of carci-
nomas of nonameloblastic type, such as primary lung
squamous cell carcinoma, primary intraosseous or
odontogenic squamous cell carcinoma, or malignant
salivary gland tumors.
Previous reviews have placed the incidence of MA
at approximately 2% of ameloblastomas, but other
investigators have agreed this is too high.34 In 2004,
Reichart and Philipsen19 combined reviews and indi-
vidual patient reports and identified 65 presumed
cases of metastasizing ameloblastoma. In our review
of 98 patient reports, and after applying minimum
documentation criteria and screening for histologic
atypia, the number of valid patient reports of MA
decreased to 24 (27 with the addition of our 3 new
reports). Although it is difficult to calculate an inci-
dence with any degree of certainty, it is clear that
metastasis of well-differentiated ameloblastoma is a
rarer event than previously believed.
MA occurs equally in men and women, and there is
no reason to suspect a racial predilection for this rare
tumor. Similar to ameloblastoma, most metastasizing
ameloblastomas arise in young adults and middle-aged
individuals. Our study disclosed a ratio of mandibular
to maxillary MA primary tumors to be 4.2:1. Laugh-
lin16 found this ratio to be 7.6:1, and Henderson et
al,18 reviewing only cases with pulmonary metastasis,
reported a mandible-to-maxilla ratio of 4.1:1 (more in
line with the present report.)
In the jaws, the primary MA tumor resembles typ-
ical ameloblastoma histologically and in its clinical
METASTASIZING (MALIGNANT) AMELOBLASTOMA
behavior. The potential to metastasize cannot be pre-
dicted based on histologic subtypes or patterns.14 The
metastatic tumor of MA, by definition, maintains the
same histologic characteristics as the parent jaw tu-
mor. Interestingly, 4 valid cases of MA with a granular
cell histologic type have been reported.23,25,30,32
This report finds that metastasis is most often a
strikingly late event (18 years on average) after pri-
mary jaw tumor treatment compared with 9 years
reported by Laughlin.16 Metastasis usually follows
multiple recurrences and is frequently associated
with presumed inadequate initial treatment.
There is a strong affinity for lung metastases (78%—
similar to the 75% reported by Laughlin16), of which
71% occurred bilaterally, in multiple lung fields, and with-
out preceding lymph node metastasis. Several patients
with pulmonary metastases developed a paraneoplastic
type of hypercalcemia,16,33 including Mayo patient 3.
Initial metastasis to a lymph node occurred in 4
patients (15%)20,34,39,41 in the present report. Metas-
tasis to the cervical and thoracic spine occurred in
only 2 patients (7%)25,30 in the present report. This is
similar to (or slightly lower than) the rate of extrapul-
monary metastasis reported by Laughlin16 (15% to
cervical lymph nodes, 15% to spine). It is unlikely that
the adamantinoma21 of long bones could be mistaken
for metastatic ameloblastoma; the former is almost ex-
clusively found in the tibia and in other small bones.
In addition to maintaining the histologic character-
istics of the parent tumor, MA metastatic tumors con-
tinue to display similar clinical behavior, namely in-
dolent but persistent growth. Consequently, a
reasonable quality of life and longevity often accom-
pany widespread pulmonary metastases. Fewer than
half of the patients in the present review had suc-
cumbed to their disease, in which case the length of
survival after metastasis averaged 3 years (compared
with 2 years reported by Laughlin16). More than half
of the authenticated cases involved patients who
were alive at the time of their reports and who had
survived an average of 10 years since the diagnosis of
metastatic tumor. We continue to follow 1 Mayo pa-
tient who enjoys an excellent quality of life 14 years
after detection of bilateral pulmonary metastasis.
Three other reports25,31,40 documented patients who
continued to survive longer than 20 years after diag-
nosis of metastasis. If rapid growth and widespread
metastasis are observed, ameloblastic carcinoma or
other carcinomas, such as mucoepidermoid carci-
noma or primary squamous cell carcinoma of the
lung, should be suspected.
Treatment decisions are limited by a lack of expe-
rience with these rare tumor subtypes. Erroneous
assumptions about treatment possibilities (eg, surgi-
cal resection) may also have been made due to per-
ceived poor prognosis of MA. Adjunctive chemother-
VAN DAM, UNNI, AND KELLER
apy or radiation therapy has not been shown to
provide any survival benefit or sustained clinical re-
sponse in a limited number of reports. However,
there may be a role for these modalities in the clinical
symptomatic management of the metastatic disease.
It is difficult to justify any routine whole body or
lung imaging screening for potential detection of me-
tastasis of ameloblastomas, because of exceedingly
rare incidence, the long interval between treatment of
primary tumor and development of metastasis, and no
known curative treatment for metastatic disease.
The mechanism by which ameloblastoma metasta-
sizes has been the subject of considerable debate. The
theory of lung aspiration, proposed by some early
investigators,80 has largely been discounted because
of the high incidence of bilateral lung lesions. The
theory of surgical implantation was convincingly pre-
sented in a single case,102 and the investigators have
repeatedly concluded that surgical transplantation of
tumor cells is unlikely and rare.19,105 Lymphatic
spread of MA tumor cells is a well-accepted route
according to a few investigators,19,34,104 but the he-
matogenous route has been generally favored16 as the
most likely route of spread. In this review of MA, most
tumors metastasized to bilateral and multiple lung
fields, without accompanying lymph node metastasis,
which strongly suggests a hematogenous route of
spread. Clusters of tumor cells have also been ob-
served in surrounding blood vessels.19
Eisenberg105 proposed the phenomenon of hetero-
topias to explain the occurrence of ameloblastoma in
cervical lymph nodes. According to this theory, odon-
togenic epithelium becomes entrapped in lymphoid
tissue during embryogenesis and subsequently may
undergo benign neoplastic transformation. The result
could be the development of an ameloblastoma
within a cervical lymph node (ie, a “second primary”),
rather than metastasis or local spread to the lymph
node from a primary jaw ameloblastoma. However, if
the theory of heterotopias is reasonable, we would
expect to see more reports of MA in patients without
a history of previous jaw ameloblastoma. Further-
more, because lymph node metastasis appears to be
the exception, the diagnosis of MA should be applied
with caution in this setting, also keeping in mind that
primary local extension of an ameloblastoma could be
mistaken for lymph node metastasis.
AMELOBLASTIC CARCINOMA
Ameloblastic carcinoma is an ameloblastic tumor
characterized by distinct cytologic atypia. An amelo-
blastic carcinoma may be of primary type, or second-
ary (dedifferentiated), implying in the latter case that
it developed from a pre-existing cytologically inno-
cent ameloblastoma (ie, carcinoma ex ameloblas-
toma). Ameloblastic carcinoma continues to be a
2971
useful and well-accepted term for a jaw tumor with
ameloblastic cell of origin, but with histologic fea-
tures of malignancy (less differentiated/prominent
cellular atypia), in the primary and/or metastatic site.
A recently published review of the literature106 from
1984 to 2004 has provided valuable clinical and demo-
graphic data for 37 cases of ameloblastic carcinoma.
Also, a 1992 Mayo Clinic report107 of this entity high-
lights the distinct histopathologic features of ameloblas-
tic carcinoma. Although no reliable data are available
concerning the prevalence, incidence, or relative fre-
quency of MA or ameloblastic carcinoma, until recently
metastasizing ameloblastoma has been thought to be
more common.19
The present research appears to contradict this
claim. Due to evolving definitions and confusion re-
garding terminology, it is reasonable to assume that
the incidence of MA has been exaggerated and the
incidence of ameloblastic carcinoma underestimated.
As these entities are studied separately, it is likely that
ameloblastic carcinoma will continue to emerge as a
distinctly more aggressive and relatively more com-
mon disease, requiring different treatment protocols
than MA.
As well-documented patient reports continue to
emerge and are studied, genetic and molecular differ-
ences between MA and ameloblastic carcinoma will
likely help explain the differences observed clinically
between these rare tumors. If or when mechanisms,
such as diverse genetic polymorphisms that dictate
phenotype are identified, nosologic reclassification
could be in order.
Summary
The present review of the world literature and
first-hand clinical experience strongly supports treat-
ing an ameloblastoma that gives rise to histologically
well-differentiated metastases as a distinct clinical
pathologic entity. The present research also points to
a strong correlation between the innocent histologic
features of MA and its relatively indolent clinical
course.
After a review of the world literature, and with the
addition of 3 previously unpublished reports from the
Mayo Clinic files, we have identified 27 patient re-
ports in which the diagnostic criteria for MA are
convincingly met. A review of the clinical and histo-
logic data of these 27 reports confirms the following
emerging picture of metastasizing ameloblastoma:
1. MA is less common than ameloblastic carci-
noma.
2. Late metastasis usually follows multiple recur-
rences of the jaw tumor.
2972
3. The mandible is the most common site of origin.
4. There is a high incidence of metastasis to bilat-
eral lung fields via the hematogenous route.
5. MA exhibits relatively indolent yet persistent
metastatic site growth.
6. Current treatment protocol of metastatic tumor
includes close observation, surgical management
(thoracotomy with selected wedge resections), or
selective experimental chemotherapeutic combi-
nations.
Progress in understanding and treating MA will be
hastened by critically applying histologic diagnostic
criteria to new cases and by searching for the genetic
and molecular differences between malignant (metas-
tasizing) and truly “benign” ameloblastomas.
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