Oral manifestations in myelodysplastic syndrome

Oral manifestations in myelodysplastic syndrome Review of the literature

and report of a case

J. B. Epstein, D.M.D., iU.S.D.,* R. W. Priddy, D.D.S., MSc., T. Sparling, M.D.. F.R.C.P.(C), F.R.C.P. (Haem),*** and L. Wadsworth, M.B., Ch.B., F.R.C.P.(C), F.R.C.Path.,**** Vancouver, British Columbia, Canada SHAUGHNESSY

HOSPITAL

AND

UNIVERSITY

OF BRITISH

F.R.C.D.(C),**

COLUMBIA

Gingival hyperplasia in a patient with myelodysplastic syndrome is described. Gingival infiltration was the first sign of acceleration of a stable disease process and was followed by development of a more aggressive phase of chronic myelomonocytic leukemia that was not responsive to therapy. Oral and dental assessment of patients with the myelodysplastic syndromes should be a part of routine management. (ORAL SURG. ORAL MED. ORAL PATHOL. 61:466-470, 1986)

T he incidence of oral complications of the myeloproliferative disorders and their management is estimated to be between 15% and 85%.‘-9 These complications include hemorrhage, mucositis, gingival hyperplasia and ulceration, infection, alteration or loss of taste, pain, and associated diet and nutritional concerns. Pre-existing dental, periodontal, and other oral diseases may exacerbate during medical management of the myeloproliferative diseases. Oral manifestations of the disease and oral complications of medical management may result in significant symptoms and have an impact on the systemic condition of the patient. The myelodysplastic syndromes are a group of stem cell disorders characterized by a reduction in one or more formed elements of the blood.*“-*2 The syndrome may occur with anemia, neutropenia, and thrombocytopenia, alone or in combination. The bone marrow may demonstrate increased cellularity

*Cancer Control Agency of British Columbia; Oncology Clinic and Department of Dentistry, Shaughnessy Hospital. **Head, Section of Oral Pathology, Department of Pathology, Shaughnessy Hospital; Associate Professor, University of British Columbia. **Director of Medical Oncology, Ambulatory Care Program, Shaughnessy Hospital; Clinical Assistant Professor of Medicine, University of British Columbia. ****Head, Hematology Laboratory, Shaughnessy Hospital; Associate Clinical Professor, Department of Pathology, University of British Columbia. 466

and may show dysplastic features, including megaloblastic change, ringed sideroblasts, and increased myeloblasts. Approximately 50% to 75% of these disorders will enter an accelerated phase, and some will transform into acute leukemia. Most patients will ultimately die of progressive bone marrow failure. In patients with acute leukemia, myeloblastic proliferation becomes dominant in a short time. Myelodysplastic syndromes may represent an intermediate stage of variable duration between isolated cytopenia and acute leukemia. These syndromes can remain stable, with no evidence of acute leukemia, for months or years. CASEREPORT Clinical findings’

A 68-year-oldmanwasseenin April 1983with anemia, neutropenia,and monocytosis.Bone marrow biopsy and cytogenetic analysis confirmed a diagnosisof type IV myelodysplasticsyndrome(chronic myelomonocyticleukemia [CMMoL]).” He was managedwith transfusion therapy. In August 1983a new finding of gingival hyperplasiawasnoted,and dental evaluationwasundertakenas part of his continuingcare in a multidisciplinary oncology clinic. There were no specific complaints regarding the dental condition. The gingivae were enlarged, firm, and hemorrhagic,but not inflamed.Isolated pseudopockets of up to 7 mm were seenin the areasof gingival hyperplasia (Fig. 1). A completeradiographicexaminationrevealedno abnormality. A gingival biopsyspecimenwasobtainedand managementwasinstituted with gentletissuedebridement and scalingof teeth, rinsingwith chlorhexidinesuspension

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1. Gingival presentationin August 1983.The gingival tissueswere enlarged,pink, firm, and uninflamed.

Fig.

(0.2% solution in peppermint water, 5 ml., four times daily) and an anestheticrinseof benzydaminehydrochloride (Tantum oral rinse, Riker Canada,Ltd., 5 ml, four timesdaily). The gingival condition continuedto progress with involvement of additional sitesand with ulceration and pseudomembrane formation (Fig. 2). The patient was subsequentlyadmitted to the hospitalfor additional study andtreatment. A courseof radiationtherapy with a doseof 600 cGy (rads) was delivered to the oral cavity with parallelopposedfields,in a singleexposure.No subsequent improvementwasnoted. On Nov. 25, 1983,the patient wasdischargedfrom the hospital on a regimen of penicillin and chlorhexidine following a brief admissionfor care of a dental infection. He had been feeling unwell and was found to have a low-grade fever, hepatosplenomegaly,and a leukocyte count of 55 X lo9 per liter. A secondgingival biopsy specimenwasobtained.The patient wasreadmitted7 days later with a leukocyte count of 180X lo9 per liter and multiple organ failure due to leukostasisand extensive leukemicinfiltration. He died on Dec. 7, 1983. Laboratory

findings

The patient had a normochromicanemia(hemoglobin, 6.6 g/dl), with small numbersof macrocytes,when the gingival hyperplasiawasnoted.The leukocytecount wasin the low normalrangeand showedan absoluteneutropenia (1.4 x 1O9per liter) and a marked absolutemonocytosis (2.15 X lo9 per liter). The platelet count wasnormal. The preliminary bonemarrow aspirationwasfrom the sternum. The subsequentmarrow aspiration and both Jamshidi biopsyspecimenwere taken from the posterioriliac crest. The bone marrow showed4% myeloblastsand dysplastic featuresin all cell lines. The blood and marrow appearanceswereconsistentwith myelodysplasticsyndrometype IV (chronic myelomonocytic leukemia).” Chromosome studiesat the time of diagnosisshowedtwo cell lines.The cytogeneticdiagnosiswas46xy, 47xy + 15. Colony culture studieswere normal. Histopathologicstudy of the first gingival biopsy specimen (August 1983) showedmarginal gingival mucosain

Fig.

syndrome

467

2. Progressiveenlargementand ulceratin of gingi-

va. which the deeperportionsof the lamina propria contained an inflammatory cellular infiltrate of mixed morphology. Presentwithin this cell population were numerouslarge monomorphic,mononuclear,eosinophiliccells containing irregular pale-stainingnuclei with an open-facedchromatin pattern and occasionalmitotic figures (Fig. 3). The diagnosiswas consistentwith a leukemic infiltrate. The bone marrow biopsy (August 1983) was consistentwith CMMoL (Fig. 4). The secondgingival biopsyspecimen(November 1983) revealed almost total effacementof the normal lamina propria architectureby a malignantinfiltrate (Fig. 5). The cellular infiltrate wasarrangedin parallelarrays reflecting infiltration between collagen fiber bundles.The mixed inflammatory cell backgroundwasnot asevident asin the first biopsymaterial. Immunoperoxidase stainingfor lysozyme was positive for the monocytoidcells. The nonspecific esterasestain wasnegative.A repeatmarrow asperation wasperformed7 monthsafter presentationbecauseof a rising leukocyte count and increasingorganomegaly. Although the peripheralblood and bone marrow findings weremuchmorepronouncedthan at the time of diagnosis, the morphologicfindingswerestill thoseof CMMoL (Fig. 6). There was not sufficient evidence to substantiatea transformationto acute leukemia.In particular, marrow blast cell countswere not greater than 30%. The autopsy showedextensiveleukemicinfiltration of the marrow, liver, spleen,kidneys, gingiva, lymph nodes, pancreas, heart, bowel, bladder, and adrenal glands. Although the numbersof immaturecellsin someof these organsappearedgreaterthan the marrow blastpercentage (5%), nowheredid there appearto be 30% blasts.These changesare consistentwith an intermediatestagebetween a myelodysplasticsyndromeand frank acute monocytic leukemia. DISCUSSION

Infiltration of skin and oral mucous membrane by leukemic cells, in patients with myeloproliferative disorders, is a well-established clinical and histopathologic entity. In a study of fifty patients with

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Fig. 3. A, Low-power view of first gingival biopsy specimen showing atypical cellular infiltrate (ACI) in deeper portions of lamina propria. Note the relatively acellular papillary lamina propria. B, High-power view of cellular infiltrate with large, atypical monocytoid cells.

Fig. 4. Bone marrow biopsy specimen obtained of first gingival biopsy.

at tim

le

granulocytic sarcoma, Neiman and associatesI found that 30% of the study group had lesions with no evidence of leukemia at the time of skin biopsy. After a mean latency of 11 months, thirteen of these patients (8’7%) had acute myelocytic leukemia. In 65% of their cases, granulocytic sarcoma was the harbinger of acute leukemia, at a stage in the patient’s disease when all clinical and hematologic parameters were stable. Duguid and colleagues’5 studied skin infiltrates in patients with CMMoL. These studies suggest that cutaneous lesions in patients with known myeloproliferative disorders have prognostic significance and indicate that the disease is entering a more aggressive phase. Although dermal granulocytic sarcomas are relatively well documented, infiltrates of the oral mucosa of the aleukemic patient are rare.16-18In these reports, the gingival involvement progressed prior to significant findings on bone marrow biopsy or in the peripheral blood. Acute leukemia developed, and the disease progressed until it caused the patient’s death. The prognosis of involvement of the oral mucosa reflects the generally poor prognosis of granulocytic sarcoma of the skin.‘6-‘8 Dreizen and co-workerss’9 studied gingival and skin infiltrates in 1076 adults with leukemia. The mor-

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Fig. 5. High-power view of secondgingival biopsy specimen.Note the parallel arrangementof the infiltrating monocytoidcellsand mitotic figures.

Fig. 6. Bone marrow biopsy specimenobtained at time of secondgingival biopsy, demonstrating morphologiccharacteristicsof chronic myelomonocyticleukemia.

phology of the disease was shown to be the most important factor in the development of skin or gingival infiltrates. The tendency was greatest in the monocytic and myelomonocytic leukemias and least in the lymphocytic leukemias19-2’ (Table I). The degree of gingival hypertrophy has been correlated with the number of abnormal cells in the peripheral blood.’ A relationship between local irritants and trauma and gingival infiltrates has been reported.‘,5v20.22,23Dreizen et a1.19were unable to demonstrate a relationship between peripheral white cell counts and gingival changes. It appears that gingival and skin lesions are associated with local conditions in addition to the systemic disease process.

Few authors have discussed the pathobiologic nature of the mucocutaneous infiltrates that may arise in leukemic patients. Driezen and his associates19 consider these proliferations to represent local metastases whose development is determined primarily by the morphologic type of leukemia involved. However, the evolution of gingival infiltration in any one patient appears unpredictable. Although dermal invasion may be due to a chance localization of circulating tumor cells, in some instances there seems to be a pattern of perivascular and periadnexal distribution in the reticular dermis.24 The lack of adnexal structures in the gingivae, the almost “normal” background of mild chronic inflam-

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Table I. Gingival diseases*

Oral May,

infiltrates

Reference Bodey’ Dully and DriscolP Lynch and Ship6 Driezen et ali9 Present et al.2o Boggs et al.*i

in myeloproliferative Frequency

(%)

2-45 45 33 3-66 2-35 2-34

*In papers with ranges expressed, a low percentage represents lymphoeytic leukemia and the high percentages represent acute monoeytic leukemia.

mation in this tissue, and the finding of leukemic infiltrates in the gingival tissues of patients with excellent oral hygiene tend to confuse the true nature of leukemic infiltrates in oral mucosa. There are no reports in the literature of leukemic gingival infiltration and hypertrophy in the myelodysplastic syndromes. The case report that we have presented describes the clinicopathologic features of the oral manifestations of a chronic myelodysplastic syndrome. While CMMoL is typically associated with a prolonged clinical course, skin infiltration has been reported as an ominous sign. Skin infiltration was noted before a more aggressive stage of disease, in the absence of changes in morphology, cytochemistry, and membrane markers of the leukemic cellsI In the four patients studied by Duguid and colleaguesI survival ranged from 1.l to 2.5 months following the development of skin lesions. The case presented in this article also demonstrated acceleration of disease and death in 4 months following the development of gingival lesions. The gingival changes were diagnostic of leukemic infiltration, clinically and histologically, prior to evidence of disease in the marrow or the peripheral blood. One of the authors (R.W.P.) has personal knowledge of a similar case of myelodyplasia in which gingival infiltration was the initial manifestation of progression of the disease. This case documents an additional clinical manifestation affecting the oral tissue of the myelodysplastic syndromes. The physician and dentist must be alert for changes in the oral health status of patients suffering from these hematologic disorders. It is recommended that patients with a myelodysplastic syndrome be given periodic oral examinations as a routine part of their management. REFERENCES I. Bodey GP: Oral complications of the myeloproliferative diseases. Postgrad Med 49: 115- 121, 197 1. 2. Love AA: Manifestations of leukemia encountered in otolar-

Surg. 1986

yngologic and stomatologic practice. Arch Otolaryngol 23: 173-221, 1936. 3. Resch CA: Oral manifestations of leukemia. Am J Orthod 26: 901-907, 1940. 4. Wentz FM, Anday G, Orban B: Histopathologic changes in the gingiva in leukemia. J Periodontol 20: I 19- 128, 1949. 5. Duffy JH, Driscoll EJ: Oral manifestations of leukemia. ORAL SURG ORAL MED ORAL PATHOL 11: 484-490, 1958. 6. Lynch MA, Ship II: Initial manifestations of leukemia. J Am Dent. Assoc 75: 932-940, 1967. 7. Shepherd JP: The management of the oral complications of leukemia. ORAL SURG ORAL MED ORAL PATHOL 45: 543-548, 1978. 8. Peterson DE, Overholser CD: Increased morbidity associated with oral infection in patients with acute nonlymphocytic leukemia. ORAL SURG ORAL MED ORAL PATHOL 51: 390-393, 1981. 9. Greenberg MS, Cohen SG, McKitrick JC, Cassileth PA: The oral flora as a source of septicemia in patients with acute leukemia. ORAL SURG ORAL MED ORAL PATHOL 53: 32-36, 1982. 10. Sultan C: Dysmyeloplastic syndromes. In Gralnick HR (editor): Classification of acute leukemia. Ann Intern Med 87: 740-153, 1911. of preleukemia. Cancer Genet Cyto11. Nowell PC: Cytogenics genet 5: 265-278, 1982. 12. Streuli RA, Testa JR, Vardiman JW, Mintz U, Golomb HM, Rowley JD: Dysmyelopoietic syndrome: sequential clinical and cytogenetic studies. Blood 55: 636-644, 1980. 13. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C: The French American British (FAB) cooperative group: proposals for the classification of myelodysplastic syndromes. Br J Haematol 51: 189-199, 1982. 14. Neiman RS, Barcos M, Berard C, Bonner H, Mann R, Rydell RE, Bennett JM: Granulocytic sarcoma: clinicopathologic study of 6 I biopsied cases. Cancer 48: 1426- 1437, I98 1. 15. Duguid JKM, Mackie MJ, McVerry BA: Skin infiltration associated with chronic myelomonocytic leukaemia. Br J Haematol 53: 257-264, 1983. 16. Pogrel MA: Acute leukemia, an atypical case presenting with gingival manifestations. Int J Oral Surg 7: l19- 122, 1978. 17. Hansen LS, et al: Granulocytic sarcoma: an aleukemic oral presentation. CDAJ 10: 41-46, 1982. 18. Reichart PA, Roemeling RV, Krech R: Mandibular myelosarcoma (chloroma): primary oral manifestations of promyelocytic leukemia. ORAL SURG ORAL MED ORAL PATHOL 58: 424-421, 1984. KB, Keating MJ, Luna MA: Malignant 19. Dreizen S, McCredie gingival and skin infiltrates in adult leukemia. ORAL SURF ORAL MED ORAL PATHOL 55: 572-579, 1983. 20. Present CA, Safdar SH, Cherrick HC: Gingival leukemic infiltration in chronic lymphocytic leukemia. ORAL SURG ORAL MED ORAL PATHOL 36: 672-674, 1973. 21. Boggs DR. Wintrobe MM, Cartwright GE: The acute leukemias. Medicine 41: 163-225, 1972. I: Clinical periodontology, Philadelphia, 1972, 22. Glickman W.B. Saunders Company, pp. 395-399. of plaque and gingivitis in patients 23. Levin SM: Relationship with leukemia. Va Dent J 50: 22-25, 1973. 24. Sun NCJ, Ellis R: Granulocytic sarcoma of the skin. Arch Dermatol 116: 800-802, 1980.

Reprint requests to: Dr. J. B. Epstein Division of Dentistry Cancer Control Agency 600 West 10th Ave Vancouver, B. C., V5Z

of British 4E6 Canada

Columbia