Oncology 32: 118-126 (1975)
Ameloblastoma of the Mandible with Pulmonary Metastasis Joseph A. Gall, George P. Sartiano and David P. Shreiner' University of Pittsburgh Health Center, Department of Medicine, Division of Hematology and Oncology, Pittsburgh, Pa.
Key Words. Ameloblastoma • Adamantinoma • Odontogenic tumors • Metastatic ameloblastoma • Jaw tumors Abstract. A patient with ameloblastoma of the mandible with histologically confirmed pulmonary metastases 9 years after onset of tumor is described. The effectiveness of three chemotherapeutic agents (cyclophosphamide, methotrexate, Adriamycin), each given alone intravenously, were evaluated. Marked symptomatic improvement was noted with Adria mycin therapy. Ten previous cases of metastatic ameloblastoma are reviewed. The incidence of metastases cannot be predicted on the basis of histology. Three commonly discussed modes of metastasis are via hematogenous and lymphatic routes and the unusual mechanism of aspiration of tumor cells.
Ameloblastoma (adamantinoma) is a rare odontogenic epithelial tumor (7, 12, 22), accounting for only 1 % of all jaw tumors and cysts (29). It is noted for its slow growth, histologically benign appearance, local invasiveness and its high incidence (50-72 %) of local recurrence after therapy (20, 26). 80 % of all ameloblastomas occur in the mandible, of which 70% are found in the 3rd molar region. Virtually all of the remaining 20 % are found in the maxilla, where this tumor also shows a high predilection (60%) for the 3rd molar region (1, 24). Rare extra-osseous ameloblastomas have been reported in the lip (5), cheek (4), and orbit (34). Microscopically, most of these tumors demonstrate either a follicular or plexiform pattern (29), although other histologic patterns have been described (31). They are thought to arise variously from the epithelial lining of
Downloaded by: King's College London 137.73.144.138 - 1/11/2019 2:02:57 AM
1 The authors are grateful to Dr. Robert E. Lee, Professor of Pathology, University of Pittsburgh School of Medicine, for reviewing the histologic material.
Gall/Sartiano/Shreiner
119
dentigerous cysts, remnants of dental lamina, enamel organ, or the basal cell layer of oral mucosa. Ameloblastoma is most commonly seen in the age group of 3 0 -4 0 years, although it has been described at 6 months of age (24), as well as in a 76-year-old male (24). Most reports state an equal sex incidence with no racial preponderance (1, 7, 24, 29). Occasional reports, however, have described a 2:1 male/female ratio (30), and an 11:1 Negro/Caucasian ratio (15). Various modes of local therapy have been advocated, including segmental and radical jaw resection (13, 19, 27), curettage and cryotherapy (6), and radio therapy (9). In one review of treatment of 245 cases of ameloblastoma (2), the lowest incidence of recurrence (4.5 %) occurred in 89 patients undergoing radi cal jaw resection. Recurrence rates for radiotherapy (36 patients) was 41.6% and conservative surgery (120 patients) was 59.1 %. 25 % of the patients treated with radiotherapy died of postradiation sarcoma rather than of their primary disease. Metastatic ameloblastoma is extremely uncommon, only 10 previous histol ogically confirmed cases being present in the medical literature (table I). In only two of these reports (10, 11), is there mention of chemotherapy. We present an eleventh patient with histologically confirmed ameloblastoma in whom three chemotherapeutic agents (cyclophosphamide, methotrexate, Adriamycin) were evaluated.
The patient is a 45-year-old salesman who first noted a mass under the right side of the jaw'in 1965, which remained unchanged until December, 1967, when subsequent to light trauma to the jaw, the mass gradually enlarged, became tender to touch, and he noted numbness of the right lower lip. Examination in June, 1969, revealed a soft tissue swelling over the body of the mandible on the right side with no distinct mass outline. The patient was edentulous; otherwise, the oral cavity was unremarkable. There were no palpable neck nodes or hepatosplenomegaly. X-ray examination of the mandible showed a defect along the inferior margin on the right side, including the canal for the mandibular nerve consistent with neoplastic invasion. Skull and chest X-rays were normal. Complete blood count and laboratory chemistry studies were also within normal limits. Biopsy of the mandibular tumor revealed ameloblastoma and a segmental resection of the body of the mandible was performed (fig. 1). The surgical specimen consisted of a rectangular piece of bone, mea suring 8 X 3 X 1 cm in the center of which was an oval tumor, measuring 2 X 1.5 X 1 cm. The margins of the resected mandible were free of tumor. Three months after the segmental resection, the patient underwent a mandibular reconstruction, utilizing a left iliac bone graft with good results. He was well until mid-1973, when he noted chest tightness and a non-productive cough, becoming more severe over a 6-month period. Chest X-ray taken in December, 1973, revealed multiple pulmonary densities compatible with metastatic carcinoma (fig. 2). Exami nation revealed a well-healed right mandibular incision with good reconstruction. There was no adenopathy or organomegaly. Skull X-rays, skeletal survey and liver, spleen, brain and
Downloaded by: King's College London 137.73.144.138 - 1/11/2019 2:02:57 AM
Case History
Gall/Sartiano/Shreiner
120
Author
Year Age at onset of tumor years
Sex
Metastatic site
Interval Therapy from onset to metas tasis years
Simmons (28)
1928 22
F
regional lymph node
12
surgery
Vorzimer and Perla (33)
1932 17
M
lung, pleura
20
surgery radiotherapy
Schweitzer and Barnfield (25)
1943 23
F
lung, pleura
11
surgery radiotherapy
Lee et al. (17)
1958 18
F
lung, pleura, liver, brain
8
surgery radiotherapy
Tsukada et al. (32)
1965 28
F
lung
31
surgery radiotherapy
Pennisi et al. (22)
1966
M
lung, kidney, spleen
27
surgery radiotherapy
Hoke and HarreIson (14)
1967 44
F
cervical vertebrae
18
surgery
Lash and McCoy (16)
1969 23
F
lung
3
surgery
Harrer and Patchefsky (10)
1970 29
F
lung, brain, neck
23
surgery chemotherapy
Herceg and Harding (11)
1972
9
M
lungs, pleura, liver, diaphragm
10
surgery radiotherapy chemotherapy
Gall et al.
1975 35
M
lungs, pleura
9
surgery chemotherapy
9
Downloaded by: King's College London 137.73.144.138 - 1/11/2019 2:02:57 AM
Table I. Ameloblastoma with metastasis
Ameloblastoma of the Mandible with Pulmonary Metastasis
121
Fig. 1. Mandibular tumor removed in 1969 showing sheets of tumor with peripheral palisading, central acellular stroma, and a few foci of squamous cell metaplasia. HE. X 125.
Downloaded by: King's College London 137.73.144.138 - 1/11/2019 2:02:57 AM
Fig. 2. Chest X-ray taken in December, 1973, showing multiple pulmonary métastasés.
Gall/Sartiano/Shreiner
122
Fig. 3. Nests of tumor cells replace portions of lung parenchyma. The tumor cell clusters show focal cystic areas. The peripheral palisading of the tumor cells is not as apparent as was present in the jaw. HE. X 125.
bone scans were normal. Laboratory data revealed: hemoglobin 15.3, hematocrit 43.6 %, WBC 9,000/mm3 with normal differential count, and platelets 276,000/mm3. An iliac crest bone marrow aspirate and biopsy were normocellular with no tumor cells being seen. At thoracotomy, the pleura was covered with numerous firm nodules, some measuring up to 1 cm in diameter, biopsy of which revealed metastatic ameloblastoma histologically identical to the original jaw tumor (fig. 3). Systemic chemotherapy, using single agents administered intravenously, was begun in February, 1974 (table II). Although there was no objective response to any of the three agents (cyclophosphamide, methotrexate, Adriamycin), he did notice marked symptomatic improvement with Adriamycin therapy. All therapy was suspended in August, 1974, be cause of toxicity and failure of any of the drugs to produce measurable tumor regression.
Discussion
Downloaded by: King's College London 137.73.144.138 - 1/11/2019 2:02:57 AM
Adamantinomas are generally thought of as benign tumors both on the basis of their histologic appearance and their clinical course. The term ‘malignant’ has been used to describe ameloblastomas with extensive local infiltration and bone destruction (15), or those with squamous metaplasia in addition to extensive
Ameloblastoma of the Mandible with Pulmonary Metastasis
123
Table II. Summary of chemotherapy Date
Drug
2-06-74 3-07-74 4-15-74 5-16-74 6-13-74 6-27-74 7-25-74 8-25-74
cyclophosphamide 2,500 cyclophosphamide 2,000 Adriamycin 100 Adriamycin 120 methotrexate 90 methotrexate 90 methotrexate 100 methotrexate 100
Dose, mg*
Comments NR, WBC 2,600/mm3 **, gross hematuria marked symptomatic improvement, NR WBC 3,200/mm3 NR, WBC 3,700/mm3
local disease (24). Gorlin and Goldman (7) report having seen a few examples of ameloblastoma with numerous mitotic figures and marked aggressiveness that they feel should be classified as ‘malignant ameloblastoma’. Simmons (28) re ported that a cuboidal type of ameloblastoma is more prone to distant metastases. Histologically benign appearing tumors have been reported with distant metastases (17), and it is generally accepted that the tendency of an ameloblas toma to metastasize cannot be predicted on the basis of its histological appear ance (8). Metastases were reported by Tsukada et al. (32), to occur in a setting of extensive local disease with a history of multiple unsuccessful attempts at local excision and/or radiotherapy. Nine of the eleven cases reviewed here fit this description. The present case, and that of Lash and McCoy (16), had no evidence of local recurrence at the time of appearance of distant metastases and lacked a history of multiple procedures. The lung was the most frequent metastatic site, being involved in 9 of 11 cases. Less common were liver (2/11), neck (2/11), cervical vertebra (1/11), and kidney and spleen (1/11) (table I). The median age of onset was 23 years, ranging from 9 to 44 years. Six of the patients were white, three were Negro, and one was Mongoloid. The race of one patient is unknown. The mandible was the primary site in all but one patient, in whom the tumor originated in the maxilla. The interval from onset to metastasis ranged from 3 to 31 years with a median of 12 years. Three commonly mentioned modes of metastasis of ameloblastoma are by aspiration of tumor cells, presumably around the time of surgery and general anesthesia when the cough reflex is depressed, and by hematogenous and lym phatic routes. Tumor spread by aspiration is an attractive hypothesis because of
Downloaded by: King's College London 137.73.144.138 - 1/11/2019 2:02:57 AM
NR = No objective response. * All doses are i.v. push over 5 min. ** Lowest WBC count with treatments.
Gall/Sartiano/Shreiner
124
the high incidence of pulmonary involvement at a time when there is no evi dence of tumor in other organs. The case report by Vorzinter and Perla (33), in which there was an endobronchial tumor cast on the right side, the side more commonly involved in aspiration of any foreign object, probably occurred by aspiration of tumor cells. A diffuse pattern of pulmonary involvement, however, is better explained by hematogenous spread. In 2 of the 10 previously reported cases systemic chemotherapy was used. Herceg and Harding (11) reported a 19-year-old white male who, 10 years after curettage of a mandibular ameloblastoma, developed a rapidly growing jaw tumor with subsequent pulmonary métastasés and died after a very short course. Thé patient received radiotherapy to the jaw and simultaneous systemic chemotherapy (cyclophosphamide 500 mg i.v. daily X 5 followed by 4 days rest for a period of 6 weeks). Despite control of the jaw tumor, the patient died of extensive lung métastasés. Harrer and Patchefsky (10) mention treating a termi nal 52-year-old woman with recurrent metastatic ameloblastoma with imidazole and 5-fluorouracil. Although long-term survival with untreated pulmonary métastasés has been reported (23), we elected to start chemotherapy in attempt to control symptoms of cough and chest tightness. Chemotherapeutic agents were selected on the basis of their known activity against head and neck tumors in general (metho trexate) (18), or activity against epithelial and mesenchymal tumors (Adriamycin) (3), or past use (cyclophosphamide) (11). The drugs were used alone rather than in combination in order to evaluate their individual activity. No objective regression of tumor nodules, as evaluated by serial chest radio graphs, was noted with any of the agents. Marked symptomatic improvement was noted with Adriamycin therapy, however. This may have been solely a placebo effect, but possibly may also have been due to regression of the numer ous smaller pulmonary tumor implants that could never be visualized on routine chest films, but were seen at thoracotomy.
1 2 3 4 5
Baden, E.: Odontogenic tumors; in Sommers Pathology annual 1971, vol. 6 (Apple* ton-Century-Crofts, New York 1971). Becker, R. und Peril, A.: Zur Therapie des Ameloblastoms. Dt. Zahn-Mund-Kieferheilk. 49: 423-436 (1967). Blum, R.H. and Carter, S.K.: Adriamycin: a new anti-cancer drug with significant clinical activity. Ann. intern. Med. 80: 249-259 (1974). Braunstem, E.: Case report of an extra-osseous adamantinoblastoma. Oral Surg. 2: 726-728 (1949). Ch’in, K.Y.: Adamantinoma in Chinese; pathologic study of 41 cases. Chin. Med. J., Peking2: suppl., pp. 91-130 (1938).
Downloaded by: King's College London 137.73.144.138 - 1/11/2019 2:02:57 AM
References
Ameloblastoma of the Mandible with Pulmonary Metastasis
125
Downloaded by: King's College London 137.73.144.138 - 1/11/2019 2:02:57 AM
6 Emmings, F.G.; Gage, A.A., and Koepf S.W.: Combined curettage and cryotherapy for recurrent ameloblastoma of the mandible. Report of case. J. oral Surg. 29: 41-44 (1971). 7 Gorlin, R.J. and Goldman, H.M.: Thoma’s oral pathology; 6th cd., vol. 1 (Mosby, St. Louis 1970). 8 Gorlin, R.J.; Ballantyne, L.W., and Pindborg, J.J.: Odontogenic tumors. Cancer 14: 73-101 (1961). 9 Hair, J.A.G.: Radiosensitive adamantinoma. Br. med. J. i: 105-106 (1963). 10 Harrer, W.V. and Patchefsky, A.S.: Mandibular ameloblastoma with intracerebral and pulmonary metastasis. Oral Surg. 29: 893-898 (1970). 11 Herceg, S.J. and Harding, R.: Malignant ameloblastoma with pulmonary metastases. Plastic reconstr. Surg. 49: 456-460 (1972). 12 Hodson, J.J.: Observations on the origin and nature of the adamantinoma with special reference to certain muco-epidermoid variations. Br. J. plast. Surg. 10: 38-59 (1957-58). 13 Horrman, P.J.; Baden, E.O.; Rankow, R.M., and Potter, G.D.: The fate of the uncon trolled ameloblastoma. Oral Surg. 26: 419-426 (1968). 14 Hoke, H.F. and Harrelson, A.B.: Granular cell ameloblastoma with metastases to the cervical vertebrae. Observations on the origin of the granular cells. Cancer 20: 991-999 (1967). 15 Kegel, R.F.C.: Adamantine epithelioma. Archs Surg. 25: 498-528 (1932). 16 Lash, M. and McCoy, G.: Ameloblastoma of the mandible with distant metastases. Ann. Otol. Rhinol. Lar. 78: 430-435 (1969). 17 Lee, R.E.; White, W.L., and Totten, R.S.: Ameloblastoma with distant metastases. Archs Path. 68: 23-29 (1958). 18 Leone, L.A.; Albala, M.M., and Rege, V.B.: Treatment of carcinoma of the head and neck with intravenous methotrexate. Cancer 21: 828-837 (1968). 19 Lucas, R.B. and Thackray, A.C.: The histology of adamantinoma. Br. J. Cancer 5: 289-300 (1951). 20 Masson, J.K.; McDonald, J.R., and Figi, F.A.: Adamantinoma of the jaws. A clinicopathologic study of 101 histologically proven cases. Plastic reconstr. Surg. 23: 510-525 (1959). 21 McGregor, L.: A report of eleven instances of adamantinoma with a review of the malignant cases in the literature. Acta radiol. 16: 254-274 (1935). 22 Pennisi, V.R.: Young, A., and Anlyan, A.J.: Ameloblastoma with long-standing pulmonary metastases. Plastic reconstr. Surg.38: 534 -5 4 0 (1966). 23 Pennisi, V.R.; Young, A., and Anlyan, A.J.: Ameloblastoma with long-standing pulmonary metastases. Follow-up clinic. Plastic reconstr. Surg. 47: 595 (1971). 24 Robinson, H.B.: Ameloblastoma: survey of 379 cases from literature. Archs Path. 23: 831-843 (1937). 25 Schweitzer, F.C. and Barnfietd, W.F.: Ameloblastoma of the mandible with metastases to the lungs. Report of a case. J. oral Surg. 1: 287-295 (1943). 26 Sharp, G.S.; Bullock, W.K., and Binkley, F.C.: Ameloblastoma of the jaws. Oral Surg. 8: 1013-1025 (1955). 27 Shatkin, S. and Hofmeister, F.S.: Ameloblastoma: a rational approach to therapy. Oral Surg. 20: 421-435 (1965). 28 Simmons, C.C.: Adamantinoma. Ann. Surg. 88: 693-704 (1928). 29 Small, LA. and Waldron, C.A.: Ameloblastoma of the jaws. Oral Surg. 8: 281-297 (1955). 30 Smith, J.F.: The controversial ameloblastoma. Oral Surg. 26: 4 5 -7 5 (1968).
Gall/Sartiano/Shreiner 31
32 33 34
126
Thoma, K.H. and Goldman, H.M.: Odontogenic tumors. A classification on observa tions of the epithelial, mesenchymal and mixed varieties. Am. J. Path. 22: 433-471 (1946). Tsukada, Y.; De La Pava, S., and Pickren, J.W.: Granular-cell ameloblastoma with métastasés to the lungs. Cancer 18: 916-925 (1965). Vorzimer, I. and Perla, D.: An instance of adamantinoma of jaw with metastasis to right lung. Am. J. Path. 8: 445-454 (1932). Wohl: cited by Robinson (24).
Downloaded by: King's College London 137.73.144.138 - 1/11/2019 2:02:57 AM
Joseph A. Gall, MD, Department of Medicine, Division of Hematology, University of Pittsburgh School of Medicine, 931 Scaife HM, Pittsburgh, PA 15261 (USA)