MYCN, THE DECISION MAKER

Risk stratification involving MYCN mutations is crucial to tailor-make treatment for neuroblastoma

MYCN, THE DECISION MAKER

Neuroblastoma is a rare paediatric cancer that affects immature nerve cells, typically in infants and children under the age of 5. It can occur in multiple locations, but most commonly occurs in and around the adrenal medullary tissue. Typically, afflicted children present with an abdominal mass, and may or may not show additional symptoms such as tiredness, weakness and pain. Prognostic factors, including the age of the child, the metastasis of the cancer, the histological appearance of the cancer cells and certain chromosomal/genetic abnormalities in the cancer cells are used to stratify patients into very low, low, intermediate, and high-risk groups, based on the International Neuroblastoma Risk Group (INRG) classification system. Treatment is then based on the risk group stratification.

Dr Swati Kanakia, Paediatric Hematologist Oncologist at Lilavati Hospital and Research Center, Mumbai, shared two neuroblastoma cases to showcase the importance of multiple tests in ensuring appropriate treatment for good outcomes.

The first case is of a 4-month old female child, Meera (name changed). An abdominal mass was picked up during a routine 2-month paediatric checkup. She was advised to get an abdominal ultrasound for further investigation. The parents were however not able to take Meera for further investigation immediately. They returned to the paediatrician a month later when the mass had grown bigger and an ultrasound was finally done. The ultrasound detected a large solid solitary retroperitoneal mass in the left paravertebral region. A urinary test showed the presence of vanillylmandelic acid (VMA), suggestive of neuroblastoma. Meera’s parents opted to immediately have the mass surgically removed via laparoscopy. The tumour was completely removed (R0 resection) and sent for pathological examination. Histological investigation showed poorly differentiated neuroblastoma with a favorable histology. Several other tests were also performed post-surgery to stratify the risk and customize additional treatment. 68Ga-DOTATATE tracer uptake is very specific for somatostatin receptors and a sensitive assay to determine the presence of cancer cells. No tracer uptake was observed anywhere, indicating that the cancer had not metastasized. Multiplex ligation-dependent probe amplification (MLPA) testing revealed somatic gene mutation within the tumour. There were some gains in chromosome 17p, 17q, 2p and 2q. While the significance of these chromosomal aberrations is still not defined, the absence of amplification in the MYCN gene was good prognosis for Meera. A repeat urinary test done at 4 months post-surgery also revealed normal VMA levels. Thus, Meera was stratified into a low-risk group and not offered any further treatment. She is however advised to come in for regular follow ups every 3 months.

The second case is of 13-month old Raj (name changed), who was visiting his paediatrician for a routine checkup as well, when the paediatrician identified a large mass in the abdomen. An ultrasound showed the presence of a large mass over the adrenal gland and urinary tests indicated high VMA levels. It was not advisable to immediately operate on him to surgically remove the tumour as the growth was considerably large and encasing the aorta. Therefore, a biopsy was done for histological assessment, which confirmed the presence of neuroblastoma. 68Ga-DOTATATE tracer uptake indicated tracer uptake to at least one distal location in the cortical bone, indicating that the tumour had spread. Further, a CT scan also revealed 3 image defined risk factors, including the encasement of the aorta. An MLPA testing showed an amplification of the MYCN gene. Thus, although Raj would normally have been stratified in the intermediate risk group based on age and metastatic disease, the amplification of MYCN pushed him into the high-risk group and he had to undergo intensive chemotherapy as treatment.

He was started on a rapid COJEC induction schedule, comprising chemotherapeutic agents cisplatin (C), vincristine (O), carboplatin (J), etoposide (E), and cyclophosphamide (C). This schedule is administered in 15-day cycles and is completed over a period of 72 days. Human recombinant granulocyte colony stimulation factor (GCSF) has been shown to be beneficial to raise neutrophil counts and prevent infections and is recommended after such high-intensity chemotherapy schedules. Therefore, Raj was also given GCSF injections after each chemo cycle. After the rapid COJEC was completed, the tumour was surgically removed and a repeat DOTATATE was done, which showed no uptake anywhere. A second, highly intense myeloablative chemotherapy session which destroys not only the cancer cells but also normal cells in the body was required. To get around the destruction of normal cells, an autologous bone marrow transplantation was done after this second chemotherapy session. Raj’s bone marrow was harvested prior to the chemotherapy session and then transplanted back after the session was completed.

Newer treatment options include anti-GD2, a monoclonal antibody that specifically targets GD2 found on neuroblastoma cells and is often part of the treatment regime for high-risk neuroblastoma patients post the autologous bone marrow transplantation. However, it is not yet available in India. Currently, Raj is in the post-bone-marrow-transplant stage and is recuperating well.

Dr Kanakia stresses the need to appropriately risk stratify patients to

tailor-make therapy. While the importance of MYCN mutations are critical in deciding the risk group such that MLPA test results may completely alter the treatment route provided to a child with neuroblastoma, there may also be other chromosomal abnormalities that may eventually be associated with neuroblastoma. Newer methods of diagnosis truly impact therapeutic decisions and can be game changers as illustrated in this case.

 

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