Chapter 2 Early Warning Signs and Diagnostic Approach in Childhood Cancer
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1 Chapter 2 Early Warning Signs and Diagnostic Approach in Childhood Cancer Case Presentation Abdu, a 14-month-old boy, presents with fever. He has a poor appetite and has developed peri-orbital bruises in the absence of any trauma. Whenever his mother picks him up, he seems to be in pain. Weight = 12 kg, height = 78 cm (Fig 2.1) On examination the child appears unwell, irritable, and in pain. His pulse rate is 160/min, respiratory rate 40/min, and his temperature 38 C. His blood pressure and oxygen saturation are normal. He is very pale. Left-sided peri-orbital bruising is present, as well as mild proptosis of the left eye. His right upper arm and left knee are tender to touch. His abdomen is distended, but not tender. A left flank mass (8 10 cm) is found. It is not ballotable. The liver is palpable 4 cm under the costal margin. What diagnostic investigations should be requested in this case? Hematology: Complete blood count, reticulocyte count and peripheral blood smear, clotting profile Biochemistry: U&E, LDH, ferritin, urine VMA and HVA Abdominal sonar, followed by a CT or MRI abdomen if available Biopsy of abdominal mass Once neuroblastoma has been confirmed: MIBG scan and bone marrow aspirate and biopsy Diagnostic Delay in Childhood Cancer The majority of children with cancer in developing countries are diagnosed too late, when advanced disease is already present, and many more die without ever being diagnosed. Various factors contribute to the diagnostic delay (Fig. 2.2). Springer Science+Business Media New York 2017 D.C. Stefan, M. Harif, Pediatric Cancer in Africa, DOI / _2 15
2 16 2 Early Warning Signs and Diagnostic Approach in Childhood Cancer Fig. 2.1 Fig. 2.2 Factors contributing to diagnostic delay and abandonment of treatment
3 Case Presentation 17 The site of the solid tumor will determine if the presentation is early or late. If it is in the close proximity of a vital structure such as the airway, it may present earlier, as compared to a tumor in the parenchyma or pleura. A high proliferation rate may also ensure that a tumor is noted earlier, e.g., Burkitt lymphoma or acute leukemia. Systemic symptoms, like night sweats or fever may prompt a visit to the doctor and lead to a cancer diagnosis or may be misdiagnosed with common infection. In young babies it may be difficult to note neurological signs and symptoms early, since the tumor can grow to a significant size due to the pliable skull bones and open fontanelle. Adolescents may not want to discuss their health problems with their parents for various reasons, including cultural reasons or privacy issues. Parents may not recognize symptoms as possible early warning signs of childhood cancer. In the African setting, because of difficulties in accessing health care and also because of religious and social beliefs, parents often first seek help from traditional healers. Therefore awareness campaigns and education in the community are extremely important, as well as ensuring access to health care and specified referral pathways. However, a South African study showed that the biggest reason for delay in diagnosis in their setting was the failure of health care practitioners to recognize the warning signs. Thus health care practitioners should be adequately trained regarding the suspicion and early diagnosis of childhood cancer. Awareness and outreach campaigns among health care practitioners are important to keep the focus on childhood cancer. Early Warning Signs of Childhood Cancer The early warning signs of childhood cancer are present in about 85 % of childhood cancers, although they are not specific for cancer. They are easy to remember and easy to identify on history or clinical examination. Every country should have simple pamphlets or posters of early warning signs to be distributed among health care practitioners and the community (Fig. 2.3). A study performed in South Africa showed that after an awareness campaign using the Saint Siluan early warning signs of childhood cancer was started, an increased number of new cancer cases were diagnosed (Fig. 2.4). The Saint Siluan signs have been adopted by SIOP-PODC (International Society of Pediatric Oncology s Committee on Developing Countries) and the International Confederation of Childhood Cancer Parent Organization (ICCCPO). Another example of a list of warning signs is CHILD CANCER, an acronym which is also endorsed by international childhood cancer organizations (Table 2.1). Children with a High Risk of Cancer High-risk groups should be identified early and follow-up/surveillance programs should be instituted as soon as possible. Conditions with a high risk for cancer include neurocutaneous syndromes (neurofibromatosis, tuberous sclerosis), certain
4 18 2 Early Warning Signs and Diagnostic Approach in Childhood Cancer Fig. 2.3 Poster for caregiver s awareness program in Morocco genetic disorders (Down syndrome, Fanconi anemia, Beckwith Wiedemann syndrome, etc.), primary and secondary immunodeficiency disorders, history of a previous malignancy, as well as congenital malformations (aniridia, hemi-hypertrophy). Some conditions will require regular clinical follow-up and others intermittent abdominal ultrasound investigations.
5 Case Presentation 19 Fig. 2.4 St Siluan early warning signs of childhood cancer (South Africa) Clinical Diagnosis of Childhood Cancers In Africa, where resources are limited, a thorough history and meticulous examination are essential and often form the backbone of the diagnosis. A histological diagnosis is always required whenever is possible. Besides signs and symptoms, knowledge regarding the age of onset of the different malignancies is also helpful (Fig. 2.5). Signs and symptoms of childhood cancers can be divided into four main groups (Fig. 2.6). The most frequent signs are related to the tumor mass. Childhood cancer is often rapidly growing and a mass may be palpable or visible. Depending on its site, the mass is more or less noticeable. Complications, symptoms, and signs due to compression/obstruction are frequently present with tumors of the digestive tract, chest, and orbit, while they often appear late with abdominal tumors.
6 20 2 Early Warning Signs and Diagnostic Approach in Childhood Cancer Table 2.1 Child cancer acronym C Continued, unexplained weight loss H Headaches, often with early morning vomiting I Increased swelling or persistent pain in the bones, joints, back, or legs L Lump or mass, especially in the abdomen, neck, chest, pelvis, or armpits D Development of excessive bruising, bleeding, or rash C Constant, frequent, or persistent infections A A whitish color behind the pupil N Nausea that persists or vomiting without nausea C Constant tiredness or noticeable paleness E Eye or vision changes that occur suddenly and persist R Recurring or persistent fevers of unknown origin Fig. 2.5 Typical age of onset in different childhood cancers Symptoms and signs due to metastases may prompt a patient to present, but are most often only found during the diagnostic workup. Bone metastases often present with pain, pathological fractures (less common), or masses. General signs and symptoms and particularly fever, are not specific and do not occur with all cancers in childhood. They become meaningful when they are associated with a mass, lymphadenopathy, or another clinical feature of cancer. Paraneoplastic signs and symptoms occur rarely.
7 Case Presentation 21 Fig. 2.6 Modes of cancer expression Diagnostic Procedures Diagnostic procedures should be adapted to local and national available resources. In Africa, the cost thereof and potential delay should be taken into account. In this setting, clinical signs and symptoms remain the most important factor. A confident diagnosis needs to be made, however, before therapy is initiated. The development of telepathology and/or teleradiology systems may be very helpful. In the case of life-threatening situations, specific treatment may need to be started while diagnostic procedures are still being performed. In most cases, a fine needle aspiration or biopsy is necessary for diagnostic confirmation. In the case of retinoblastoma, some brain tumors and tumors of the kidney, clinicoradiological diagnosis may be sufficient. A surgical biopsy is the gold standard for the diagnosis of solid tumors. It must be performed by an experienced surgeon, preferably by the surgeon who will be in charge of tumor excision. When complete resection is possible without performing mutilating surgery, the surgeon should consider this option. The pathologist involved should provide guidance as to the type of biopsy and preservation technique. If a tumor is excised, the margins should be identified as anterior, posterior, etc. Percutaneous biopsy or aspiration is best performed under ultrasound or CT guidance. When good clinical evaluation and communication with the pathologist is in place, most of childhood cancers can reliably be diagnosed by standard HE pathology staining. Good quality of staining is important for accurate diagnosis. Immunohistochemistry and genetic or molecular studies to characterize these tumors are sometimes required.
8 22 2 Early Warning Signs and Diagnostic Approach in Childhood Cancer Fine needle aspiration may confirm Burkitt lymphoma, the most frequent tumor in Africa, when clinical features are also consistent with the diagnosis. It should preferably only be used if a pathologist, who is experienced in cytological interpretation, is available. Bone marrow aspiration confirms the diagnosis of leukemia and also in some cases of non-hodgkin lymphomas and advanced cases of neuroblastoma. It should be done to exclude bone marrow infiltration in all cases of neuroblastoma, rhabdomyosarcoma, retinoblastoma, and Ewing sarcoma. Tumor markers, such as alpha fetoprotein (AFP) and beta human chorionic gonadotropin (BHCG), may also contribute to the diagnosis and follow-up. Other diagnostic and staging investigations include urine catecholamines, ferritin, lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), and bone scan. Abdominal Mass Abdominal mass is one of the most frequent expressions of childhood tumors. The age of onset is important. The clinical examination must note the tumor volume, mobility, and consistency. In the neonatal period, the origin is often congenital malformation. Between 1 and 5 years of age, nephroblastoma and neuroblastoma are the most frequently encountered malignancies. Non-Hodgkin lymphoma, especially Burkitt lymphoma, usually presents with several confluent masses associated with pain, vomiting, and constipation. Not infrequently, Burkitt lymphoma presents with acute intussusception or perforation, requiring urgent surgery. An association with other signs may also help in narrowing down a diagnosis: A facial mass with or without an abdominal mass is most often due to Burkitt lymphoma. This tumor is endemic in Africa. The presence of macroscopic or microscopic hematuria is usually associated with a renal tumor. Aniridia, hemi-hypertrophy or genitourinary abnormalities are associated with nephroblastoma. The presence of subcutaneous nodules, peri-orbital bruising, proptosis, or opsomyoclonus point towards neuroblastoma. Finally, precocious puberty associated with an abdominal mass is suggestive of gonadal or adrenal tumors. Abdominal ultrasound is the first step in the diagnostic evaluation. If performed by an experienced radiologist, it is in the majority of cases sufficient to clarify the origin of the tumor and its locoregional impact. Plain abdominal radiography can identify calcifications, which are sometimes seen in teratomas or neuroblastoma and are helpful if an acute abdomen is present. CT scan or MRI, when available, is the investigation of choice and provides detailed anatomical information. Further staging investigations are determined by the type of malignancy, as well as the availability of special investigations. Tuberculosis with or without HIV infection should be considered in most parts of Africa.
9 Case Presentation 23 Intra-Thoracic Masses Most intra-thoracic tumors are located either in the mediastinum or the thoracic wall. The most common symptom of mediastinal tumors is dyspnea. In more advanced disease, superior vena cava syndrome may develop. It is a medical emergency and needs to be treated without delay. Mediastinal masses are more frequent in older children and are most often due to T-cell lymphomas and leukemias. These malignancies are often associated with airway compression and/or pleural effusion. Masses in the middle mediastinum are usually hilar lymph node metastases or Hodgkin disease. Neurogenic tumors, particularly neuroblastoma, ganglioneuroma, or neurofibroma, are found in the posterior mediastinum. Sometimes intraspinal extension of the tumor can occur, giving rise to spinal cord compression, which is also a medical emergency. Careful analysis of the chest X-ray may be very helpful. Ultrasound and CT scan provide details regarding possible pleural or pericardial effusion, the exact site of the tumor and locoregional extension of the tumor. In the event of acute lymphoblastic leukemia, the diagnosis is confirmed by a CBC, peripheral blood smear and bone marrow biopsy. In the case of non-hodgkin lymphoma, cytology of the pleural fluid may be sufficient for the diagnosis. Otherwise a lymph node biopsy or biopsy of the chest wall mass should be performed. Chest wall tumors are usually due to Ewing sarcoma or soft tissue sarcomas. Intracranial Masses Clinical symptoms and signs of brain tumors vary according to the age of the child, the site of the tumor, and its aggressiveness. Diagnostic delay is usually longer for supratentorial tumors. The diagnosis is made by CT or preferably MRI. Initially, an ultrasound may be helpful to identify a mass and hydrocephalus in babies with an open fontanelle. Headaches are the most common symptom. It is indicative of raised intracranial pressure when they occur early morning, and are associated with vomiting and papilledema. In a young child, behavioral changes or learning problems may be observed. Very often, focal neurological signs (motor deficit, cranial palsy), seizures, ataxia, or a visual field deficit are found. Lymphadenopathy Lymphadenopathy is a common finding in children of all ages. Reactive lymphadenopathy needs to be distinguished from sinister lymphadenopathy. The site, size, consistency, mobility, progression in size, and associated signs are of major importance. Nodes are considered to be pathological if their size exceeds 1 cm (cervical and axillary) and 1.5 cm (inguinal). Any supraclavicular lymphadenopathy must be considered to be pathological. Left-sided supraclavicular lymphadenopathy may be
10 24 2 Early Warning Signs and Diagnostic Approach in Childhood Cancer related to metastases of an intra-abdominal tumor, particularly neuroblastoma, while the right side can be due to metastases of intra-thoracic tumors. Malignant lymph nodes are usually firm or hard, fast-growing, and can become confluent and fixed. In the event of suspicious lymph nodes without an obvious etiology, the evaluation should include a CBC, reticulocyte count and peripheral blood smear, chest X-ray, tuberculosis workup and viral tests, particularly HIV. Antibiotic treatment may be given for 1 2 weeks. In the case of cytopenias, circulating blasts or mediastinal lymphadenopathy/mass, a bone marrow biopsy should be performed. The indications of a lymph node biopsy are: persistent or increasing lymphadenopathy beyond 4 6 weeks, lymph nodes of more than 2.5 cm in the absence of signs of infection or response to antibiotic treatment, supraclavicular involvement and/or an association with fever, night sweats, weight loss or other worrying signs. The biopsy should be a complete excision of the largest and most accessible lymph node. Lymph node cytology imprints must always be prepared for better characterization. Soft Tissue Masses Soft tissue sarcomas may present as a mass literally at any site. Complete resection may be attempted if surgery would not be mutilating or extensive, otherwise a biopsy should be performed. Bone Pain Bone pain is a common symptom in children with cancer and is a presenting feature of leukemia. It often reflects metastatic bone involvement in various cancers, such as non- Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, and some renal tumors. Localized pain may be due to a primary bone tumor, such as osteosarcoma and Ewing sarcoma. Bone pain (and limb or joint swelling) is often attributed to trauma or growing pains and not adequately investigated until the tumor is advanced. When bone pain does not respond to analgesia, is not associated with trauma and if swelling is present, an X-ray should be performed and properly interpreted. Lytic lesions, onion skin appearance, Codman triangle, and soft tissue swelling are radiological signs of a bone tumor. A biopsy should be performed as soon as possible. Summary Childhood cancer is a relatively rare disease (incidence between 1 10%). The clinical expression is not always specific, which contributes to the difficulties in making a diagnosis. Early diagnosis is crucial, since survival rates are closely correlated to
11 Suggested Reading 25 the stage of disease: early stage disease equals excellent patient outcome, while advanced disease usually leads to poor outcomes. Primary care practitioners and parents should be trained to recognize signs and symptoms that may be suggestive of cancer. As soon as cancer is suspected, appropriate basic investigations should be performed without delay, after which patients should be referred as soon as possible to an oncology unit. Children with an increased risk of developing cancer, such as children with Beckwith Wiedemann or other syndromes, should be identified early and surveillance programs should be instituted for them. Suggested Reading Feltbower RG, Lewis IJ, Picton S, Richards M, Glaser AW, Kinsey SE, McKinney PA (2004) Diagnosing childhood cancer in primary care a realistic expectation? Br J Cancer 90: Haimi M, Perez-Nahum M, Stein N, Ben Arush MW (2011) The role of the doctor and the medical system in the diagnostic delaying pediatric malignancies. Cancer Epidemiol 35:83 89 Okoko AR, Ekouya Bowassa G, Oko AP, Mbika-Cardorelle A, Moyen GM (2012) Epidemiology of palpable abdominal masses in children in Brazzaville. Arch Pediatr 19(8): Pollock BH, Krischer JP, Vietti TJ (1991) Interval between symptom onset and diagnosis of pediatric solid tumors. J Pediatr 119: Poyiadjis S, Wainwright L, Naidu G, Mackinnon D, Poole J (2011) The Saint Siluan warning signs of cancer in children: impact of education in rural South Africa. Pediatr Blood Cancer 56(2): Raab CP, Gartner JC (2009) Diagnosis of childhood cancer. Prim Care Clin Office Pract 36: Stones DK (2010) Childhood cancer: early warning signs. CME 28(7): Twist CJ, Link MP (2002) Assessment of lymphadenopathy in children. Pediatr Clin North Am 49:
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