Isolated Relapse in the Oral Cavity of a Child with T-lineage Acute Lymphoblastic Leukemia

Acute leukemias are the most common malignancy in childhood. They represent approximately 30% of malignant diseases in patients under the age of 15 years. Acute lymphoblastic leukemia (ALL) is the most frequent type of leukemia in children (1-3). Leukemia etiology remains unknown and seems to involve both genetic mechanisms and environmental factors. Its clonal origin is well established. Disorganized proliferation of a single progenitor cell disturbs hematopoiesis (2,3). Clinical manifestations are due to the inhibition of hematopoiesis by leukemic cells and to leukemic infiltration in several organs and systems. Anemia, secondary to decreased red blood cell production, bleeding due to thrombocytopenia and infections due to neutropenia are the cardinal manifestations. Infiltration of organs results in hepatomegaly, splenomegaly and lymphadenopathy. Isolated Relapse in the Oral Cavity of a Child with T-lineage Acute Lymphoblastic Leukemia


INTRODUCTION
Acute leukemias are the most common malignancy in childhood.They represent approximately 30% of malignant diseases in patients under the age of 15 years.Acute lymphoblastic leukemia (ALL) is the most frequent type of leukemia in children (1)(2)(3).
Leukemia etiology remains unknown and seems to involve both genetic mechanisms and environmental factors.Its clonal origin is well established.Disorganized proliferation of a single progenitor cell disturbs hematopoiesis (2,3).Clinical manifestations are due to the inhibition of hematopoiesis by leukemic cells and to leukemic infiltration in several organs and systems.Anemia, secondary to decreased red blood cell production, bleeding due to thrombocytopenia and infections due to neutropenia are the cardinal manifestations.Infiltration of organs results in hepatomegaly, splenomegaly and lymphadenopathy.

Isolated Relapse in the Oral Cavity of a Child with T-lineage Acute Lymphoblastic Leukemia
Leukemic infiltration in the central nervous system (CNS) and testes are also common events.ALL diagnosis is confirmed when more than 25% of leukemic cells are detected in bone marrow aspiration.Immunophenotyping, molecular and cytogenetic tests are useful to characterize the leukemic cells and also have prognostic value (1).ALL treatment involves long-term chemotherapy, which has in the last decades undergone striking advances, leading to the current mark of around 80% of children and adolescents with ALL achieving cure (3).Despite these high cure rates, approximately 20% still have disease relapse (3), with bone marrow as the most frequent site, followed by the CNS (3)(4)(5).Nevertheless, relapse can occur in any tissue or organ.
Isolated recurrence in the oral cavity is extremely uncommon in ALL.Few case reports were found in a literature review, mostly in adolescents or adult patients who had histologically proven lesions in the oral cavity months or years after the end of the leukemia treatment.
The purposes of this paper are to report a case of isolated recurrence in the oral cavity of a child with T-lineage ALL and highlight the relevance of dental care during and after chemotherapy for ALL.

CASE REPORT
A 4-year-old male child was first diagnosed with T-lineage ALL and treated according to the protocol of the Brazilian Group for Leukemia Treatment in Childhood ALL-99 (GBTLI-LLA99) for patients with high-risk for recurrence (10), relapsing at the age of 8.At diagnosis karyotyping of bone marrow (BM) cells showed no metaphases for analysis.Dental monitoring was done during the whole treatment.
One year and four months after the end of the treatment, the child had swelling and pain in the oral cavity, in the right maxilla, with no other clinical or hematological signs or symptoms.The extraoral evaluation revealed swelling on the middle third of the right side of the face, with no signs of inflammation, causing facial asymmetry.Oroscopy showed swelling in the vestibular region of the primary maxillary right first and second molars and the permanent maxillary right first molar.The swelling extended further anteriorly into the palatal mucosa.The involved teeth had abnormal mobility and no caries.The swelling was firm and painful upon palpation and was covered by intact mucosa.Panoramic radiograph image showed radiolucent area involving an unerupted tooth and the presence of radiodensity on the right maxillary sinus (Fig. 1).
An incisional biopsy of the lesion was performed.The histological diagnosis confirmed oral mucosa infiltration by lymphoid precursor neoplastic T-cells.Histochemically they were positive for BCL-2, cytoplasmatic CD3 (polyclonal), CD45/LCA, CD99, and irregularly positive for TDT (polyclonal).Bone marrow aspiration and cerebrospinal fluid examination did not show evidence of leukemia infiltration.Computed tomographs of chest, sinuses, neck, abdomen, and pelvis were all negative for other organ infiltration.Gingival lesion spontaneously remitted soon after biopsy.Watchful waiting (no treatment) was adopted in view of the spontaneous regression and no signs of infiltration in other organs and systems.
Five months after the initial manifestation in the oral cavity, mild leukopenia and neutropenia were detected, without any other clinical or laboratory manifestations.Bone marrow aspiration showed infiltration by lymphoblasts with T-immunophenotype.Karyotype of bone marrow cells was 46, XY, t (10; 11) (p11; q13) [14]/46, XY [16].No CNS infiltration was detected.Relapse treatment was started according to the GBTLI-LLA 2009 chemotherapy protocol for T-immunophenotype ALL.The child has been in remission now for 25 months, with no changes in the oral cavity.He is scheduled to receive additional maintenance therapy in up to 34 months.An HLAmatched donor has not been identified yet for eventual bone marrow transplantation.Regular dental follow-up has been maintained.

DISCUSSION
Dental monitoring of patients with leukemia during and after treatment is extremely relevant for early detection and appropriate treatment of diseaserelated lesions and side effects of chemotherapy (6,11).The oral cavity in leukemia is prone to complications  ranging from exacerbation of pre-existing pathological conditions to new mucosal lesions and infections (11)(12)(13).
Lesions resulting from infiltration of oral tissues by leukemia cells may occur in the gingival tissues or less frequently in the alveolar bones.These are less common in ALL than in the myeloid subtypes (14).
Very few relapses of ALL in the oral cavity of children have been reported (16,17).Most cases refer to adolescents and adult patients (Table 1).Nonspecific clinical manifestations -swelling and pain in the gingiva -were detected in the present report.Evaluation by an oral and maxillofacial surgeon, lesion biopsy, and immunohistochemical study were essential for the correct diagnosis, as also reported by many authors.
Relapse treatment can be done with combined chemotherapy, radiotherapy or bone marrow transplantation (BMT), whether autologous or allogeneic.Treatment results are usually unsatisfactory, since most institutions do not have standard treatment protocols for this type of relapse and the best therapy has not yet been defined.The option should take into consideration the prognostic factors for survival of children with relapse (4,5,18).The patient referred to in this report had unfavorable prognostic factors such as bone marrow infiltration and T-immunophenotype.Children with isolated extramedullar relapse usually have a better prognosis than those with medullar involvement and patients with T-ALL had unfavorable outcome in several studies (5).Many papers demonstrated that the duration of the first remission is the most significant variable to influence an event-free survival.Children with late relapses have better prognosis than those with early recurrences.The reported case can be classified as of late recurrence, since it occurred three years after the initial diagnosis (4,5,18).
Spontaneous local remission and absence of infiltration in other organs led to the initial approach of "watchful waiting".As in most of the reported cases (6-9), bone marrow infiltration occurred shortly after relapse in the oral cavity.Systemic chemotherapy was chosen, so far with favorable results.
In summary, even considering that ALL is curable in about 80% of the children, the challenge remains in trying to avoid relapses and in treating the relapsed child.As shown in the literature, new recurrences are the main obstacle for curing a significant number of patients.Isolated relapses in the oral cavity are rare and may precede bone marrow infiltration.Dental monitoring and investigation of lesions in this region are extremely relevant for an integral approach to the child with ALL and for early detection of disease relapse.

Figure 1 .
Figure 1.Radiographic features of child with acute lymphoblastic leukemia: panoramic radiograph showing radiolucent lesion near the unerupted permanent mandibular left canine and presence of radiodensity of the right maxillary sinus.

Table 1 .
Case reports of leukemia relapse in the oral cavity reported in English-language data literature from 1983 to date.