M A N I F E S T AT I O N O F A C U T E M O N O C Y T I C L E U K E M I A I N T H E O R A L C A V I T Y

ARTICLE
ABSTRACT
This case history describes a 26-yearold male with gingival bleeding who presented for care and was treated accordingly. Within a week he developed signs and symptoms of systemic disease and upon further investigation, he was diagnosed with acute monocytic leukemia to which he succumbed within 72 hours. The implications of gingival bleeding are discussed, and the necessity to consider systemic disease in the differential diagnosis is emphasized.

Manifestation of acute monocytic leukemia in the oral cavity: a case report

Mahnaz Fatahzadeh, DMD;* A. Michael Krakow, DMD, MS, MFS
Division of Oral Medicine, Department of Diagnostic Sciences, New Jersey Dental School, University of Medicine & Dentistry of New Jersey, New Jersey *Corresponding author: e-mail: fatahza@umdnj.edu

KEY WORDS:

case report, gingival diseases, leukemia, monocytic, acute

Spec Care Dentist 28(5): 190-194, 2008

Introduction
It is estimated that this year nearly 45,000 individuals will be diagnosed with leukemia in the United States and approximately 50% of them will die from this disease.1 Leukemia is characterized by an abnormal proliferation of immature leukocytes and their precursors in bone marrow.23 The leukemic cell population also has the propensity to invade extramedullary tissues and its presence as leukemic infiltrates has been reported in the kidneys, lungs, bowels, breasts, testes, eyes, meninges, lymph nodes, liver, prostate, skin, and oral cavity. The diagnoses have been confirmed by tissue biopsy or fine needle aspiration cytology.411 Acute leukemia is often associated with a high incidence of oral complications1213 such as mucosal pallor, petechiae, ecchymoses, bleeding, ulceration, gingival enlargement, trismus, mental nerve neuropathy (numb chin syndrome), facial palsy, and infections.11,1421 Mucosal pallor, hemorrhagic diathesis, and increased susceptibility to infection are the consequences of anemia, thrombocytopenia, and leukopenia.13 Enlargements of mucosa, gingiva, or masticatory muscles are typically the result of direct infiltration by malignant leukoctyes.2,13,2223 Early manifestation of these clinical signs and symptoms in the oral cavity may signify underlying leukemia, thereby providing an opportunity for timely diagnosis.11,13,22,2425 In addition, direct and indirect effects of cytotoxic medications used in the treatment of leukemia often impact the oral cavity and require management.13 This manuscript describes a young man with an occult hematological malignancy, whose complaints were confined to gingival signs and symptoms typical of generalized gingivitis until three days before his death, at which time indications of systemic involvement became apparent and his condition deteriorated rapidly.

Case descr iption

A 26-year-old male presented to the University Hospital Dental Medicine Clinic with a chief complaint of sore, bleeding gums for the past three days. Gingival pain was intermittent, dull, and generalized. He denied having a fever, malaise, weight loss, or a sore throat in the recent past, and reported that he brushed his teeth only three to four times per week. He experienced bleeding on brushing, and shared a toothbrush with others in what he described as a group-home environment. His past medical history was essentially noncontributory, including a negative HIV test in 2002, but he was unsure about herpes labialis and he had been

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around small children recently. He was not taking any medications, specifically those known to cause gingival enlargement or hyperplasia (anticonvulsants, immunosuppressants, calcium channel blockers) and denied having any allergies. His social history included a 10-pack per year history of cigarette smoking, moderate alcohol consumption, occasional and recent use of marijuana, and unprotected sexual activity subsequent to his negative HIV test Vital signs were normal and an extraoral examination revealed mild, slightly tender, bilateral submandibular, and right anterior cervical lymphadenopathy. There were no muscle spasms or limitations of opening. Intraorally, the anterior gingivae were somewhat edematous, erythematous, enlarged, and tender to palpation with localized bleeding on probing. There was no evidence of punched out papillae, but there was fetor oris, moderate, generalized staining, plaque, and calculus throughout the dentition along with several carious teeth. All of these findings were consistent with the history of his less-than-ideal oral hygiene practices. Clinical and radiographic examination revealed no evidence of periodontal bone loss or other abnormalities. In view of the patients history, poor oral hygiene, and clinical findings, a diagnosis of generalized gingivitis secondary to local factors was made, with ANUG and acute herpetic gingivostomatitis included as part of the differential diagnosis. Gentle debridement was performed under local anesthesia and oral hygiene measures were initiated. Chlorhexidine 0.12% mouthrinse, penicillin VK 500 mg q6h, and analgesic medications were prescribed. He was also given a new toothbrush, advised not to share it, and reappointed to assess resolution and response to therapy. Depending on his response, or lack thereof, a gingival biopsy was contemplated. On his first follow-up visit a few days later, he reported feeling a little better, had normal vital signs, but still had mild submandibular lymphadenopathy. The gingival

Figure 1. Clinical photo depicting edematous, hyperplastic gingiva with focal erythema during patients first follow-up visit after debridement.

Figure 2. Clinical photo depicting erythematous, boggy gingiva with necrotic, sloughing interdental papilla on lingual aspect of mandibular anterior teeth.

inflammation had improved, but some sloughing of the marginal gingiva was observed (Figure 1). Oral hygiene measures were re-emphasized, and metronidazole was added to accelerate the resolution of his problem. Two days later, however, he presented with complaints of worsening gingival swelling, pain, and bleeding, and stated that he was unable to take the metronidazole because he had developed nausea, vomiting, and diarrhea. He also reported spitting and coughing up blood, insomnia, and night sweats. This was the first time since having been examined a week prior that he felt ill, and his vital signs were commensurately elevated. Extraorally, the bilateral submandibular lymphadenopathy persisted. Intraorally, the lingual aspect of his anterior mandibular gingiva and buccal aspects of his maxillary posterior gingiva had become more erythematous and were now boggy and cyanoticthe first instance of an abnormal color change. Slight gingival manipulation provoked hemorrhagic exudates around most of his teeth. Although not punched-out, the affected interdental papillae were necrotic and sloughing (Figure 2). The failure of simple local therapy to resolve his acute periodontal complaints, and his clinical presentation and symptomatology, prompted an investigation into an underlying systemic disease. The differential diagnosis included systemic disorders of hematological, immunosuppressive, and infectious etiology. Thus, a

full workup (CBC with differential, HIV antibody screen, hepatitis panel, Quantiferon-Gold TB assay, HSV I/II IgM, and IgG, erythrocyte sedimentation rate (ESR), and a metabolic panel) was ordered immediately. Within an hour, the laboratory called with the following critical values: WBC: 112,000 cells/ml3 (normal/nl 5,00010,000) with a predominance of monocytes; platelets: 15,000 cells/ml3 (nl 150,000400,000); hemoglobin: 6.6 g/dl (nl 13.817.2 g/dl); and ESR: 60 (nl 20). His working diagnosis was now acute monocytic leukemia, and he was immediately escorted to the ER for admission. A review of the peripheral blood smear revealed a marked increase in monocytes with 26% blast cells, together with anemia and significant decrease in platelets. A subsequent bone marrow biopsy showed in excess of 95% hypercellularity predominated by immature blast cells and absence of megakaryocytes. The result of follow-up immunohistochemical staining confirmed the working diagnosis of acute myelocytic leukemia. On the day after admission, the patient developed respiratory distress and hypoxemia as a result of persistently low hemoglobin and hematocrit despite multiple transfusions. The hemodynamic instability worsened and he underwent intubation in preparation for imminent respiratory compromise. He subsequently developed severe and persistent biochemical abnormalities causing EKG changes, and suggestive of

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acute renal failure. While preparations for emergency dialysis were underway, he became asystolic and could not be resuscitated. The causes of death were respiratory failure, acute myeloctic leukemia, clostridium difficile, and hyperkalemia. By request of the family, an autopsy was not performed.

Discussion
Signs of a bleeding diathesis including petechiae, oral ecchymosis, gingival hemorrhage, and progressive gingival enlargement have been described in patients with leukemia.1517,21,2628 Gingival overgrowth may be caused by hereditary conditions, medications, hematological disorders, and local irritants secondary to poor oral hygiene.2,2932 The hereditary gingival overgrowth is frequently pink, firm, and noninflamed while gingival enlargement associated with leukemia often presents as a soft, edematous, hemorrhagic, and tender swelling of the interdental, marginal, and attached gingiva with loss of stippling, and color variation ranging from normal mucosal color to dark purple.11,22,3134 The change in gingival morphology and its cyanotic appearance may result from reactive hyperplasia, dense leukemic infiltration of connective tissue, and compression of local vasculature causing ischemia.5,22 The extent of gingival overgrowth ranges from minimal to complete tooth coverage, creating functional and aesthetic concerns.22 Leukemic gingival infiltration appears limited to dentate subjects, implying a potential role for toothassociated local factors.35 Caries, calculus, and poor oral hygiene place the patient at risk for oral pain, bleeding, superinfection, and tissue necrosis, exacerbating gingival signs and symptoms.22,36 Bleeding diathesis, gingival hyperplasia and extramedullary leukemic infiltration are more frequently seen in the context of acute rather than chronic leukemia.35 In addition, gingival hyperplasia has been found in association with aleukemic and subleukemic

forms of leukemia.15,35,37 In acute leukemia, monocytic (M5), myelomonocytic (M4), and myelocytic (M1, M2) subtypes have been reported with gingival hyperplasia in 66.7%, 18.5%, and 3.75% of cases, respectively.22,35 Despite its frequency, the occurrence of gingival infiltration is unpredictable in leukemic patients22 and the development of gingival hyperplasia has no bearing on disease prognosis.22 The gingival enlargement is frequently responsive to chemotherapy, sometimes without any periodontal intervention.15 Dental professionals have a role in the comprehensive management of patients with leukemia before, during, and after therapy.12,14 Dentists should be familiar with the clinical manifestations of leukemia and the differential diagnosis of gingival enlargements.38 Gingival manifestations caused by leukemic infiltration have reportedly been the initial complication in 5% of patients with acute myeloblastic leukemia.11,33 This was the case with our patient whose gingival signs and symptoms were the first manifestation of his systemic disease and the main complaint for which he sought dental care. Early recognition of clinical findings in the oral cavity by an astute clinician, and investigation into potential systemic causes, may uncover an underlying systemic disease and lead to its timely diagnosis and management.3940 Dentists should be familiar with the therapeutic interventions for this malignant disease, and the treatment-related oral complications, as well as the interceptive and palliative measures used to manage them.38 Chemotherapy predisposes the oropharyngeal mucosa to epithelial disruption, mucositis, and ulceration negatively impacting nutritional intake.20,41 Other direct and indirect stomatotoxic effects of chemotherapy include varying degrees of trismus, bleeding, and infections, such as herpes, pseudomoniasis, and candidiasis, in the oral cavity.18,20,22 Leukemia-associated gingival enlargement affects the ability of the patient to maintain oral hygiene care. Maintenance

of oral hygiene is essential for preventing oral and systemic complications during chemotherapy.39,4243 All patients may develop immune compromise from neutropenia during chemotherapy and should receive a comprehensive oral evaluation and management plan prior to initiating the therapeutic protocol14,38,44 in order to reduce the potential for increased morbidity and mortality from oral infections and septicemia.38 Furthermore, because of the potential risk for bleeding and infection associated with the disease or its therapy, elective surgery should be avoided and emergency procedures should be rendered only in association with broad spectrum antibiotic coverage and appropriate hemostatic measures.2,15,42 A simple, safe, and less invasive diagnostic alternative to gingival biopsy for confirmation of leukemic gingival infiltration is fine needle aspiration cytology.5,7 However, in order to expediate the diagnostic process, we deferred both gingival biopsy and fine needle aspiration cytology, and pursued a systemic workup for an occult malignancy. Dental professionals are important members of a multidisciplinary oncology team for educating patients, emphasizing prevention, and offering modifications to oral hygiene routines for optimal effectiveness.45

Conclusion
Leukemia is a hematological disorder with frequent oral manifestations. This case history illustrates the importance of including systemic disease in the differential diagnosis of gingival pain, bleeding, and hyperplasia, and highlights the significance of a systematic approach to diagnosis. Close patient follow-up and re-evaluation of the working diagnosis is important if routine therapy fails to resolve the problem. Unfortunately, this patient had an oral hygiene history, which suggested periodontal disease due to local factors, and the absence of any systemic manifestations until a few days prior to his demise which makes this case history unusual.

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