Leukemia

Leukemia is a malignant neoplasm of hematopoietic stem cells characterized by uncontrolled proliferation of immature white blood cells in the bone marrow, with subsequent infiltration of peripheral blood and extramedullary tissues.[1][2] Oral and maxillofacial involvement arises through two principal mechanisms: direct infiltration of leukemic cells into the gingiva, periodontal ligament, alveolar bone, and periapical tissues; and secondary effects of marrow failure (thrombocytopenia, neutropenia, anemia) producing hemorrhage, infection, and impaired healing.[1][3] The jaws may show a spectrum of radiographic changes ranging from subtle loss of the lamina dura and widened periodontal ligament spaces to frank osteolytic destruction.[4][5] Oral findings may be the initial presentation of disease or a sign of relapse.[6][7] Management is systemic, directed by hematology-oncology, with dental care coordinated around the patient's hematologic status.[8]

Current Classification

The 5th edition WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO-HAEM5, 2022) and the concurrent International Consensus Classification (ICC, 2022) define leukemia subtypes primarily by lineage (myeloid vs. lymphoid), clinical tempo (acute vs. chronic), and recurrent genetic abnormalities.[9][10][11] The four principal subtypes are:

• Acute myeloid leukemia (AML) — further subclassified by defining genetic abnormalities or differentiation[9][12]
• Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) — subclassified into B-cell and T-cell lineages with numerous genetic subtypes[10][13]
• Chronic lymphocytic leukemia (CLL) — now classified among lymphoid neoplasms but historically grouped with leukemias[14]
• Chronic myeloid leukemia (CML) — defined by the BCR::ABL1 fusion[9]

Relevant Aliases

• Myeloid sarcoma (formerly granulocytic sarcoma or chloroma): an extramedullary tumor of immature myeloid cells that may present in the jaws or oral soft tissues, occurring de novo or in association with AML, CML, or myeloproliferative neoplasms. The older term "chloroma" refers to the green color sometimes imparted by myeloperoxidase in the tumor.[15][16][17][18]

The FAB (French-American-British) classification, based solely on morphology, is now considered obsolete for clinical decision-making but may still be encountered in older literature.[19][20]

• Leukemia is the most common cancer in children, accounting for approximately 28% of pediatric malignancies; ALL predominates in childhood (approximately 70% of pediatric leukemia), with a peak incidence at ages 1–4 years.[14][21][22]
• In adults, AML is the most common acute leukemia, and CLL is the most common leukemia overall in high-income countries; median ages at diagnosis are 17 years for ALL, 65 for CML, 68 for AML, and 70 for CLL.[14][21]
• Males are affected more frequently than females across all subtypes.[21][23][24]
• Oral manifestations are reported in more than 30% of patients with newly diagnosed acute leukemia. Gingival enlargement, the most recognized oral sign, is present in only approximately 6% of newly diagnosed cases, though it is more common in monocytic subtypes of AML.[3][6][25]
• Jaw involvement by leukemic infiltration or myeloid sarcoma is uncommon; the oral cavity accounts for a minority of extramedullary myeloid sarcoma sites, with only approximately 37–38 reported oral cases in cumulative literature reviews.[26][27]

Systemic Presentation

Patients typically present with constitutional symptoms (fatigue, fever, weight loss) related to bone marrow failure — anemia, thrombocytopenia, and neutropenia.[2][12] Hepatosplenomegaly and lymphadenopathy are common in ALL; gingival infiltration is more characteristic of AML, particularly the monocytic subtypes.[2]

Oral Manifestations

• Gingival enlargement: Diffuse, boggy, erythematous to deep purple swelling of the interdental papillae, marginal, and attached gingiva, caused by direct leukemic cell infiltration; characteristically disproportionate to the amount of local plaque. Most common in acute monocytic and myelomonocytic leukemia but can occur in any subtype.[3][28][29][30]
• Gingival bleeding: Common, occurring as an initial oral sign in approximately 18% of acute leukemia and 4% of chronic leukemia; results from thrombocytopenia and clotting factor deficiencies.[29][31]
• Mucosal petechiae and ecchymoses: Reflect thrombocytopenia.[1][32]
• Oral ulceration: Due to neutropenia and secondary infection.[1][31]
• Mucosal pallor: Reflects underlying anemia.[1][32]
• Numb chin syndrome (mental nerve neuropathy): Occasional; results from leukemic infiltration of the inferior alveolar nerve or mandibular bone.[7][33]
• Myeloid sarcoma (granulocytic sarcoma): Presents as a firm, localized soft-tissue mass in the gingiva, palate, or alveolar mucosa; may be the initial manifestation of AML or a sign of relapse.[15][34][35]

Red Flags

Rapidly progressive gingival enlargement disproportionate to local factors, spontaneous oral bleeding, and unexplained tooth mobility — particularly in a patient with constitutional symptoms — should prompt urgent hematologic evaluation including complete blood count and peripheral smear.[29][36] Notably, initial blood counts may occasionally be normal, and gingival enlargement can be misdiagnosed as inflammatory periodontal disease.[36]

Radiographic findings in the jaws are variable and nonspecific; many patients with leukemia have no detectable jaw changes on dental imaging. When present, findings reflect leukemic infiltration of the marrow space, periapical tissues, or periodontal structures, or the secondary effects of marrow failure on bone homeostasis.[4][5]

Location and Distribution

• Leukemic jaw involvement may affect the mandible, maxilla, or both, with no consistent site predilection.[4][5][37]
• Lesions may be solitary or multifocal; multifocal involvement of the jaws and calvarium simultaneously has been reported, particularly in ALL.[37][38]
• In children with ALL, skeletal radiographic changes (including the jaws) may be part of widespread skeletal involvement that includes the long bones, spine, and skull.[38]

Periphery and Shape

• Osteolytic lesions are characteristically ill-defined and non-corticated, with ragged or moth-eaten margins reflecting aggressive, permeative bone destruction.[37][39]
• Occasionally, well-defined, punched-out radiolucencies resembling those of Langerhans cell histiocytosis or multiple myeloma may occur, particularly in ALL.[37]
• Mixed osteolytic and osteoblastic lesions are rare but reported, particularly in childhood AML.[40]

Internal Architecture

• Affected areas show loss of normal trabecular pattern with replacement by a diffuse radiolucency reflecting marrow infiltration by leukemic cells.[4][5]
• Generalized osteopenia or reduced bone density of the jaws may be present, reflecting diffuse marrow replacement.[5][38]
• A "ground-glass" or washed-out appearance of the trabecular bone has been described in some cases.[5]

Effects on Teeth and Adjacent Structures

• Loss of the lamina dura: A characteristic early finding; may be localized or generalized, reflecting leukemic infiltration of the alveolar bone surrounding the teeth.[3][4][5]
• Widened periodontal ligament space: Results from leukemic cell infiltration of the periodontal ligament and adjacent alveolar bone.[4][5]
• Alveolar bone loss: Rapid, severe destruction of alveolar bone extending to the apical thirds of teeth has been reported, mimicking aggressive periodontitis.[3][33]
• Tooth displacement: Developing teeth may be displaced by expanding leukemic infiltrates within the jaw.[7]
• Root resorption: Occasional; external root resorption may occur adjacent to areas of leukemic infiltration.[4]
• Periapical radiolucency: Leukemic infiltrate may accumulate in the periapical region, mimicking endodontic pathology; pulp vitality testing is essential to distinguish infiltrative from inflammatory periapical disease.[41]

Cortical Involvement and Extent

• Cortical destruction and erosion may occur with advanced infiltration; loss of the cortical outline of the inferior alveolar canal has been described as a sign of mandibular infiltration.[7]
• Cortical expansion is uncommon but may be seen with myeloid sarcoma presenting as a localized jaw mass.[26][42]
• Extension into the maxillary sinus has been reported in cases of maxillary involvement.[40]

Variants and Special Patterns

• Myeloid sarcoma in the jaws: Presents as a localized destructive radiolucency, sometimes with cortical expansion, in the alveolar bone or jaw body; may precede systemic evidence of leukemia.[15][26][35]
• Childhood ALL skeletal pattern: Diffuse osteopenia, metaphyseal lucent bands (in long bones), and multiple punched-out lytic lesions of the skull and jaws; the jaw component may closely mimic Langerhans cell histiocytosis.[37][38]

PET/CT

FDG-PET/CT may demonstrate increased uptake in areas of jaw involvement and is useful for assessing the extent of extramedullary disease. In a reported case of childhood AML presenting with maxillary lesions, PET/CT showed enhanced FDG uptake in the right maxillary sinus and diffuse uptake throughout the entire bone marrow, confirming systemic disease; uptake resolved after successful chemotherapy.[40]

MRI

On MRI, myeloid sarcoma masses are typically isointense to muscle on T1-weighted images and mildly hyperintense on T2-weighted images, with homogeneous contrast enhancement.[43][44] MRI is superior to conventional radiography for detecting marrow infiltration and assessing soft-tissue extension of jaw lesions.[44][45]

CT

On medical CT, granulocytic sarcoma appears as soft-tissue-density masses, isodense to muscle, with variable enhancement; cranial involvement characteristically affects the orbit.[43][46] CT is useful for delineating cortical destruction and sinus involvement in maxillary lesions.[40][46]

When leukemic jaw involvement produces multifocal or solitary osteolytic lesions, the radiographic differential includes other aggressive processes that destroy alveolar and jaw bone. The clinical context — particularly the patient's age, systemic symptoms, and hematologic status — is critical for narrowing the differential.

The highest-risk diagnostic pitfall is misinterpreting leukemic gingival or alveolar infiltration as inflammatory periodontal disease, particularly when initial blood counts are normal.[36] Any rapidly progressive, treatment-refractory periodontal destruction — especially with constitutional symptoms — warrants urgent complete blood count with differential and hematology referral; biopsy of gingival or osseous lesions with immunohistochemistry confirms the diagnosis.[28][36]

Gingival and Soft-Tissue Infiltration

Biopsy of involved gingiva or oral soft tissue reveals dense sheets of immature blast cells infiltrating the connective tissue, often with a perivascular distribution.[28][30] In AML, the infiltrate consists of myeloblasts or monoblasts; in ALL, lymphoblasts predominate. Immunohistochemistry and flow cytometry are essential for lineage determination.[19][30]

Myeloid Sarcoma

Myeloid sarcoma shows a diffuse infiltrate of immature myeloid cells ranging from well-differentiated (with recognizable granulocytic maturation and eosinophilic myelocytes) to poorly differentiated or blastic forms that lack morphologic evidence of myeloid origin.[16][47] The poorly differentiated variant is frequently misdiagnosed as non-Hodgkin lymphoma.[16][48]

• Key immunohistochemical markers: CD43 and lysozyme are the most sensitive markers, positive in virtually all cases. Myeloperoxidase (MPO) is highly specific but less sensitive, particularly in blastic variants. CD68 is positive in the majority of cases. CD34 and CD117 mark immature myeloid progenitors and are variably expressed.[47][48][49][50][51][52][53]
• Recommended diagnostic panel: An immunohistochemical panel including MPO, CD43, CD68, and CD20 (to exclude B-cell lymphoma) can identify the vast majority of myeloid sarcomas in paraffin sections.[47]
• Chloroacetate esterase (Leder stain): A cytochemical stain that highlights granulocytic differentiation; useful as an adjunct but less sensitive in blastic tumors.[16][48]
• Cyclin D1: Recently shown to be absent in myeloid sarcoma but strongly positive in malignant histiocytic neoplasms, providing a useful discriminator in morphologically ambiguous cases.[54]

Radiologic-Pathologic Correlation

Periapical radiolucencies caused by leukemic infiltration are histologically distinct from inflammatory periapical pathology: the infiltrate consists of blast cells rather than granulation tissue, and the associated tooth typically tests vital on pulp testing.[41]

Pre-Treatment Dental Evaluation

Current MASCC/ISOO guidance recommends thorough dental assessment before initiation of chemotherapy, hematopoietic cell transplantation, or CAR T-cell therapy.[8] The goals are to prevent oral infection, systemic pathogen dissemination, and treatment interruptions.[8][55]

• Acute oral foci of infection should be eliminated before chemotherapy when time permits; chronic asymptomatic dental pathology can generally be deferred until hematologic treatment is completed.[55]
• Apical radiolucencies and severe periodontitis are considered the highest-priority conditions for pre-chemotherapy elimination.[56]
• Oral hygiene instruction and preventive care (bland rinses, topical fluorides) should be initiated before therapy.[8][57]

Definitive Treatment

Treatment of leukemia is systemic and subtype-specific:

• AML: Intensive induction chemotherapy (typically cytarabine-based regimens), followed by consolidation and, in many cases, allogeneic hematopoietic stem cell transplantation.[12][32]