Acute myelomonocytic leukemia presenting with gingival enlargement as the only clinical manifestation
Identifieur interne : 001E13 ( Pmc/Corpus ); précédent : 001E12; suivant : 001E14Acute myelomonocytic leukemia presenting with gingival enlargement as the only clinical manifestation
Auteurs : Lilian Menezes ; Jyoti R. RaoSource :
- Journal of Indian Society of Periodontology [ 0972-124X ] ; 2012.
Abstract
A 34 year old woman reported for evaluation of generalized gingival swelling pain and bleeding. The patient also reported menstrual irregularities. Based on the oral and systemic examinations and hematological investigations, a provisional diagnosis of ‘menstrual cycle associated gingivitis’ was made. The patient was referred for a gynecologic consultation. At the three-week dental recall, a worsening of gingival overgrowth with a necrotic component was noted. The hematologic investigations revealed markedly elevated leukocyte counts. The clinical and hematological findings led us to a diagnosis of leukemia. This report emphasizes the importance of the dentist as well as the physician (in this case, the gynecologist) in correlating the oral, systemic and hematological findings in the diagnosis and also of regular recall in the management of a case.
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DOI: 10.4103/0972-124X.106926
PubMed: 23493961
PubMed Central: 3590734
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Acute myelomonocytic leukemia presenting with gingival enlargement as the only clinical manifestation</title><author><name sortKey="Menezes, Lilian" sort="Menezes, Lilian" uniqKey="Menezes L" first="Lilian" last="Menezes">Lilian Menezes</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Rao, Jyoti R" sort="Rao, Jyoti R" uniqKey="Rao J" first="Jyoti R." last="Rao">Jyoti R. Rao</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23493961</idno><idno type="pmc">3590734</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590734</idno><idno type="RBID">PMC:3590734</idno><idno type="doi">10.4103/0972-124X.106926</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001E13</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001E13</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Acute myelomonocytic leukemia presenting with gingival enlargement as the only clinical manifestation</title><author><name sortKey="Menezes, Lilian" sort="Menezes, Lilian" uniqKey="Menezes L" first="Lilian" last="Menezes">Lilian Menezes</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Rao, Jyoti R" sort="Rao, Jyoti R" uniqKey="Rao J" first="Jyoti R." last="Rao">Jyoti R. Rao</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Indian Society of Periodontology</title><idno type="ISSN">0972-124X</idno><idno type="eISSN">0975-1580</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>A 34 year old woman reported for evaluation of generalized gingival swelling pain and bleeding. The patient also reported menstrual irregularities. Based on the oral and systemic examinations and hematological investigations, a provisional diagnosis of ‘menstrual cycle associated gingivitis’ was made. The patient was referred for a gynecologic consultation. At the three-week dental recall, a worsening of gingival overgrowth with a necrotic component was noted. The hematologic investigations revealed markedly elevated leukocyte counts. The clinical and hematological findings led us to a diagnosis of leukemia. This report emphasizes the importance of the dentist as well as the physician (in this case, the gynecologist) in correlating the oral, systemic and hematological findings in the diagnosis and also of regular recall in the management of a case.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Williams, Wj" uniqKey="Williams W">WJ Williams</name></author><author><name sortKey="Beutler, E" uniqKey="Beutler E">E Beutler</name></author><author><name sortKey="Erslev, Aj" uniqKey="Erslev A">AJ Erslev</name></author><author><name sortKey="Litchman, Ma" uniqKey="Litchman M">MA Litchman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Burkett, L" uniqKey="Burkett L">L Burkett</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bressman, E" uniqKey="Bressman E">E Bressman</name></author><author><name sortKey="Decter, Ja" uniqKey="Decter J">JA Decter</name></author><author><name sortKey="Chasen, Ai" uniqKey="Chasen A">AI Chasen</name></author><author><name sortKey="Sackler, Rs" uniqKey="Sackler R">RS Sackler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Love, A" uniqKey="Love A">A Love</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Glickman, I" uniqKey="Glickman I">I Glickman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mariotti, A" uniqKey="Mariotti A">A Mariotti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoffbrand, Av" uniqKey="Hoffbrand A">AV Hoffbrand</name></author><author><name sortKey="Lewis, Sm" uniqKey="Lewis S">SM Lewis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Forkner, Ce" uniqKey="Forkner C">CE Forkner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dreizen, S" uniqKey="Dreizen S">S Dreizen</name></author><author><name sortKey="Mccredie, Kb" uniqKey="Mccredie K">KB McCredie</name></author><author><name sortKey="Keating, Mj" uniqKey="Keating M">MJ Keating</name></author><author><name sortKey="Luna, Ma" uniqKey="Luna M">MA Luna</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boggs, Dr" uniqKey="Boggs D">DR Boggs</name></author><author><name sortKey="Wintrobe, Mm" uniqKey="Wintrobe M">MM Wintrobe</name></author><author><name sortKey="Cartwright, Ge" uniqKey="Cartwright G">GE Cartwright</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shepherd, Jp" uniqKey="Shepherd J">JP Shepherd</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Osgood, Ee" uniqKey="Osgood E">EE Osgood</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kaufman, J" uniqKey="Kaufman J">J Kaufman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stafford, R" uniqKey="Stafford R">R Stafford</name></author><author><name sortKey="Sonis, S" uniqKey="Sonis S">S Sonis</name></author><author><name sortKey="Lockhart, P" uniqKey="Lockhart P">P Lockhart</name></author><author><name sortKey="Sonis, A" uniqKey="Sonis A">A Sonis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barrett, Ap" uniqKey="Barrett A">AP Barrett</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sinrod, Hs" uniqKey="Sinrod H">HS Sinrod</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barrett, Ap" uniqKey="Barrett A">AP Barrett</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berkeisev, S" uniqKey="Berkeisev S">S Berkeisev</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="case-report"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Indian Soc Periodontol</journal-id><journal-id journal-id-type="iso-abbrev">J Indian Soc Periodontol</journal-id><journal-id journal-id-type="publisher-id">JISP</journal-id><journal-title-group><journal-title>Journal of Indian Society of Periodontology</journal-title></journal-title-group><issn pub-type="ppub">0972-124X</issn><issn pub-type="epub">0975-1580</issn><publisher><publisher-name>Medknow Publications & Media Pvt Ltd</publisher-name><publisher-loc>India</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23493961</article-id><article-id pub-id-type="pmc">3590734</article-id><article-id pub-id-type="publisher-id">JISP-16-597</article-id><article-id pub-id-type="doi">10.4103/0972-124X.106926</article-id><article-categories><subj-group subj-group-type="heading"><subject>Case Report</subject></subj-group></article-categories><title-group><article-title>Acute myelomonocytic leukemia presenting with gingival enlargement as the only clinical manifestation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Menezes</surname><given-names>Lilian</given-names></name><xref ref-type="aff" rid="aff1"></xref><xref ref-type="corresp" rid="cor1"></xref></contrib><contrib contrib-type="author"><name><surname>Rao</surname><given-names>Jyoti R.</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib></contrib-group><aff id="aff1"><italic>Department of Periodontics, Government Dental College and Hospital, Bambolim, Goa, India</italic></aff><author-notes><corresp id="cor1"><bold>Address for correspondence:</bold> Dr. Lilian Menezes, Department of Periodontics, Government Dental College and Hospital, Bambolim, Goa - 403 202, India. E-mail: <email xlink:href="applegate2k@yahoo.com">applegate2k@yahoo.com</email></corresp></author-notes><pub-date pub-type="ppub"><season>Oct-Dec</season><year>2012</year></pub-date><volume>16</volume><issue>4</issue><fpage>597</fpage><lpage>601</lpage><history><date date-type="received"><day>02</day><month>9</month><year>2011</year></date><date date-type="accepted"><day>20</day><month>8</month><year>2012</year></date></history><permissions><copyright-statement>Copyright: © Journal of Indian Society of Periodontology</copyright-statement><copyright-year>2012</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-sa/3.0"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>A 34 year old woman reported for evaluation of generalized gingival swelling pain and bleeding. The patient also reported menstrual irregularities. Based on the oral and systemic examinations and hematological investigations, a provisional diagnosis of ‘menstrual cycle associated gingivitis’ was made. The patient was referred for a gynecologic consultation. At the three-week dental recall, a worsening of gingival overgrowth with a necrotic component was noted. The hematologic investigations revealed markedly elevated leukocyte counts. The clinical and hematological findings led us to a diagnosis of leukemia. This report emphasizes the importance of the dentist as well as the physician (in this case, the gynecologist) in correlating the oral, systemic and hematological findings in the diagnosis and also of regular recall in the management of a case.</p></abstract><kwd-group><kwd>Gingival enlargement</kwd><kwd>leukemia</kwd><kwd>neoplastic</kwd></kwd-group></article-meta></front><body><sec id="sec1-1"><title>INTRODUCTION</title><p>Leukemia is a heterogeneous group of hematological disorders that are characterized by disordered differentiation and proliferation of neoplastic hematopoietic stem cells and the diffuse replacement of the bone marrow by these cells.</p><p>Thus, there is a diminished production of normal erythrocytes, causing anemia, weakness, fatigue, and pallor; granulocytes causing granulocytopenia, fever, and infection; and platelets causing thrombocytopenia, bleeding, petechiae, and bruising. Leukemic cells may also infiltrate spleen, lymph nodes, the central nervous system, skin, gingiva and other tissues throughout the body.[<xref ref-type="bibr" rid="ref1">1</xref>]</p><p>Most frequent oral finding in leukemia is erythematous or cyanotic gingival hyperplasia with or without necrosis, petechiae, ecchymosis, mucosal ulcers and hemorrhage.[<xref ref-type="bibr" rid="ref2">2</xref><xref ref-type="bibr" rid="ref3">3</xref>]</p><p>In 1936, Love reported the pathologic changes in 82 patients with leukemia and suggested that oral lesions appeared to be a diagnostic indicator for leukemia.[<xref ref-type="bibr" rid="ref4">4</xref>] The gingival findings may be partially dependant on the inflammatory condition of the tissues.[<xref ref-type="bibr" rid="ref5">5</xref>]</p><p>This article reports a case of Acute Myelomonocytic Leukemia (AML) diagnosed following laboratory studies initiated solely due to gingival hyperplasia as the classic systemic changes accompanying the acute stage of this disease were not present.</p></sec><sec id="sec1-2"><title>CASE REPORT</title><p>A 34-year-old female of Asian Indian origin reported to the Department of Periodontology, Goa Dental College and Hospital on 23<sup>rd</sup> February, 2011, with the chief complaint of swelling, pain, and bleeding of the maxillary and mandibular gingiva. These symptoms had been present for about 15 days. The patient had been in good health until the last two weeks at which time she began to notice gingival swelling, pain, and bleeding which grew progressively worse, which was why she sought dental treatment.</p><p>On oral examination, the gingiva appeared enlarged, smooth, shiny, edematous, and lacked stippling [Figure <xref ref-type="fig" rid="F1">1a</xref>–<xref ref-type="fig" rid="F1">c</xref>]. According to the patient, she was also having menstrual irregularities for the past 3 months and experienced excessive tiredness ever since.</p><fig id="F1" position="float"><label>Figure 1</label><caption><p>Frontal view of the gingival inflammation and overgrowth at first visit. (b) Mandibular occlusal and (c) Maxillary occlusal view of the gingival overgrowth at first visit</p></caption><graphic xlink:href="JISP-16-597-g001"></graphic></fig><p>There was no evidence of lymphadenopathy, hepatospleenomegaly, cutaneous bruising, or petechiae.</p><p>The patient was not taking any medications. She indicated no family history of hematological disease in her parents or siblings.</p><p>A routine blood investigation revealed a total leukocyte count of 10,000 cells/cmm and Hemoglobin count of 10 mg/dl.</p><p>A provisional diagnosis of ‘Menstrual cycle – associated gingivitis’[<xref ref-type="bibr" rid="ref6">6</xref>] was made. Routine scaling, root planing and pocket irrigation were performed and the patient was referred to the Department of Obstetrics and Gynecology at the Goa Medical College and Hospital for consultation regarding her menstrual irregularities. She was prescribed oral androgenic steroids (Medroxyprogesterone, 30 mg/day to be gradually tapered to 10 mg/day) over a period of 3 weeks.</p><p>At the 3 week dental recall, her menstruation had regularized but the gingival swelling, bleeding, and pain did not improve; rather the gingival swelling seemed to worsen [<xref ref-type="fig" rid="F2">Figure 2a</xref>]. Furthermore, necrosis along the gingival margins of the maxillary and mandibular teeth was noted [Figure <xref ref-type="fig" rid="F2">2b</xref> and <xref ref-type="fig" rid="F1">c</xref>]. The patient also informed that she had fever of 102°F for the last two days before the follow-up visit.</p><fig id="F2" position="float"><label>Figure 2</label><caption><p>Frontal view of the increase in the gingival overgrowth 3 weeks after initial presentation. (b) Mandibular occlusal and (c) Maxillary occlusal view of the necrotic component of the gingival overgrowth</p></caption><graphic xlink:href="JISP-16-597-g002"></graphic></fig><p>Multiple soft and tender lymph nodes ranging from 1.0-1.5 cm in diameter were palpable bilaterally in the neck as well as axillae. A routine blood count revealed leukocytosis white blood cell (WBC) count, 58,000/cmm and anemia (HBG 6 g/dl) suggesting an acute leukemia and the patient were referred to Department of Medicine, Goa Medical College and Hospital. She was subsequently admitted to a ward on 16<sup>th</sup> March 2011.</p><p>The laboratory examination the following day included complete blood count and differential count for classification of the WBC. A complete battery of laboratory tests, including glucose tolerance, blood chemistry and urine analysis showed results within normal limits. Her routine blood count at this time revealed leukocytosis, anemia and thrombocytopenia [<xref ref-type="table" rid="T1">Table 1</xref>].</p><table-wrap id="T1" position="float"><label>Table 1</label><caption><p>Hematological findings</p></caption><graphic xlink:href="JISP-16-597-g003"></graphic></table-wrap><p>The leukocyte differential count displayed 6% neutrophils, 31% monocytoid cells, 3% lymphocytes, 48% blast form, 4% myelocytes, and 8% stabs. The peripheral smear displayed mostly immature monocytes as well as some myeloblasts. A diagnosis of AML - FAB classification M4[<xref ref-type="bibr" rid="ref7">7</xref>] was made. Subsequent bone marrow biopsy revealed 90% hypercellularity.</p><p>During the hospital stay, the patient was given symptomatic and supportive treatment, which included chemotherapy, whole blood transfusion and antibiotics. The patient underwent an induction regimen consisting of intravenous administration of cytosine arabinoside (ARA-C, 100/m<sup>2</sup>/day × 7 days) and idarubicin hydrochloride (Idamycin, 12mg/m<sup>2</sup>/day × 3 days). The patient tolerated the chemotherapy with minimal complications.</p><p>The oral hygiene instructions consisted of gentle brushing and mouth rinsing with chlorhexidine 0.2% twice daily.</p><p>The general condition and primary gingival enlargement of leukemic infiltration were well controlled in that, the enlargement although persistent, was non-progressive, firm and devoid of its necrotic component [Figure <xref ref-type="fig" rid="F3">3a</xref>–<xref ref-type="fig" rid="F3">c</xref>].</p><fig id="F3" position="float"><label>Figure 3</label><caption><p>(a) Reduction in the inflammation and no increase in the gingival enlargement after the chemotherapy. (b and c) Resolution of the necrotic component of the gingival overgrowth: Maxilla and mandible</p></caption><graphic xlink:href="JISP-16-597-g004"></graphic></fig><p>The patient was discharged with a WBC count of 7,500/cmm and hemoglobin 8 gm/dl.</p><p>Routine dental treatment included cautious debridement of plaque and food debris followed by chlorhexidine irrigation every fortnight.</p><p>Unfortunately, approximately 4 months after the initial symptoms, a recurrence of the leukemia with sepsis resulted in the patient's death on 5<sup>th</sup> June 2011.</p></sec><sec sec-type="discussion" id="sec1-3"><title>DISCUSSION</title><p>The recognition of gingival enlargement as an initial oral manifestation of leukemic infiltration assumes great importance, particularly in the early diagnosis of myelomonocytic leukemia.[<xref ref-type="bibr" rid="ref8">8</xref>–<xref ref-type="bibr" rid="ref10">10</xref>] Forkner has concluded that the oral manifestation of marked swelling, particularly in the gingiva, can usually be regarded as a characteristic typical of acute monocytic leukemia, while it is usually absent in acute leukemia of the myelogenous or lymphatic varieties.[<xref ref-type="bibr" rid="ref8">8</xref><xref ref-type="bibr" rid="ref11">11</xref>] Osgood reviewed 127 cases of monocytic leukemia, and found that swelling of the gingiva took place in 53% of the patients.[<xref ref-type="bibr" rid="ref12">12</xref>] Furthermore, Kaufman[<xref ref-type="bibr" rid="ref13">13</xref>] reported 35% of 40 patients and Berkheiser reported 52% of 29 patients with monocytic leukemia having gingival swelling respectively.</p><p>Stafford <italic>et al</italic>.[<xref ref-type="bibr" rid="ref14">14</xref>] evaluated 500 leukemic patients and found 65% had some oral manifestation that caused them to seek care. In fact, oral manifestations are often the first indications of disease. Although physicians most commonly diagnose leukemia, dentists have been responsible for initiating the diagnosis in 25% patients with acute myelogenous leukemia and 33% of patients with AML.[<xref ref-type="bibr" rid="ref14">14</xref>] Thus, the dental practitioner should have an awareness of diagnostic signs and complications associated with leukemia to better aid in diagnosis, subsequent treatment, and management.</p><p>Of interest is the high frequency of primary gingival enlargement as an early and only manifestation of leukemia. This emphasizes the importance of the initial diagnosis of myelomonocytic leukemia in the present case.</p><p>The lack of reported incidence of gingival hyperplasia in edentulous patients led to the hypothesis that local irritants related to teeth and periodontium promoted and acted as cofactors in the development of gingival infiltration by leukemic cells.[<xref ref-type="bibr" rid="ref15">15</xref>] However, gingival hyperplasia occurs in patients with excellent oral hygiene, indicating that local factors are not required to promote or induce local infiltration of oral tissues.[<xref ref-type="bibr" rid="ref9">9</xref>] Sinrod[<xref ref-type="bibr" rid="ref16">16</xref>] and Boggs <italic>et al</italic>.[<xref ref-type="bibr" rid="ref10">10</xref>] also indicated that gingival enlargement might be due to leukemic infiltration or a secondary inflammatory response to local irritation of preexisting periodontal disease, or both. In the present case, it was not possible to take a gingival biopsy as the leukocyte counts of the patient were high. Furthermore, Williams <italic>et al</italic>.[<xref ref-type="bibr" rid="ref1">1</xref>] reported that gingival infiltration represents a 5% frequency as the initial presenting complication of AML.</p><p>In 1986, Barrett[<xref ref-type="bibr" rid="ref17">17</xref>] explained the selective infiltration of gingival tissues as being due in part to the inherent extravascular infiltrative properties of the leukemic cell, and in part due to the unique gingival microanatomy. Furthermore, Dreizen <italic>et al</italic>.[<xref ref-type="bibr" rid="ref9">9</xref>] reported that both the apparent acceleration in the mitotic rate and the absolute number of leukemic cells are key factors in initiating this infiltration. While these concepts have contributed to our understanding of leukemic cell infiltration of the gingiva, the precise mechanisms remain elusive.</p><p>In the present case, the initial diagnosis of ‘Menstrual cycle – associated gingivitis’[<xref ref-type="bibr" rid="ref6">6</xref>] was made as the hematological picture did not compel us to look for alternative causes of the gingival inflammation and enlargement. The blood counts changed rather dramatically within a short period of 3 weeks. As in the present case, marked gingival enlargement occurred within 3 weeks, vividly revealing the predisposition of gingival tissues to leukemic cell infiltration when other possible causes of gingival enlargement are not found. Here, it is prudent to emphasize the importance of regular recall and follow up even in seemingly simple cases. Following chemotherapy, WBC count decreased gradually to 7,200/cmm. Although the enlargement persisted, it did not progress and was devoid of its inflammatory and necrotic component. Based on these observations, it appears that leukemic cell infiltration was the major cause of the sudden onset of gingival enlargement,[<xref ref-type="bibr" rid="ref9">9</xref><xref ref-type="bibr" rid="ref11">11</xref><xref ref-type="bibr" rid="ref15">15</xref>] thereby excluding other systemic causes, local irritants, or trauma.</p></sec><sec sec-type="conclusion" id="sec1-4"><title>CONCLUSION</title><p>AML often has oral manifestations as its first indication of the disease,[<xref ref-type="bibr" rid="ref14">14</xref>] which is what compels them to seek dental care. Hence, dentists are responsible for initiating the diagnosis in 25-33% of patients with AML.[<xref ref-type="bibr" rid="ref18">18</xref>] Early diagnosis and treatment can improve the patients’ chances for remission. Thus, the professional (dental as well as medical) who maintains a high degree of suspicion of unusual oral conditions can play an important role in the prompt referral and treatment of these patients. In this case, the gynecologist was in a unique position to aid in diagnosis by suspecting and referring to a specialist.</p><p>In conclusion, to aid in early diagnosis and enable subsequent early treatment and management, the dental and medical practitioner (in this case the gynecologist) must have full knowledge of the diagnostic signs and complications associated with leukemia.</p></sec></body><back><fn-group><fn fn-type="supported-by"><p><bold>Source of Support:</bold> Nil</p></fn><fn fn-type="conflict"><p><bold>Conflict of Interest:</bold> None declared.</p></fn></fn-group><ref-list><title>REFERENCES</title><ref id="ref1"><label>1</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Williams</surname><given-names>WJ</given-names></name><name><surname>Beutler</surname><given-names>E</given-names></name><name><surname>Erslev</surname><given-names>AJ</given-names></name><name><surname>Litchman</surname><given-names>MA</given-names></name></person-group><source>Hematology</source><year>1990</year><edition>4th ed</edition><publisher-loc>New York</publisher-loc><publisher-name>Mc Graw Hill</publisher-name><fpage>243</fpage><lpage>4</lpage></element-citation></ref><ref id="ref2"><label>2</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Burkett</surname><given-names>L</given-names></name></person-group><source>Oral Medicine Diagnosis and Treatment</source><year>1977</year><edition>7th ed</edition><publisher-loc>Philadelphia</publisher-loc><publisher-name>J. 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