Classical presenting symptoms in a child diagnosed with a Neuroblastoma are stomach pain, abdominal distention, and a hard painless neck mass (1). The patient can also present with opsoclonus-myoclonus syndrome, known as “dancing eyes, and dancing feet” syndrome (2). The age of onset in children is usually before the age of 5 (2). KB’s main presenting symptoms was recurrent fever which is a very non specific symptom and carries a wide differential. Her initial presentation was attributed to a urinary tract infection and subsequent visits were attributed to respiratory infection. It was not until the patient had developed worsening abdominal and back discomforts and developed anorexia and weight loss that additional investigations were undertaken. KB’s initial working diagnoses included a viral illness such as mononucleosis or atypical pneumonia. However upon more rigorous physical examination was undertaken the findings of a supra-clavicular mass and abdominal mass changed the direction of diagnostic investigations. With a conformation of a large supra renal mass and the finding of elevated urinary catecholamines, the differential placed Neuroblastoma high on the list. The confirmatory diagnosis of a Neuroblastoma was made by left supra-clavicular mass biopsy along with bilateral bone aspiration/biopsy with pathology confirming an undifferentiated Neuroblastoma. Genetic analysis of the biopsy showed that the neuroblastoma had increased MK1 (midkine 1), a protein in human that functions in activities such as angiogenesis, cell migration and cell proliferation (3), but N-MYC, a proto-oncogene protein associated with more aggressive Neuroblastoma, was not found to be amplified, however there was a deletion in chromosome 11, which has shown to be seen in familial and sporadic cases of Neuroblastoma.
Management Plan Since Admission
Current Medical Management:
Upon diagnosis, KB was referred to Crumlin Children’s Hospital in Dublin and was given a diagnoses of a high-risk stage 4 metastatic Neuroblastoma. She was started on a 18 month care plan which included induction chemotherapy, attempted surgical excision of the mass, high dose chemotherapy, radiotherapy, stem cell rescue and immunotherapy. KB’s management plan is following a randomized study of the European SIOP Neuroblastoma Group (SIOPEN) in high risk neuroblastoma cases (4). On July 18, 2017, KB began her first round of induction of chemotherapy.
Psycho-Social Support:
One of the most important aspects when managing a paediatric oncology patient is providing psycho social support not only for the patient but for the family as well. This support requires a multidisciplinary team with includes the treating physician, specialized physicians, psychologist and/or psychiatrists, nursing staff, social workers, teachers and resources such as the Childhood Cancer Foundation and the Irish Cancer Society. It is important to realize that the family of KB, face a emotional and challenging situation when someone they love is diagnosed with cancer. This illness can challenge the relationship between the siblings and the parents and may throw off the balance of the family (5). The immediate and extended family needs be given knowledge about this type of cancer and the active and instant treatment that follows its diagnosis. The parents of KB will need assistance in not only caring for their ill child but also for providing care for their other children. Support groups that offer interaction and participation involving the siblings of KB need to be used, as well as parent only support groups. Regarding the patient, children suffering from an aggressive cancer such as a Neuroblastoma, need help to understand their illness. It will then be important to help them accept and understand the intense and sometime invasive treatments that they will be going through in order to treat there illness. They must always be encouraged to look to the future with optimism and hope.
Follow Up:
July- November 2017: Continue treatment of induction chemotherapy at Crumlin Children’s Hospital in Dublin. 10 day cycles for 70 days. Continue support for patient at Letterkenny General Hospital.
Letterkenny General Hospital
November 3, 2017: Patient maintained in a isolation environment, with close monitoring for any signs of infection or bleeding. KB appeared well and was sitting up in bed. The patient had gum-bleeding and was afebrile. Management is to continue fluids.
November 4, 2017: KB appeared flat and ill with a new onset of stomatitis. She had poor appetite she was given IV maintenance fluids and an feeding NG was inserted to aid enteral nutrition. Temp: 37 C HR: 114 RR: 18.
November 5, 2017: Patient appeared stable and was sleeping.
November 6, 2017: KB was complaining of abdominal pain and nausea. Chemistries showed reduced magnesium and potassium levels and replacement was undertaken with Mg2+ sulfate and Potassium chloride intravenously.
November 11, 2017: KB was allowed to go home for two nights as she was feeding well and her full blood count has been improving. Patient is being sent to Crumlin Children’s Hospital on Monday November 13, 2017 for a reassessment of her tumor progression and to initiate peripheral blood stem cell harvest and complete excision of the primary tumor to be attempted as outlined in her care plan.
Discussion
To understand this case we must look at the genesis of such a tumor, the associated risk factors and the staging for paediatric Neuroblastomas. A Neuroblastoma is the most common cause of a solid tumor in the adrenal medulla in children. The word “Neuroblastoma” is commonly used to define many different neuroblast tumors which have the ability to secrete catecholamines because they arise from the primitive sympathetic ganglion cells (6). These tumors consist of Neuroblastomas, Ganglioneuromas, and Ganlioneuroblastomas (6). A common misconception about Neuroblastoma is that the origin of the tumor arises from the primitive sympathetic ganglion cells in the adrenal medulla. However Neuroblastoma may originate in any area along the sympathetic nervous cells, such as the abdomen, the spinal cord, or the chest (7). It has been established that a vast majority of Neuroblastomas are secreting tumors. The tumor, because of its origin from neural crest tissue and neuroendocrine properties, has the ability to secrete catecholamines such as norepinephrine and dopamine (8). These hormones create some of the classical symptoms seen in patients, such as early onset hypertension, tachycardia, and flushing (8). However these symptoms are not present in all patients, such as KB, because there is a broad difference in the type of catecholamines which are secreted as well as a difference in the metabolic bi-products that are found in the urine (8). Catecholamines tested from a patients urine sample is a diagnostic tool when suspecting a neuroblastic malignancy. The raised catecholamines seen in this case were HMMA and HVA, which are derived from the break down of dopamine, norepinephrine, and epinephrine respectively (8).
There are two main staging guidelines for Neuroblastoma. The first guideline for staging is outlined in the International Neuroblastoma Risk Group Staging System (INGRSS). It divides the tumor into two specific categories, either localized or metastatic. Localized tumors are classified as L1 and L2 and the two stages of the metastatic disease are classified M and MS (9). Data relating to the presence or absence of image defined risk factors (IDRF) are needed for this staging system. The staging can be further outlined in the table 1 below.
Table 1 (10):
A list of the IDRF that one may be looking for when staging a neuroblastic tumor can be further outlined in table 2 below.
Table 2 (10):
Another staging system which can be used in staging a Neuroblastoma is the International Neuroblastoma Staging System (INSS). This system takes into account the results of surgery to remove the tumor compared to the previous staging system, INGRSS (11). The INSS was used to stage KB in this case. Her Neuroblastoma was staged as a Stage 4 Neuroblastoma. The stages of the INSS are seen in table 3 below.
Table 3 (11):
The imaging that is required for optimal staging of a neuroblastoma includes CT and MRI. Ultrasound, used to diagnose the patient as in this case, is often the initial radiologic study in the evaluation of abdominal mass in a child (6). Computed tomography or magnetic resonance imaging is used when evaluating the suspected tumor, and is used to evaluate the primary tumor site and nodal spread. The patient may also need imaging of chest and pelvis if a retroperitoneal primary tumor is suspected as it may also extend into these spaces. A scan that is now currently being utilized to specifically evaluate Neuroblastoma is scintigraphic imaging utilizing the I123-MIBG scan (6). MIBG is an analog of norepinephrine that can be labeled with radioactive iodine and then imaged. This chemical analog will selectively concentrate in sympathetic nervous tissues such as a neuroblastoma (6). When bone metastases are expected bone marrow aspirant and biopsy are necessary, as seen in this case with KB. Additionally imaging of the cranium also needs to be considered if clinically indicated by symptoms
As mentioned above, the average onset age for patients diagnosed with a Neuroblastoma is children less than 5 years old. It becomes an increasingly rare diagnosis in children older than 10 (12). Age of diagnosis is important when looking at the behavior of the tumor itself. In most cases diagnosed with a Neuroblastoma in-utero or in infancy, the tumor is more likely to spread less aggressively and many become benign. Compared to children with a late diagnosis, ages 2-5, the tumor tends to spread more aggressively and is more likely to metastasize to vital organs (2). This changes the prognosis of the patient dramatically. As seen in KB’s case, she was diagnosed with a later onset neuroblastoma at the age of 5. This put her at a risk of developing a far more aggressive tumor. Screening programs for Neuroblastomas are being developed as the outcome is significantly increased if detected in younger patients with localized disease. Several screening studies for Neuroblastoma in infancy have started by screening for urinary catecholamines at birth (6). There results showed that the screening led to more Neuroblastoma being diagnosed, however many of the tumors presumably would have had spontaneous regression and never would have presented clinically. The study showed that even with early onset screening there was no decrease in the incidence of high-risk tumors in children older than one years old (6). The final recommendation given by these studies was that screening for catecholamines at a young age did not reduce the mortality of patients suffering from high risk neuroblastoma malignancy and that universal screening for catecholamines in infants is not recommended (6).
When looking at the risk factors that may contribute to the development of Neuroblastoma in young children it often stems from a combination of clinical, pathologic and genetic factors. One of the classic genetic markers that is looked for upon diagnosis is the proto-oncogene N-MYC which is encoded by the MYCN gene. The MYCN gene is a member of the MYC transcription factors which encode for the protein N-MYC which is increasingly expressed in the fetal nervous system and brain (13). This genetic marker was negative in KB’s case however there was a deletion in chromosome 11, which is another genetic marker looked at when assessing risk. Germline deletions at 11q14-13 locus are found somatically in familial and sporadic Neuroblastoma (14). Seeing as there is no family history of early onset malignancies in KB’s background makes the diagnosis of a sporadic malignancy related to a genetic mutation a likely cause.
In this case it is instructed to look at the patients presenting symptoms before her diagnosis was made, in order to see the entire clinical picture. Neuroblastomas typically present obscurely, as exemplified in KB’s case, and often mimic other conditions. It is thought that the location of pain or discomfort associated with malignancy is related to where the tumor originates. The clinical symptoms in this case were vague which made a diagnosis difficult. The patient first presented with what seemed to be a pyrexia of unknown origin. This brings to question if the underlying malignancy was the source of pyrexia or if it was related to other concomitant conditions such as respiratory and urinary tract infections. Pyrexia of unknown origin is a symptom which is commonly linked to childhood neoplasms such and lymphoma, leukemia and Wilms tumor (15). While this may be a common symptom is a less common symptom with a presenting Neuroblastoma. However it must also be taken into account that KB presented with a an advanced stage of malignancy, and an unexplained fever is common in disseminated disease (15). Another interesting aspect of this case was how KB presented to the Emergency Department and to her GP on multiple occasions in the months leading up to her diagnosis. As seen in her past medical history, KB had an recent infection with Varicella Zoster in June 2017. It poses an interesting thought about whether the development of the Varicella Zoster Virus could be related to her Neuroblastoma, as Varicella is a highly specific herpesvirus targeting the sensory ganglionic neurons (16). KB’s presenting symptoms show how undefinable a Neuroblastoma can be to diagnosis. This case showed how a variety of symptoms from fever to abdominal pain can mimic common childhood illnesses and viruses but serious conditions such as Neuroblastoma always need to be considered as part of the differential diagnosis.
Reflection
This was a complex case that resulted in an unfortunate diagnosis in this young child. It showed an example of how common presenting symptoms in paediatrics patients, such as a fever and abdominal pain, must be taken seriously and fully evaluated and examined. This case showed me how a serious illness such as a Neuroblastoma, can present in a paediatric population and how difficult certain diagnosis can be and how easy it is to be mislead by common complaints. This case will help improve my future practice in medicine by demonstrating how important detailed and systematic physical examination is in formulating differential diagnosis. It was also instructive in complex management of not only medical but psychosocial aspects of the disease not only for the patient but for surrounding family. This case showed how multidisciplinary care involved in treating childhood cancer is extremely important. The more the physician, patient, and family understands about the situation and treatment options surrounding the disease, the more helpful it will be to keep the patient-doctor relationship in harmony. It was heartbreaking to see how poor the prognosis is in metastatic Neuroblastoma, but it shows how continued research into early diagnosis and identification of risk factors are greatly needed to help make this disease more manageable in the future.