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Corresponding author. Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University 5 Fu-Shin Street, Kwei-Shan, 333, Taoyuan, Taiwan.
and the early identification of these cases is of interest. Herein, we report a case of bilateral parotid gland swelling as an uncommon extramedullary manifestation preceding the clinical onset of ALL.
A 17-month-old boy presented with a 4-week history of bilateral parotid gland swelling. Physical examination showed non-tender, fixed masses in bilateral parotid regions and marked hepatosplenomegaly. Diagnostic laboratory studies showed white blood cell (WBC) counts 142.7 × 109/L with 92.4% blasts, hemoglobin 51 g/L, platelets 13 × 109/L, lactate dehydrogenase 914 U/L, and uric acid 0.106 g/L. Soft tissue ultrasound revealed bilateral swollen parotid glands (Fig. 1) and multiple cervical lymphadenopathies. Abdominal ultrasonography revealed hepatosplenomegaly and nephromegaly. He was consequently diagnosed with ALL harboring P2RY8-CRLF2 rearrangement. Pathological evidence could not be obtained, as a surgical biopsy of the parotid gland is not recommended due to the risk of seeding in case of malignancy, violation of tissue planes, fistula formation, and facial nerve damage. The swelling resolved after chemotherapy.
Figure 1Bilateral masseteric hypertrophy in a 17-month-old boy. (a) Clinical photography shows broad, smooth cheek bulges (left more than right). (b) Soft tissue echography demonstrated bilateral prominent parotid glands.
Bone marrow analysis was positive for CD10, CD19, CD22, and cCD79a but negative for myeloid-lineage or T-lineage markers. Cytogenetic analysis of GTG banded metaphases revealed 46 XY chromosomes with deletion of 9p21, monosomy 16, and trisomy 22 in all dividing cells. Total RNA sequencing of the bone marrow specimen further confirmed the presence of the P2RY8-CRLF2 fusion along with overexpression of CRLF2. The high WBC count and P2RY8-CRLF2 fusion gene raised significant suspicion for Ph-like ALL. Ruxolitinib was prescribed to exert a synergistic effect with standard-of-care drugs used in treating ALL. As of September 2022, the patient had achieved 6 months of continuous complete remission with a Lansky score of 100.
CRLF2 is located on chromosomes Xp22.3 and Yp11.3 and, along with the IL7R alpha (IL7RA) unit, forms the thymic stromal lymphopoietin receptor. Genomic rearrangements of the CRLF2 gene result in overexpression of CRLF2 itself, leading to JAK2-mediated activation of STAT5, which promotes B cell precursor proliferation and a high rate of disease relapse. These cases show an interstitial deletion of the PAR1 gene family on Xp22.3 and Yp11.3, which juxtaposes CRLF2 to the promoter of the P2RY8 gene. Rearrangements of CRLF2 are identified in 50% of Ph-like ALL patients. It was essential to recognize and identify these cases at the presentation.
Bilateral parotid involvement as an initial presentation of ALL has rarely been reported.
To our knowledge, this was the first case linking bilateral parotid swelling with CRLF2 overexpression. The etiology of parotid swelling remains unclear since pathological evidence was lacking in all the previous literature. Theoretically, leukemic cell infiltration of the affected organs could be the cause.
Intuitively, high CRLF2 expression was linked to poor survival among ALL cases. Ph-like ALL when identified should be perceived as a distinct, high-risk entity, and future research on improving treatment approaches is required in our locality. Physicians should be aware of the possibility of extramedullary manifestation of ALL with CRLF2 overexpression.
Conflicts of interest
The authors declare no conflicts of interest.
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