Topics on Continuous Training

J. Huerta Aragonés, C. Mata Fernández

Pediatric and Adolescent Hematology and Oncology Section. Pediatrics Service. Gregorio Marañón General University Hospital. Maternal and child Hospital. School of Medicine. Complutense University of Madrid. Gregorio Marañón Health Research Institute (IiSGM). CIBEREHD

Key words: Supervivientes de cáncer infantil; Efectos secundarios tardíos; Toxicidad a largo plazo; Segundas neoplasias.

Palabras clave: Childhood cancer survivors; Late side effects; Long-term toxicity; Second malignancies.

Pediatr Integral 2021; XXV (7): 372 – 385

Follow-up of childhood cancer in Primary Care. How to detect late effects

Introduction

Cancer survival rates in the pediatric age have notably increased in recent decades, where prevention as well as early diagnosis of late sequelae strategies have become essential.

The number of childhood cancer survivors has increased significantly in the last 40 years, increasing from 58% survival between 1975-1977 to 83% between 2008-2014(1). In Spain, a 23% increase in survival was observed (from 54 to 77%, from 1980-1984 to 2000-2004), with a 50% decrease in the risk of death in that period (https://www.uv.es/rnti/cifrasCancer.html). In Europe, 1 in 500-600 children will develop a malignancy before the age of 15 and it is estimated that, in the next few years, one in 450 young adults will be a childhood cancer survivor in Europe(2). In contrast to this great advance, there is a high prevalence of morbidity in the form of late side effects. The Children’s Oncology Group (COG) in a childhood cancer survival study observed the existence of at least one chronic problem in the second decade of life in almost 60% of survivors and more than 30% of severe chronic sequelae 30 years after diagnosis(3). The St. Jude Lifetime Cohort Study published a study in which it was observed that at 45 years of age, 95.2% of the survivors reported at least one chronic health condition, being it serious, disabling or life threatening in 80% of the cases (twice that of the general population at that age)(4).

Cancer treatments predispose recipients to excess morbidity and premature mortality compared to the general population. The risk is directly proportional to the intensity of the treatment to achieve the cure of the disease, being more burdensome in the case of multimodal therapy and in patients who have received several treatments due to relapse. Age is a determining factor, the younger the more toxic effects on linear growth, skeletal maturation, intellectual functionality, sexual development and organic functionality.

Although these are worrisome data, the impact of these late effects can be modified through early detection and adequate management of the pathologies, as well as, prevented in part through a modification of lifestyle habits(1). Likewise, it has become a generalized trend of current protocols to seek, in cases where a good long-term survival result has been achieved, to reduce acute and chronic toxicity without detriment to survival (e.g., acute lymphoblastic leukemia, nephroblastoma, Hodgkin lymphoma, certain brain tumors…), in particular, reducing the use of radiotherapy and adjusting the intensity of treatment to the individual risk(5,6).

Reducing late effects and early detection of them, if they exist, has become a goal for these patients, in order to improve their quality of life. Follow-up and recommendations must be individualized according to the personal characteristics of each survivor, type of tumor, treatment received, age, comorbidities, lifestyle, and existence of dysmorphic syndromes or predisposition to cancer(1) (Fig. 1). Side effects increase with age, but can manifest throughout life, hence, an adequate monitoring based on recommendations and consensus guidelines, from pediatric age to adulthood is essential.

Follow-up Models of Childhood Cancer Survivors

There is not a unique model for the monitoring of long-term side effects, and the superiority of one over the others has not been demonstrated by studies of adequate duration and methodology. Table I contains a comparison between the different models, their advantages and disadvantages(1).

In general, the most suitable option would be the one that best suits the individual characteristics of the patient. In our environment, joint work between healthcare professionals from the hospital and Primary Care setting is essential, as well as a progressive and structured transition to the adult care model. Information transfer is crucial, especially: previous medical history, dates of diagnosis and end of treatment, diagnostic tests at diagnosis and during follow-up, multimodal treatments received and their doses, complications related to them or to the disease itself, relapses and follow-up plan (Table II).

Producing detailed medical reports for the physicians who will provide ongoing care for survivors in Primary Care or during their adulthood is paramount and often one of the deficits of hospital care. In this sense, a good number of Pediatric and Adolescent Oncology and Hematology services are making efforts to implement specific follow-up consultations for the survivor and transition to adult care, paying special attention to the elaboration of “survivor’s passport”. There are tools promoted by the International Society of European Pediatric Oncology (SIOPe) (http://www.survivorshippassport.org/) and through European projects such as the PanCareSurPass project (Horizon 2020-EU.3.1.5 Framework Program, https://cordis.europa.eu/project/id/899999/es).

Follow-up recommendations

There are consensus guidelines for the follow-up of survivors from different international groups that, although heterogeneous and variable in the recommendations, result very useful.

In recent years, national and international guidelines have been developed for the monitoring of long-term side effects in survivors. In the United States, the Children’s Oncology Group (COG) periodically publishes the “Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers” (latest version: 5.0, October 2018). It is a guide based on the individual risk, tools for diagnosis and management of side effects. The current version is accessible through the website www.survivorshipguidelines.org(7). In Europe, three large groups have developed similar guidelines: the UKCCSG (United Kingdom Children’s Cancer Study Group) “Therapy Based Long-Term Follow Up Practice Statement”(8), the “Long Term Follow Up of Survivors of Childhood Cancer, A National Clinical Guideline” (Scottish Intercollegiate Guidelines Network, SIGN)(9) and the “Guidelines for follow-up after childhood cancer more than 5 years after diagnosis” (Late Effects Taskforce of the Dutch Childhood Oncology Group, DCOG LATER)(10). Each of these recommendations uses a different methodology and, at times, the recommendations are variable. With the aim of homogenizing them, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) was created, however, given the complexity of the issue, for now, it has only prepared documents for the screening of breast cancer, cardiomyopathy, early ovarian failure, male gonadal toxicity, thyroid cancer and ototoxicity (www.ighg.org/guidelines/). The Spanish Society of Pediatric Hematology and Oncology (SEHOP) published the guide “Late effects in survivors of childhood cancer” in 2012, which constitutes a tool of indisputable value(11). The need to develop consensus guidelines is obvious, but the long-term cost-effectiveness of these recommendations remains unknown(1).

Late effects on organs and body systems

There are guidelines for side effects tailored to each specific treatment that, due to their breadth, far exceed the length of this article(7,8). Thus, we will focus on side effects by organs or systems. They are shown in table III in a very summarized manner.

Cardiology sequelae

Patients at greatest risk are those receiving high-dose anthracyclines, chest or mediastinal radiation therapy, or both; however, other conventional and targeted therapies also require vigilance.

Cardiovascular complications are one of the main problems for survivors, with an increased risk of heart failure compared to the general population (15 times higher) and premature death from cardiac causes (7 times higher)(12). Anthracyclines, regardless of the type, produce direct and indirect toxicity (free radicals) on the myocyte. There is no safe dose if long-term normal cardiovascular status is the goal. Chronic toxicity manifests itself months or even many years later, consisting of dose-dependent non-ischemic degenerative dilated cardiomyopathy (more frequent than restrictive) due to irreversible myocardial damage, as well as arterial hypertension, ischemic heart disease, and heart failure. Serious arrhythmias, tachycardia, ventricular fibrillation and even second- and third-degree blocks may appear. The incidence of conventional cardiotoxicity is 7.5-10% 30 years after finishing treatment(12,13). Female sex, earlier age, higher cumulative dose (> 250 mg/m2), and concomitant cardiothoracic irradiation are associated with an increased risk of cardiotoxicity and greater severity. There are also other classic chemotherapy agents (cyclophosphamide, cytarabine, cisplatin, ifosfamide, paclitaxel, 5-fluorouracil…) that produce cardiac toxicity by other mechanisms(14). In recent years, other emerging therapies must also be considered, such as proteasome, HER2, VEGF and tyrosine kinase (TK) inhibitors, as well as immunotherapy, including CAR-T cell therapy and immune checkpoint inhibitors(15) (Table IV).

The development of cardioprotective molecules has been a desire over the last years. Dexrazoxane has been postulated as a strong candidate, as it improves the cardiotoxicity observed with anthracyclines. Its use has been limited by the suspicion that it could interfere with the efficacy of anthracyclines, as well as by a possible contribution to the development of secondary neoplasms. None of these aspects have been proven in recent studies, including a meta-analysis with a sample of 4,639 children treated with anthracyclines for different neoplasms (Shaikh F et al., J Natl Cancer Inst. 2016). The American Heart Association and the American Academy of Pediatrics recommend its use as a cardioprotective agent in protocols that use anthracyclines (the Children’s Oncology Group -COG- recommends it since 2015 in those protocols that involve doses ≥ 150 mg/m2 or cardiothoracic radiotherapy). In our setting, it is not routinely used in the clinical practice. The use of liposomal forms of anthracyclines and analogues (epirubicin, idarubicin, mitoxantrone) could improve long-term toxicity(14) and long-term (6-96 hours) dosing regimens are recommended instead of boluses. Drugs such as enalapril or phosphocreatine (Cheuk DKL et al. Cochrane Database Syst Rev. 2016), beta-blockers, statins or anti-aldosteronic agents have not been shown to have a protective effect.

The mediastinal/thoracic radiotherapy produces acute inflammation on the cardiomyocytes and generates hypercoagulability. Oxidative stress leads to chronic inflammation and subsequent fibrosis (Velásquez CA et al. Rev Colombiana Cardiol 2018). Risk factors include: high cumulative doses (> 30-35 Gy), high daily doses (> 2 Gy/session), age <50 years at the time of therapy, previous history of heart disease or cardiovascular risk factors, and concomitant cardiotoxic chemotherapy treatment(7). Toxicity manifests as: ventricular dysfunction, endothelial damage (increased vascular risk, coronary artery disease, degenerative aortic vascular disease or supra-aortic trunk disease, stroke), dilated or restrictive cardiomyopathy, chronic/constrictive pericarditis, degenerative valvular disease and arrhythmias.

In summary, high-risk patients are those who have received ≥ 250 mg/m2 of anthracyclines, > 35 Gy of chest radiation or ≥ 100 mg/m2 of anthracyclines + ≥ 15 Gy of irradiation(12). Surveillance in high-risk patients should begin no later than 2 years after the end of cardiotoxic treatment and should be repeated 5 years after diagnosis, continuing every 5 years or sooner if necessary.

The semiology to be monitored will be dyspnea, chest pain, palpitations, intolerance to exercise and activities of daily life. Routine cardiopulmonary auscultation is recommended, as well as ruling out the presence of carotid murmurs. Echocardiography is the main imaging test for diagnosis and follow-up, with magnetic resonance imaging being an interesting supplementation in selected cases (not as a screening technique)(16). The electrocardiogram is a tool for the diagnosis of arrhythmias and cardiomyopathy, being necessary, on occasions, the performance of stress tests and Holter tests(7).

Regarding biomarkers, atrial natriuretic peptide, especially its pro-B NT fraction, could be a predictor of subsequent dysfunction if elevated during treatment. In asymptomatic patients, it should be interpreted with caution and always in combination with other elements. They are not recommended as the sole follow-up strategy in high-risk patients(12).

Regular exercise is recommended for survivors with normal ventricular function. The American College of Sports Medicine recommends 30-40 minutes of aerobic exercise, five times a week, along with 2 days of higher intensity training. In case of exercise-related symptoms, these should be promptly communicated. Other cardiovascular risk factors (hypertension, diabetes, dyslipidemia and obesity) should be monitored, and tobacco use avoided. During pregnancy, these patients should be closely followed, especially during the first trimester(12).

Finally, chronic fatigue syndrome should be considered, as it has a variable prevalence depending on the series (10-80%), although it is generally considered to affect 30% of children, adolescents and young adults. It consists of a subjective experience of persistent fatigue and severe tiredness, years after diagnosis, unexplained by organic causes, and that does not improve with rest. It is difficult to differentiate from depression. Risk factors include: having received radiotherapy (pulmonary therapy is the most clearly related), psychological stress, relapses, comorbidity of other side effects, female sex, unemployment and affective loneliness. It is inversely correlated with time progression since treatment and with an adequate social and labor integration. There are tools for its diagnosis (PROMIS pediatric fatigue measures, PedsQL MFS). Management is carried out through behavioral therapy (physical exercise, time management, social and occupational integration…), as the efficacy of pharmacological therapies has not been demonstrated(17).

Respiratory sequelae

Pulmonary toxicity is a common late complication, which can have a great impact on the quality of life of survivors, hence the importance in having a high index of suspicion.

Chronic respiratory tract damage can be related to primary or metastatic disease, infectious complications during treatment, and multimodal therapies themselves. The presentation can be acute or chronic, as summarized in Table V.

The cumulative incidence of pulmonary complications increases with the time elapsed since diagnosis(16), in particular, pulmonary fibrosis and chronic pneumonitis. Radiation therapy can cause oxidative damage to the vascular endothelium and affect the normal development of the chest wall, especially beyond 20 Gy(8,16). In patients receiving a hematopoietic stem cell transplant there is a special vulnerability, due to the conditioning regimens, complications derived from graft versus host disease (GVHD) and respiratory infections associated with the procedure.

During follow-up, watchful vigilance should be kept for guiding symptoms such as persistent dry cough, dyspnea, or exercise intolerance. Lung auscultation should be performed during visits, with baseline O2 saturation and chest X-ray, if symptoms are present. In these cases, the study of lung function is essential, specially assessing restrictive patterns (forced vital capacity, diffusion capacity). Many patients have asymptomatic or oligosymptomatic lung function abnormalities, which should be followed for possible progressive deterioration. The avoidance of tobacco use and its passive inhalation should be advised(11).

Neuropsychological sequelae

Many patients, particularly in high-risk groups, present late neurological, sensory, or cognitive toxicity that impacts their cognitive function and psychosocial integration in adult life.

Neurocognitive sequelae are observed in up to 40-45% of survivors, mainly in those who have suffered a primary or secondary tumor involvement of the central nervous system and in those who have received radiotherapy at that level (CNS tumors, acute lymphoblastic leukemia in previous protocols). Sometimes, there is a functional deficit (visual abnormalities, cranial nerve deficit, hemiparesis, ataxia…) derived from the growth of the tumor itself or from its resection surgery. In the long term, the manifestations can be sensory-motor (aphasia, paresis, focal deficits, peripheral neuropathy…) or neurocognitive (memory, attention, learning, speed of processing and execution of tasks, decreased school performance…). Radiation therapy is especially harmful in children younger than 3-5 years of age. A higher dose is associated with a higher risk of neurocognitive sequelae, in relation to leukoencephalopathy and vascular microangiopathic lesion(11).

At the peripheral nervous system level, sequelae can be observed in patients treated with cisplatin doses > 300 mg/m2 and with vinca alkaloids (especially vincristine, particularly in malnourished children). Cisplatin is often associated with sensory neuropathy. Vincristine rarely causes chronic neuropathy, but if present, it can be multiple (sensorimotor, autonomic, cranial nerves). In these cases, neurophysiological studies are required, as well as offering adequate rehabilitation support, occupational therapy and analgesia if the neuropathy is painful(9).

A follow-up assessment of intellectual, visual, sensory perception, memory, language and learning capacity is recommended, assessing academic performance and behavior in the family and social environment. When stagnation or deficits are observed in any of these areas, early intervention is deemed necessary. Imaging tests (CT angiography, MR angiography) may be required to complete the global assessment, as well as an assessment by Neuropediatrics and Psychology(10).

At a psychological level, there is up to 80% more probability of presenting psychological limitations that affect the quality of life and two times more emotional stress when a comparison with the patient’s siblings is established. Not all tumors present the same pattern of psychological sequelae. Brain tumor survivors display a higher rate of depression, somatization, fatigue, and drowsiness; and those of leukemia, more stress, depression and anxiety during adolescence, compared to other tumors and the general population(8).

Brain irradiation is associated with psychological stress, somatization, a greater feeling of fatigue, poorer physical and mental performance, sleep disruption, and poorer school and social integration. Patients treated with intensive chemotherapy, especially with alkylating agents, present with more stress, anxiety, depression and somatization, especially with alkylating treatments. Risk behaviors associated with psychological dysfunction, high smoking rate and alcohol consumption (in relation to worse socioeconomic status) have been described. In adults, a high rate of suicidal ideation and suicide attempts has been described, with brain tumor survivors having the highest incidence (10.4%)(7). No association has been found with age at diagnosis, time since diagnosis, type of treatment, recurrence or second tumors. Low educational level, low income, unemployment and emotional loneliness have been described as risk factors. In this regard, close monitoring of the social, psychological and emotional situation is relevant.

Sequelae on the senses

Sensory sequelae, especially vision and hearing, can limit the social or work capacity of survivors, so these must be carefully monitored.

The most frequent ocular abnormality is the detection of cataracts. It is related to the use of high and prolonged doses of steroids, radiotherapy at this level (ocular-orbit, cranial, total body, being dose dependent and, especially, if ≥ 2 Gy directly on the lens), busulfan or intrathecal chemotherapy(16). Xerophthalmia and lacrimal duct atrophy can occur and, more rarely: orbital hypoplasia, enophthalmos, keratitis, telangiectasia, retinopathy, maculopathy, optic chiasm neuropathy, papillary damage and glaucoma. The risk increases in case of radiotherapy ≥ 30 Gy on the eye-orbit, in case of treatment with 131-I for thyroid cancer, actinomycin-D or doxorubicin combined with radiotherapy, GVHD, frequent ocular exposure to sunlight and if there is comorbidity (diabetes mellitus, arterial hypertension). Other visual disturbances that may develop are: hypersensitivity to light, blurred vision, diplopia, nyctalopia (night blindness) and alterations in ocular refraction. The risk lasts for more than 20 years beyond the end of treatment(7).

Annual ophthalmological examination is recommended in all survivors, and in those with a history of treatment with corticosteroids or radiotherapy to the eyeball-orbit, orbital tumors, GVHD, treatment with radioactive iodine or abnormal diaphoresis. The use of approved glasses with UV protection is recommended(7).

When it comes to hearing, the most common long-term side effect is ototoxicity. Risk factors include having received high doses of cisplatin or carboplatin, radiation therapy over the head or ear (≥ 30 Gy) and having received therapies such as: aminoglycosides, furosemide, NSAIDs or iron chelators (deferasirox). The usual manifestation is sensorineural deafness, sometimes with tinnitus, and less frequently vertigo, transmission hearing loss and otosclerosis(7). Hearing evaluation is recommended at the end of treatment in patients at risk and then annually for those aged < 6 years (auditory evoked potentials), every 2 years between 6-12 years of age (tonal audiometry of 1,000-8,000 Hz, being best high frequency > 8,000 Hz) and, subsequently, every 5 years in those aged > 12 years. In patients with a ventriculoperitoneal bypass valve, a hearing assessment is recommended at the end of treatment and then every 5 years, even in the absence of other risk factors(7). Avoiding loud noises is recommended.

Smell can be affected in the form of anosmia or chronic rhinitis/sinusitis, usually in patients who have received radiotherapy or surgical resection of a nasal tumor.

Oral and dental sequelae

Patients undergoing chemotherapy before 5 years of age, especially with high-dose cyclophosphamide, are of special risk. One of the main problems of the oral cavity is xerostomia, in general, related to craniofacial radiotherapy, which can improve with frequent intake of liquids, sugar-free candies and artificial saliva tablets. Treatment predisposes to an increased risk of cavities, dental infections, and even speech or sleep disorders. Other dental problems are frequently described (enamel hypoplasia, tooth decay, tooth loss, microdontia, hypodontia, malocclusion). Careful and regular dental hygiene is essential, as well as an assessment by stomatology or dentistry in case of presenting problems. Occasionally, abnormalities in craniofacial development and trismus develop secondary to alterations in the temporomandibular joint(9).

Radiation therapy also increases the risk of developing second neoplasms. Occasionally, the oral cavity may be the site of GVHD involvement in hematopoietic stem cell transplant recipients. An adequate follow-up is important to detect these abnormalities early enough.

Endocrine sequelae

Half of childhood cancer survivors will present at least one late endocrinological disorder in their lifetime, with central nervous system tumors being the most frequently related(7). In the case of craniopharyngioma, abnormality of at least one hormonal axis takes place in 75% of patients. Risk factors are: direct damage from tumor growth itself, that derived from resection or biopsy surgeries, and radiotherapy ≥ 30 Gy. Cranial radiotherapy produces more disturbances in this axis the younger the age of the patient. The most common sequela is short stature due to GH deficiency, particularly with radiation therapy doses > 18 Gy. In adult life, the deficiency of this hormone is associated with metabolic problems such as: increased body fat, altered serum lipid profile, and decreased exercise capacity, bone mineral density and insulin sensitivity. Short stature may, however, be due to other causes (hypothyroidism, precocious puberty, growth impairment due to spinal or long bone radiation, and prolonged corticosteroid therapy)(7). Occasionally, a “catch up” growth occurs reaching the target height with adequate replacement treatment, but it does not always happen(16).

On other occasions, endocrine late effects manifest as central adrenal insufficiency due to ACTH deficiency (very rare, due to direct tumor or surgical damage or radiotherapy dose ≥ 30-50 Gy), central hypothyroidism due to TSH deficiency (cranial RT ≥ 30 Gy), hypogonadotropic hypogonadism due to LHRH, LH or FSH deficiency (second axis affected in order of frequency), prolactin deficiency or central diabetes insipidus due to ADH deficiency (infundibulum involvement by craniopharyngioma, germ cell tumor or optic glioma). The term panhypopituitarism is coined when deficiency of ≥ 3 hormones is present.

Precocious puberty, consisting of early pubertal development, rapid bone maturation, and final height shorter than target, can occur. It is related to radiotherapy dose > 18 Gy, younger age at exposition, and female sex. An annual physical examination is recommended, with anthropometric data and pubertal development monitoring, as well as bone age in case of suspicion. Hyperprolactinemia is observed in some patients, generally related to high-dose irradiation to the pituitary gland or development of second pituitary tumors (adenomas) after treatment. In case of suspicion, serum prolactin will be determined and pituitary MRI performed, as well as referral to Endocrinology(7).

At the thyroid level, hypothyroidism is usually associated with cervical, mediastinal, or spinal radiation therapy. It usually occurs in the first 5 years post-treatment, if exposed to doses > 30 Gy (especially ≥ 45 Gy). Other risk factors are: treatment with therapeutic metaiodobenzylguanidine (MIBG) (despite prophylaxis with oral iodine), anti-GD2 (neuroblastoma), tyrosine kinase inhibitors and secondary to thyroidectomy or ablative treatment with radioactive 131I. Rarely, hyperthyroidism, autoimmune thyroiditis, and thyroid nodules (benign and malignant) may be seen. Hypoparathyroidism secondary to thyroid resection surgery may occur, which requires follow-up and treatment(7).

At the gonadal level, toxicity derived from the use of high-dose alkylating agents (busulfan, melphalan, carmustine, lomustine, cyclophosphamide, ifosfamide, thiotepa, procarbazine, dacarbazine, platinum derivatives) can be observed, especially in combination with radiotherapy on the gonads. Girls are at higher risk if they receive the treatments during or after puberty. Ovarian failure occurs in up to 50% of patients who receive radiation therapy to the gonads (≥ 15 Gy), particularly in association with alkylating agents. Infertility has been described from doses ≥ 5 Gy on the ovaries. Likewise, surgery can produce an iatrogenic menopause (bilateral oophorectomy) or an advance of it (unilateral oophorectomy). In this case, hypergonadotropic hypogonadism would occur, which consequently can lead to an increased risk of premature osteoporosis and cardiovascular problems. Abdominal radiation therapy that involves the uterus increases the risk of intrauterine growth delay and preterm delivery. Annual clinical review of sexual maturation development, menstruation characteristics, hormonal determination (FSH, LH, estrogens) is recommended and, in case of suspected ovarian failure, a bone density scan (DEXA scan) and referral to Endocrinology should be performed(7,11).

In any case, patients whose treatment has placed them at risk for ovarian failure, may have premature menopause with a shortened fertility span, so it is the role of the Primary Care physician to warn of this risk and advise, if the woman is capable and willing to have offspring, to conceive no later than the first years of the fourth decade of life.

In men, germ cells (Sertoli) are sensitive to both chemotherapy and radiotherapy (at doses as low as 2-3 Gy), leading to azoospermia that can be irreversible in the case of radiotherapy or mostly temporary in the case of chemotherapy. Leydig cells are less radiosensitive, but can suffer toxicity from 24 Gy(16). In cases of male hypogonadism due to Leydig cell failure, referral should be made to Endocrinology so as to assess testosterone supplementation in order to avoid the symptoms that its lack generates(9).

In order to anticipate these problems, fertility preservation techniques may be performed in girls (ovarian cortex in prepubertal/postpubertal girls and oocyte vitrification in postpubertal women) and in boys (cryopreservation of semen in postpubertal men and in a few centers, cryopreservation of tissue testicular in prepubertal). The development of consensus guidelines is essential in our setting, since the preservation rate is still low, but efforts are being made to improve this situation(18). Likewise, there are surgical techniques for transposition of the testes or ovaries prior to the administration of scrotal, pelvic or inguinal radiotherapy that would avoid direct irradiation, which is the main risk factor for hypogonadism in these patients.

Regarding follow-up, height (percentile), weight, BMI and pubertal stage should be checked every 6 months until completion of sexual development and final height. Menstrual onset (prepubertal) or re-onset (pubertal), menopausal symptoms (hot flashes, dyspareunia) should be inquired, considering the risk of premature menopause. Referral to Endocrinology should be made if there is failure to thrive, delayed pubertal development, or risk of hypogonadism. It is important to advise on fertility, premature menopause, reproductive advice and individualized risks.

Finally, in the long term, some of the most relevant endocrine and metabolic sequelae are type 2 diabetes mellitus and metabolic syndrome (obesity, arterial hypertension, glucose intolerance – increased insulin resistance and dyslipidemia), which count as main risk factors along with abdominal radiotherapy, total body irradiation, prolonged corticosteroid treatment, inadequate eating habits with excessive caloric intake, sedentary lifestyle and a family history of type 2 diabetes mellitus. Consequently, there is an increase in cardiovascular risk with an increase in morbidity and mortality. Implementation of early dietary measures, increased physical activity, blood pressure and dyslipidemia control are recommended. A tight control of body mass index, blood pressure, lipid profile, blood glucose and Hb A1C will be carried out in clinic(19).

Gastrointestinal sequelae

Gastrointestinal complications can be multiple and heterogeneous depending on the therapy received, the location of the primary tumor and whether there is a history of surgery with organic lesion.

The most relevant gastrointestinal complications are shown in Table VI.

Tumor resection surgery and radiotherapy can have visceral obstructive sequelae. In the latter case, it can cause fibrosis and ischemia due to vascular injury. It can appear as a chronic manifestation in case of intestinal GVHD. Likewise, the specific sequelae derived from surgeries with wide resections should be considered (gastrectomy, pancreaticoduodenectomy, cholecystectomy, splenectomy, intestinal resection with discharge ostomy…). Guiding symptoms such as: dysphagia, heartburn, dyspepsia, reflux, nausea, vomiting, chronic diarrhea, constipation, or progressive weight loss should be monitored. In the cases with a short intestine, hypovitaminosis and lack of absorption of other nutrients ought to be monitored(7).

Chronic hepatotoxicity can appear after a long latency period, being secondary to some chemotherapeutic agents, radiotherapy, obesity, viral hepatitis or iron overload secondary to transfusions. The consumption of hepatotoxic agents, such as alcohol and other drugs of abuse, should be avoided.

Nephrourinary sequelae

Delayed kidney damage in the form of chronic kidney failure is one of the most serious complications in survivors.

The main risk factors for kidney damage at the glomerular and proximal tubular level are abdominal radiation and treatment with high doses of ifosfamide (> 16 g/m2), cisplatin (> 450 mg/m2) and, to a lesser extent, carboplatin. Other factors are the use of nephrotoxic drugs (aminoglycosides, amphotericin B, foscarnet, tacrolimus, and cyclosporine A). It should also be considered that some patients may have a single kidney, due to nephrectomy of their primary tumor (nephroblastoma) or due to metastatic renal involvement(20). Consequently, chronic renal failure, proximal tubulopathy, or Fanconi syndrome may develop(7). Some survivors of Wilms’ tumors are at particular risk, as in addition to having a single kidney, they may have an underlying syndrome (Denys-Drash) and will have received chemotherapy and radiotherapy. High blood pressure is common (30%) during follow-up. In hematopoietic stem cell transplant recipients, nephrotoxicity derived from immunosuppressants, as well as nephritis secondary to BK virus, may occur.

Bladder damage is usually associated with the use of cyclophosphamide or ifosfamide, as well as viral infections (BK virus, adenovirus, cytomegalovirus)(9). There may be lesions of the lower urinary tract, secondary to surgery of solid tumors and radiotherapy/brachytherapy. Secondarily, bladder incontinence (neurogenic bladder), bladder fibrosis, bladder cancer, sexual dysfunction, chronic pelvic pain, bladder floor disorders, fistulas and female vaginal dryness, can also occur(16).

Annual BP control is recommended, with urea, creatinine and electrolytes to assess renal function, venous blood gas, and urine electrolytes. If the post-treatment study is normal, it should be repeated after 5 years. In case of HT, proteinuria or signs of tubulopathy, refer to Nephrology(7).

Musculoskeletal sequelae

Healthy lifestyle habits are important, including regular physical exercise and sufficient amounts of vitamin D and calcium in the diet, as well as the early detection of musculoskeletal problems.

Cranio-spinal radiation, prolonged use of corticosteroids or methotrexate, nutritional alterations and a sedentary lifestyle lead to high risk of this type of sequelae. Soft tissue fibrosis and hypotrophy can occur, as well as a decrease in bone mass with osteopenia/osteoporosis derived from the treatments, prolonged bedridden and radiotherapy on musculoskeletal groups. Other long-term complications are: osteonecrosis (avascular necrosis), exostoses, pathological fractures, bone undergrowth or asymmetric growth, dysmetria and, on some occasions, the sequelae derived from amputations and prosthetic malfunctions(7). With regards to bone mineral density, there is a remarkable margin of recovery throughout adolescence provided a healthy lifestyle, regular physical activity (especially, weight-bearing exercises), controlled sun exposure and optimization of the calcium intake in the diet. Sometimes vitamin D supplements are required. Avoidance of alcohol, tobacco, excessive caffeine, and obesity are recommended(9).

Gynecological sequelae

Breast self-examination and screening based on the individual risk are essential to anticipate breast tumors in adulthood.

In the case of adolescent women, it is important to make the patient aware of the importance of breast self-examination (monthly), as well as a regular gynecological examination. The risk of secondary breast cancer is higher if the patient received chest wall or mediastinal radiation therapy, family predisposition to breast cancer (BRCA1/2 mutations) or history of Li-Fraumeni syndrome (TP53). In these high-risk cases, annual gynecological follow-up is recommended from puberty to age 25, then every 6 months. Annual mammograms should be performed from the age of 25 (other groups recommend it from the age of 30)(10) or from 8 years after treatment (whichever occurs last). Breast MRI is recommended concomitantly with the same timelines as mammograms. In case of mammary hypoplasia, an annual follow-up should take place, referring the patient to Plastic Surgery if breast reconstruction is required, once the pubertal development is completed(7).

Vaccination in the oncohematological patient

Revaccination of the oncohematological patient is of vital importance in the months and years following treatment, in a scheduled manner according to national guidelines and recommendations.

In general, routine vaccinations are suspended during treatment, which added to the fact that some patients have an incomplete vaccination schedule due to their young age at diagnosis, the loss of vaccine immunity acquired by the treatments received and the immunodeficiency maintained by some therapies (rituximab, hematopoietic stem cell transplantation, immunosuppressants), makes them a particularly high infectious risk population at the end of treatment. Given the length of this review, the reader is referred to the periodic updates of the Vaccine Advisory Committee of the AEP (https://vacunasaep.org/documentos/manual/cap-14 y -16, updated as of August 2021).

Risk of premature mortality

There is an increased risk of premature death in survivors, thus, health promotion (Fig. 1) and early diagnosis of complications, as well as second tumors, are of vital importance.

The premature mortality rate of survivors is increased compared to the general population, being higher in the first years of follow-up (cumulative mortality: 6.5% at 10 years, 11.9% at 20 years, and 18.1% at 30 years of diagnosis). The risk is higher in women, brain tumors and Ewing’s sarcoma(7). The main cause is the recurrence of the original disease (67%), which decreases in importance with the passage of time. As the years go by, the toxicity associated with the treatment takes on a more important role in the reduction of life expectancy (late mortality). A 7 times higher risk of dying from cardiovascular events has been described (especially in women, kidney tumors and Hodgkin lymphoma), almost 9 times the risk of dying from lung or respiratory problems (especially patients with AML or neuroblastoma) and more than 2 times from other medical reasons. After 20-30 years of treatment, mortality secondary to second neoplasms is the main cause of death (15 times higher than in the healthy population). Therefore, follow-up strictly restricted to 5 years post-treatment is insufficient in patients who have overcome a tumor in the pediatric age(7-9).

Risk of second neoplasms

Up to 5-20 times higher risk of suffering second tumors histologically different from the initial ones compared to the general population has been described. In general, they are observed at least 2 years after the primary tumor, and within the first 10 years of follow-up, although they can have a latency of up to 30 years(21). The cumulative incidence after 20 years is 3-10%, and after 30 years 5-30%, depending on the series. The primary tumors with the highest incidence of second neoplasms are Hodgkin lymphoma and soft tissue sarcomas. The most common secondary tumors are breast, thyroid, AML, and sarcomas(7). The main risk factors are(6,7,16):

• Chemotherapy. Alkylating agents are associated with myelodysplastic syndromes, which may or may not precede secondary acute myeloblastic leukemias. Their latency is usually 5-7 years and they are accompanied by cytogenetic abnormalities (monosomies and partial deletions of chromosomes 5 and 7). Epipodophyllotoxins (etoposide) are also associated with AML, but this usually develops earlier (2-3 years after completion of treatment). There is a greater risk with doses ≥ 2,000 mg/m2 and associated abnormalities of the MLL gene (which induces 11q23 translocations). Anthracyclines can also cause this type of leukemia, 2-3 years after treatment. The prognosis is unfavorable. Annual full blood count is recommended during long-term follow-up, at least up to 10 years after exposure to chemotherapy. The latency for the development of solid tumors is somewhat longer, on average 14 years. Etoposide increases the risk of secondary Hodgkin lymphoma, neuroblastoma, nephroblastoma, and rhabdomyosarcoma, among others.

• Radiotherapy. It is a relevant risk factor, especially when high doses are received at an early age. It is frequently used in CNS tumors, solid tumors and, historically, in Hodgkin lymphoma and the conditioning with total body irradiation of some transplants. The risk increases as time passes, with a maximum 10-15 years after treatment (although it remains until 30 years later). The types mainly observed are: breast tumors, meningiomas (cranial), bone and soft tissue tumors, thyroid cancer, non-melanoma skin cancer and bladder cancer.

• Hematopoietic stem cell transplantation. It can increase the risk of second neoplasms by up to 8 times compared to the general population (up to 60 times in recipients below the age of 10 years). Its origin is multifactorial (chemotherapy, conditioning radiotherapy and GVHD). Immunosuppressants are associated with the development of post-transplant lymphoproliferative syndrome.

• Cancer predisposition syndromes (Li-Fraumeni, DICER1, NF1-2, telomeropathies…). In recent years, hand in hand with advances in genetics, more are becoming diagnosed. This has allowed the identification of alterations in the germ line or mosaicisms that predispose to one or more tumors, increasing their importance in pediatric Hematology-Oncology. Given the length of the article, we refer the reader to review the bibliography in case of interest(22).

Sufficient information and adequate education about the personalized risks of each patient, promoting self-observation and reducing, as far as possible, risk factors (tobacco, alcohol, sun exposure) is important. Symptoms or signs that may be related to the primary tumor and that suggest a relapse should also be monitored. In this sense, to make an early diagnosis it is essential to have a high index of suspicion, to recognize the risk groups and the “red flags” (warning signs) in each patient(23,24).

The role of the Primary Care pediatrician

As previously discussed in this review, there is not a sole model for pediatric cancer survivor follow-up, and it is essential to adapt it to the individual characteristics and risks of each case, as well as to the real conditions of our healthcare system. In this sense, we have a Pediatric Primary Care network excellently prepared for the promotion of health (Fig. 1) and accompaniment of the patient during their growth. At the hospital level, progress is being made in the development of specialized units to follow-up this type of patients and in their transition to adult care, so we have a mixed care and follow-up model in the routine practice.

Primary Care professionals are a fundamental pillar of multidisciplinary teams, acting as a first line for the diagnosis of sequelae, relapses and second tumors, as well as promoting healthy lifestyle habits. An adequate transmission of the personal history, personalized risks and follow-up plan by hospital health care providers is necessary, as well as a fluid communication between both areas, which will result in a health benefit to our patients. Similarly, the patient and his family should be integrated in the responsibility of long-term care, avoidance of risk behaviors and perception of alarm signs or symptoms, which will prevent loss of adherence to follow-up or low perception of its importance in the long term.

Bibliography

The asterisks show the interest of the article in the opinion of the authors.

1.** Song A, Fish JD. Caring for survivors of childhood cancer: it takes a village. Current Opinion in Pediatrics. 2018; 30: 864-73.

2. Klassen AF, Anthony SJ, Khan A, Sung L, Klaassen R. Identifying determinants of quality of life of children with cancer and childhood cancer survivors: a systematic review. Support Care Cancer. 2011; 19: 1275-87.

3. Shad A, Myers SN, Hennessy K. Late effects in cancer survivors: “the shared care model”. Curr Oncol Rep. 2012; 14: 182-90.

4.** Bhakta N, Liu Q, Ness KK, Baassiri M, Eissa H, Yeo F, et al. The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE). The Lancet. 2017;390(10112):2569-82.

5. Essig S, Li Q, Chen Y, Hitzler J, Leisenring W, Greenberg M, et al. Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort. The Lancet Oncology. 2014; 15: 841-51.

6.** Armstrong GT, Chen Y, Yasui Y, Leisenring W, Gibson TM, Mertens AC, et al. Reduction in Late Mortality among 5-Year Survivors of Childhood Cancer. N Engl J Med. 2016; 374: 833-42.

7.*** Children’s Oncology Group. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (Internet). 2018. Disponible en: http://www.survivorshipguidelines.org/pdf/2018/COG_LTFU_Guidelines_v5.pdf.

8.*** Skinner R, Wallace W, Levitt GA. Therapy based long term follow up: practice statement: United Kingdom Children’s Cancer Study Group (Late Effects Group) (Internet). Disponible en: https://www.cclg.org.uk/write/MediaUploads/Member%20area/Treatment%20guidelines/LTFU-full.pdf.

9.*** Scottish Intercollegiate Guidelines Network (SIGN), Scotland, Healhcare Improvement Scotland. Long Term Follow Up of Survivors of Childhood Cancer, A National Clinical Guideline (Internet). Disponible en: https://www.sign.ac.uk/media/1070/sign132.pdf.

10.*** Late Effects Taskforce of the Dutch Childhood Oncology Group (DCOG LATER). Guidelines for follow-up after childhood cancer more than 5 years after diagnosis (Internet). Disponible en: https://www.skion.nl/workspace/uploads/vertaling-richtlijn-LATER-versie-final-okt-2014_2.pdf.

11.*** Grupo de trabajo sobre efectos secundarios a largo plazo y segundos tumores de la Sociedad Española de Hematología y Oncología Pediátricas. “Efectos tardíos en supervivientes al cáncer en la infancia”. Cevagraf. 2012.

12.*** Armenian SH, Hudson MM, Mulder RL, Chen MH, Constine LS, Dwyer M, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. The Lancet Oncology. 2015; 16: e123-36.

13. Chow EJ, Leger KJ, Bhatt NS, Mulrooney DA, Ross CJ, Aggarwal S, et al. Paediatric cardio-oncology: epidemiology, screening, prevention, and treatment. Cardiovascular Research. 2019; 115: 922-34.

14. Bansal N, Amdani S, Lipshultz ER, Lipshultz SE. Chemotherapy-induced cardiotoxicity in children. Expert Opinion on Drug Metabolism & Toxicology. 2017; 13: 817-32.

15. Jin Y, Xu Z, Yan H, He Q, Yang X, Luo P. A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors. Front Pharmacol. 2020; 11: 891.

16.*** Mendoza Sánchez MC. Seguimiento en Atención Primaria del niño oncológico. Cómo detectar las secuelas tardías. Pediatr Integral. 2016; XX(7): 475-84.

17. Christen S, Roser K, Mulder RL, Ilic A, Lie HC, Loonen JJ, et al. Recommendations for the surveillance of cancer-related fatigue in childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. J Cancer Surviv. 2020; 14: 923-38.

18.** Garrido-Colino C, Lassaletta A, Vázquez MÁ, Echevarría A, Gutiérrez I, Andión M, et al. Situación de la preservación de fertilidad en pacientes con cáncer en nuestro medio: grado de conocimiento, información e implicación de los profesionales. Anales de Pediatría. 2017; 87: 3-8.

19. Friedman DN, Tonorezos ES, Cohen P. Diabetes and Metabolic Syndrome in Survivors of Childhood Cancer. Horm Res Paediatr. 2019; 91: 118-27.

20. Dekkers IA, Blijdorp K, Cransberg K, Pluijm SM, Pieters R, Neggers SJ, et al. Long-Term Nephrotoxicity in Adult Survivors of Childhood Cancer. CJASN. 2013; 8: 922-9.

21.** Choi DK, Helenowski I, Hijiya N. Secondary malignancies in pediatric cancer survivors: Perspectives and review of the literature: Secondary malignancies in pediatric cancer survivors. Int J Cancer. 2014; 135: 1764-73.

22.** Ripperger T, Bielack SS, Borkhardt A, Brecht IB, Burkhardt B, Calaminus G, et al. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet. 2017; 173: 1017-37.

23.** Huerta Aragonés J. Oncología para el pediatra de Atención Primaria (I): signos y síntomas sugerentes de patología neoplásica. Form Act Pediatr Aten Prim. 2014; 1: 4-15.

24.** Huerta Aragonés J. Oncología para el pediatra de Atención Primaria (II): formas de presentación de las diferentes neoplasias infantiles. Form Act Pediatr Aten Prim. 2014; 7: 67-74.

Recommended bibliography

- Children’s Oncology Group. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (Internet). 2018. Available at:http://www.survivorshipguidelines.org/pdf/2018/COG_LTFU_Guidelines_v5.pdf.

These guidelines are a mainstay in the follow-up, diagnosis and management of late effects in survivors of childhood cancer, with a dilated experience (almost 20 years). They are currently in their 5th version, being updated approximately every 5 years.

- Scottish Intercollegiate Guidelines Network (SIGN), Scotland, Healthcare Improvement Scotland. Long Term Follow Up of Survivors of Childhood Cancer, A National Clinical Guideline. [Internet]. Available in: https://www.sign.ac.uk/media/1070/sign132.pdf.

High quality consensus guidelines, from the year 2013, organized by body organs and systems.

- Skinner R, Wallace W, Levitt GA. Therapy based long term follow up: practice statement: United Kingdom Children’s Cancer Study Group (Late Effects Group) (Internet). Available at: https://www.cclg.org.uk/write/MediaUploads/Member%20area/Treatment%20guidelines/LTFU-full.pdf.

These consensus guidelines focus on both the long-term side effects in the various body organs and those specific to the chemotherapy or radiotherapy treatment received, providing an interesting point of view.

- Grupo de trabajo sobre efectos secundarios a largo plazo y segundos tumores de la Sociedad Española de Hematología y Oncología Pediátricas. “Efectos tardíos en supervivientes al cáncer en la infancia”. Cevagraf. 2012. (Working group on long-term side effects and second tumors of the Spanish Society of Pediatric Hematology and Oncology. “Late effects in survivors of childhood cancer”. Cevagraf. 2012.)

Interesting publication by the SEHOP Working Group on Side Effects, in the form of a textbook. Excellent description of each topic that surpasses in exposure and understanding that obtained, sometimes, in more schematic guides.

- Armenian SH, Hudson MM, Mulder RL, Chen MH, Constine LS, Dwyer M, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. The Lancet Oncology. 2015; 16: e123-36.

Very good article that summarizes the recommendations for cardiac monitoring and surveillance in patients at risk, with special emphasis on risk groups and long-term problems. It is the result of the cooperative work between the Children’s Oncology Group and several European groups, which make up the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG).

- Ripperger T, Bielack SS, Borkhardt A, Brecht IB, Burkhardt B, Calaminus G, et al. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet. 2017; 173: 1017-37.

Review of the most relevant cancer predisposition syndromes, with special interest in the risks of pediatric tumor development and specific follow-up recommendations.

Topics on Continuous Training

V. Losa Frías, M. Herrera López, I. Cabello García, P.I. Navas Alonso

*Fuensalida Primary Care Center. Toledo. **Pediatric Service. Virgen de la Salud Hospital. Toledo. ***La Puebla de Montalbán Primary Care Center. Toledo. ****Pedro Fuente Primary Care Center. Bargas. Toledo

Key words: Lactante; Niño; Neoplasias; Atención Primaria; Diagnóstico precoz de cáncer.

Palabras clave: Infant; Child; Neoplasms; Primary health care; Early detection of cancer.

Pediatr Integral 2021; XXV (6): 283 – 295

How to suspect cancer in 
Primary Care

Introduction

Childhood cancer has a low incidence and often manifests nonspecifically, simulating other frequent and benign processes. These particularities make it difficult to diagnose cancer in Primary Care. However, an early suspicion, together with a rapid referral of the patient to a specialized center, may have implications at the prognostic and therapeutic level, as well as in the emotional impact secondary to the diagnosis on the patient and his family.

Epidemiology

Childhood cancer is after accidents, the second leading cause of death beyond the first year of life.

The standardized annual incidence of childhood cancer in Spain is 159 new cases per year per million children aged 0 to 14 years, which represents 1,100 new cases of childhood cancer per year, an incidence similar to that of the rest of Europe(1). It is estimated that a Primary Care pediatrician following 1,500 patients in his clinic, will see a new case of cancer every 5 years. Overall 5-year survival after the diagnosis is around 79%(1). Despite recent advances, childhood cancer is the second leading cause of death from the first year of life through adolescence. In the year 2018, 192 children under 14 years of age died in Spain from cancer, which means 4 children died per week due to this cause(2). The most frequent neoplasms from birth to 14 years of age are: leukemias (28%), central nervous system (CNS) tumors (23%) and lymphomas (12%), with a distribution pattern by sex and age similar to that of the rest of Europe, whilst between 15 and 19 years of age they are: bone tumors (24%), lymphomas (21%) and CNS tumors (15%). The most frequent diagnoses according to the age group are shown in Table I(1).

Patients at risk

Medical history is the most effective tool in identifying cancer predisposition syndromes.

There is a hereditary basis in 8-10% of all neoplasms. Within this percentage, cancer predisposition syndromes (CPS) are included, conforming a heterogeneous group of genetic conditions and immunodeficiencies, which predispose to a greater risk of cancer (Table II).

Most of these syndromes are rare and show variable expressiveness within the family members. It is important to identify these patients, as they can benefit from prevention and early detection measures, as well as the possibility of genetic counseling. During history-taking, CPS may be suspected should there be(3):

• Several cases of cancer within the family, usually of the same type.

• Multi-generational disease cases, presenting at an earlier age than in the general population.

• Presence of tumors in association with developmental defects: generalized or asymmetric body overgrowth, dysmorphic features, congenital malformations or mental retardation.

• Presence of bilateral or multifocal tumors.

• Individuals with more than one primary tumor.

• Presence of rare, benign tumors or cysts associated with CPS.

Warning signs and symptoms

Apparently benign symptomatology, but with atypical presentation or torpid course, may be the beginning of a neoplastic process.

Childhood cancer can manifest in its initial stages, with symptoms similar to frequent and benign processes(4). The purpose is to recognize when this apparently benign symptomatology may be the beginning of a serious pathology, as well as to identify those findings (red flags) that, in combination with the rest of the data from history and physical examination, should alert us of the possibility of cancer (Table III).

For this, it is necessary to listen and pay special attention to parents(5), who in general are the best observers of their children’s symptoms, and also to adolescents(6); taking a complete medical history including personal and family history, and a thorough physical examination.

Qualitative studies highlight the importance of behavioral and affective changes detected by parents, that motivate the first visits to Primary Care prior to the diagnosis of cancer, sometimes in the absence of other signs of alarm(5,7). Such is the case, that the National Institute for Clinical Excellence (NICE) recommends considering the persistent parental concern regarding their children’s symptoms as a reason for study or referral(8). In Primary Care, the following signs and symptoms have been reported to increase the possibility of cancer: paleness, head and neck masses, abdominal masses, lymphadenopathy, motor abnormalities, bruises and other signs of bleeding, asthenia, headache, visual anomalies, pain and musculoskeletal symptoms. However, except for abdominal masses, the positive predictive value of these symptoms is low, given the low frequency of childhood cancer. Even so, given the severity of the diagnosis, the presence of the aforementioned symptoms, fundamentally when it occurs without a clear cause and leads to an increase in the number of consultations (3 or more in a period of 3 months), should alert of the possibility of a neoplastic process(9). In this sense, the Pan American Health Organization has published an evaluation strategy, a cancer probability classification and attitude based on the findings of the history and examination shown in Algorithm 1(10).

Headache and other neurological signs and symptoms

Primary CNS tumors are the second most common neoplasia in childhood after leukemias(1), as well as the second leading cause of death from childhood cancer(2). Their symptoms are due to the invasion and compression of the adjacent nervous tissue, as well as the increase in intracranial pressure due to mass effect or obstructive hydrocephalus (Fig. 1), manifesting a very heterogeneous clinical presentation.

Wilne et al.(11) analyzed 74 articles (n = 4,171), identifying up to a total of 56 signs and symptoms at the diagnosis of a CNS tumor, which depended on age, location and history of neurofibromatosis (NF). For intracranial tumors, excluding NF, the most frequent symptoms were: headache, nausea and vomiting, abnormality of gait and coordination, and papilledema. In intracranial tumors associated with NF these were: decreased visual acuity, exophthalmos, optic atrophy and strabismus. In intracranial tumors in children under 4 years they were: macrocephaly, nausea and vomiting, irritability, lethargy and ataxia. And in spinal cord tumors they were: back pain, gait and coordination abnormality, spinal deformity, focal weakness and sphincter alterations. Given this clinical variability, they subsequently studied the evolution of symptoms in a retrospective cohort (n = 139), describing a progressive increase in the number of symptoms. Thus, half of the patients went from one symptom at the beginning of the process to six at the diagnosis of the tumor(12). In Primary Care, we must be alert to patients with non-resolving symptoms or in which new ones are associated, especially: visual, motor, endocrine or behavioral, as well as signs of intracranial hypertension(12-14). In this line, Ansell et al.(15) described the reasons for consultation in Primary Care, from birth to the diagnosis of a CNS tumor in a series of patients, comparing it with a control group. They observed how the cases consulted three times more often for a sign or symptom suggestive of a CNS tumor, reaching seven times more when they associated two or more symptoms.

The Children’s Brain Tumour Research Centre group has developed an evidence-based clinical guide(16) (Table IV), as well as the awareness strategy “HeadSmart: be brain tumours aware” (https://www.headsmart.org.uk/), which has shown positive results in reducing the time from the onset of symptoms to diagnosis (median 14 to 6.7 weeks), as well as the time from the first consultation to an imaging test (3.3 to 1.4 weeks)(17).

Fever and constitutional symptoms

Fever is one of the most frequent reasons for consultation in Pediatrics, being, in most cases, of infectious etiology. Only 6% of the cases of fever of unknown origin correspond to neoplasms(18). This fever can be of tumor origin (Ewing’s sarcoma, neuroblastoma, Hodking’s lymphoma…) or due to infections secondary to the alteration of the immune system due to cancer, as can occur in leukemias.

Leukemia is the most common pediatric tumor(1). Clarke et al.(19) analyzed the symptoms at the diagnosis of leukemia in childhood and adolescence in 33 studies (n = 3,084), and identified a total of 95 signs and symptoms, of which five were present in more than half of the patients: hepatomegaly, splenomegaly, paleness, fever and bruising. In addition, between a third and a half of the patients presented: recurrent infections, asthenia, pain in the extremities, hepatosplenomegaly, hematomas / petechiae, lymphadenopathies, bleeding tendency and skin rash. These findings highlight the importance of performing a complete physical examination in children with common symptoms, such as fever, but with a torpid or persistent course, paying special attention to abdominal palpation, lymphadenopathy search and careful skin examination. Despite the fact that leukemia is the most frequent pediatric cancer, there is currently no evidence of the predictive value of clinical data at the individual level, or of their combination. NICE guidelines recommend that pediatric patients with fever of unclear cause or in combination with unjustified clinical data such as: paleness, asthenia, lymphadenopathies, splenomegaly, osteoarticular pain, bruising, night sweats or weight loss, should be evaluated with a full blood count and peripheral blood smear within 48 hours; in the case of associating petechiae or unexplained hepatosplenomegaly, immediate referral is recommended(8).

Lymphadenopathies

Lymph nodes are dynamic structures that change in size during children´s growth, usually in response to infections. During childhood, palpation of small lymph nodes in cervical, axillary, or inguinal regions is normal. An increase in size above 1 cm in cervical and axillary nodes, 1.5 cm in inguinal and 0.5 cm in epitrochlear nodes, as well as stone-like consistency, irregular surface, existence of skin ulceration or fixation is considered pathological(20) (Fig. 2).

Lymphadenopathies are generalized, when they extend beyond more than 2 non-contiguous ganglion chains, and localized, when they appear in a single region. According to the course in terms of length of time, we distinguish between acute (less than three weeks) and subacute / chronic (more than three weeks / months)(21). In the history, we should inquire for: the age of the patient, the form of onset, the time of progression and the speed of growth, as well as the presence of recent or recurrent infections, contact with sick people, associated symptoms, previous antibiotic treatments, similar episodes, vaccination status, medications, contact with animals or recent travels. A complete physical examination should be performed, looking for signs of systemic disease and paying special attention to the presence of skin lesions, paleness, signs of bleeding, oropharyngeal or conjunctival lesions, hepatosplenomegaly, and abdominal masses. Adenopathies will be evaluated based on their size, location, tenderness, consistency, mobility, local inflammatory signs, and presence of skin fistulas. We must systematically palpate all accessible ganglion chains: occipital, retroauricular, preauricular, parotid, tonsillar, submandibular, submental, anterior and posterior neck, supraclavicular, infraclavicular, axillary, epitrochlear, inguinal and popliteal. Warning signs in the evaluation of adenopathies are: size greater than 3 cm, rapid growth in the absence of inflammatory signs, hard consistency, fixation to deep planes, supraclavicular, axillary, generalized or confluent location, as well as constitutional symptoms, the presence of abdominal masses, hard hepatosplenomegaly, signs of respiratory distress, paleness, jaundice or bleeding(8,20-22).

Mediastinal mass

Mediastinal masses in childhood are rare and, in most cases, are malignant. The most frequent location is the anterior mediastinum and the most frequent etiology is lymphoma(23,24). A thorough clinical evaluation and a high index of suspicion are important for an early diagnosis. Upon clinical suspicion, immediate referral to a hospital center to complete the study is recommended(8,23).

From an anatomical point of view, the mediastinum is divided into three compartments: anterior, middle, and posterior. The location of the mass will guide the diagnosis (Table V).

The most frequent neoplasms according to their location are: acute lymphoblastic leukemia and T lymphoma (Fig. 3) in the anterior mediastinum; Hodgkin lymphoma in the middle mediastinum; and neurogenic tumors (neuroblastoma and ganglioneuroma) in the posterior mediastinum. Posterior mediastinal masses (neuroblastoma) are more common in infants and young children, while anterior mediastinal masses (leukemias, lymphomas) are more common in older children and adolescents(24).

A high percentage of patients are asymptomatic at diagnosis. In symptomatic cases, the symptoms are secondary to compression of adjacent structures, so the symptoms depend on the location of the mass, its size, and the rate of growth. Compression of the airway is the most frequent symptom, giving rise to nonspecific symptoms, such as: stridor, non-productive cough, wheezing, recurrent respiratory infections, chest pain and respiratory distress that often simulate frequent respiratory diseases, such as asthma or laryngitis. Esophageal compression leads to dysphagia. Compression of the spinal cord (common in neuroblastoma) results in band or radicular back pain that increases with Valsalva, gait weakness, loss of strength and sensory and sphincter alterations. Compression of the superior vena cava (characteristic of leukemias and T lymphomas) manifests with: facial plethora, headache, blurred vision, cough, chest pain, orthopnea that increases with Valsalva, hypotension and heart failure. Compression of the phrenic leads to hemidiaphragmatic elevation. Finally, injury to the sympathetic pathway (especially neuroblastomas) can cause Horner syndrome (ptosis, miosis, and enophthalmos). And, in turn, we can find systemic symptoms secondary to the tumor process itself. Compression of the phrenic leads to hemidiaphragmatic elevation. Finally, injury of the sympathetic pathway (especially neuroblastomas) can cause Horner syndrome (ptosis, miosis, and enophthalmos). In addition, we can find systemic symptoms secondary to the tumor process itself.

We must bear in mind that treatment prior to diagnosis with systemic corticosteroids in patients with hematological malignancies may have diagnostic and prognostic implications, and precipitate serious complications, such as tumor lysis syndrome. For this reason, in patients with atypical respiratory symptoms or laryngitis in older children, performing a chest X-ray prior to starting corticosteroid treatment is recommended(23,25).

Abdominal mass

The finding of an abdominal mass is one of the most frequent forms of presentation of neoplasms in childhood. Although they may be of benign etiology, all patients with an abdominal mass must be evaluated with the suspicion of malignancy and referred to a specialized center within 48 hours(8).

An abdominal mass is often asymptomatic, and is usually detected accidentally by the parents or in a routine examination. In the history, we will take into account the patient’s age (Table VI), the associated symptoms, their intensity and duration, taking into account which rapidly evolving symptoms are suggestive of malignancy(26,27).

The most frequent presentation symptoms are: pain, organ dysfunction due to mass effect (intestinal or urinary obstruction), hematuria (nephroblastoma) and systemic symptoms (night sweats, fever, asthenia, weight loss or bone pain…). The most frequent etiology involves: genitourinary congenital malformations in children under one year of age; neuroblastoma (Fig. 4) and nephroblastoma (Fig. 5) between one and five years; and non-Hodgkin lymphoma (NHL) in older children and adolescents.

In this age group, Burkitt-type NHL presents as: a rapidly growing abdominal mass that associates abdominal distention and pain, obstructive symptoms, intussusception, and metabolic alterations secondary to tumor lysis(26). In girls and adolescents, we will take into account ovarian tumors and pregnancy. In the personal history, factors such as prematurity and low birth weight (hepatoblastoma), should also be assessed.

Physical examination should be performed with the patient relaxed and calm. It must be meticulous, checking vital signs, including blood pressure(27). On inspection, we will look for irregularities on the abdominal surface. On palpation, we must take into account that, in healthy patients, especially infants, some structures may be palpable, such as: liver, spleen, kidneys, abdominal aorta, sigmoid colon, feces and / or spine(28). It is important to establish the location, size, shape, and contour of the mass, its adherence to deep planes, as well as the presence of tenderness. Depending on the location it should be considered that: palpable masses in the right upper quadrant are usually of hepatic, renal or adrenal origin; those in the upper left quadrant often depend on the spleen and may be secondary to metastatic infiltration; and those located in the hypogastrium, are usually secondary to ovarian tumors or intestinal lymphomas. In the patient with suspected neuroblastoma, a complete neurological examination is necessary due to the possibility of invasion of the medullary canal. Other examination signs that can guide the diagnosis are: aniridia, hemihypertrophy and genitourinary malformations (nephroblastoma); subcutaneous nodules, periorbital ecchymoses, proptosis, intractable watery diarrhea, Horner syndrome or opsoclonus-myoclonus syndrome (neuroblastoma); precocious puberty, feminization or virilization (hepatic, gonadal, adrenal masses or germ tumors); and Cushing phenotype (neoplasms of the adrenal cortex).

Soft tissue and skin masses

Soft tissue sarcomas (STS) are a heterogeneous group of tumors that originate from primitive mesenchymal cells. They are subdivided into rhabdomyosarcoma (RBM) and non-rhabdomyosarcoma sarcomas. RBM is the most frequent, it has its origin in the primitive mesenchymal cells involved in the development of skeletal muscle, and it presents its maximum incidence around the age of five years and in adolescence. It is subdivided into: embryonal, alveolar and pleomorphic. On the other hand, non-rhabdomyosarcoma sarcomas are more common in older children and adolescents.

STS can appear in any anatomical location, the most frequent being: the genitourinary region, head and neck, and extremities. The clinical presentation depends on the location, size and adjacent structures. An unexplained tumor in any location with any of the following characteristics is suspicious of STS: diameter greater than 2 cm, fixation to deep planes, increased consistency, progressive growth, and presence of regional lymphadenopathies(4). In the head, orbital locations usually develop proptosis and a differential diagnosis must be made with benign pathologies, such as orbital cellulitis. Parameningeal locations can lead to nasal, sinus, or ear obstruction, persistent mucopurulent discharge, or cranial nerve involvement. In the genitourinary region, it can present as: hematuria, voiding syndrome, constipation, pelvic mass or increased testicular size. The botryoid variety is a subtype of embryonic RMS characterized by multiple polypoid projections that form clusters of gelatinous and friable consistency, that develop under the mucosal surface of body orifices, such as vagina and nose.

When a soft tissue tumor is suspected, NICE guidelines recommend performing an ultrasound within 48 hours(8).

Musculoskeletal symptoms and signs

Musculoskeletal pain is a frequent reason for consultation in Primary Care. Its etiology varies with age, the most frequent causes being traumatic. The differential diagnosis will include overuse syndromes and osteochondroses. Less frequently, but highly important as their diagnosis delay can increase morbidity, are neoplasms and osteoarticular infections. Among the most frequent neoplasms that present with bone and / or joint pain, primary bone tumors, neuroblastomas, NHL and leukemias, can be found.

Patients with primary bone tumors, such as osteosarcoma or Ewing’s sarcoma, frequently present with localized, persistent, asymmetric, progressive bone pain that responds poorly to common analgesics and may wake the child up at night. They can associate a palpable indurated mass fixed to deep planes and of rapid and progressive growth and, occasionally, a pathological fracture can occur. Generalized musculoskeletal pain manifests as: lower limb pain, back pain, arthralgia or arthritis. The tumors that produce it are leukemias, especially lymphoblastic leukemia and bone or medullary metastases of tumors, such as Ewing’s sarcoma or neuroblastoma.

Several authors(29-31) have highlighted the relevance of incorporating leukemias and bone tumors in the differential diagnosis of patients with suspected osteomyelitis or rheumatological diseases. Leukemias that present with joint symptoms (generally in the form of asymmetric oligoarthritis) are less frequently associated with typical leukemia symptoms, such as: constitutional syndrome, hepatosplenomegaly or cytopenia, which makes diagnosis difficult(29). In the evaluation of patients with musculoskeletal symptoms, the association of leukopenia (less than 4 x 109 / L), platelets in the lower limit of normality (150-250 x 109 / L) and a history of nocturnal pain, represents a sensitivity of 100% and specificity of 85% in the diagnosis of leukemia(30). The importance of an accurate diagnosis prior to the start of steroid treatment should be noted, given the possibility of masking a hematological neoplasm or triggering a tumor lysis syndrome. For this reason, some authors suggest performing a bone marrow study prior to initiating treatment with steroids, in those patients with suspected rheumatological disease and atypical data(31).

A complete medical history that includes: characterization of the pain (onset, location, duration, intensity, number of affected joints); presence of other accompanying symptoms (inflammation, increased temperature, joint instability); precipitating factors (previous infection or trauma); and associated systemic symptoms, as well as a thorough physical examination, will guide the diagnosis. In a patient with bone and / or joint pain with suspected cancer, an X-ray as well as a full blood count and peripheral blood smear shall be performed within 48 hours. In case of a pathological X-ray, the patient should be referred to a specialized center within 48 hours. When leukemia is suspected (cytopenia of two or more cell lines and / or blasts), referral will be immediate(8).

Eye disorders

Retinoblastoma is the most common ocular neoplasm, representing 3% of childhood tumors(1). It is usually diagnosed between the first and third year of life, and 95% of them before the age of 5 years(1). 30% are bilateral and 40% hereditary. Leukocoria is the presenting sign in more than half of the cases, and it appears as a consequence of the presence of a mass located behind the crystalline lens. In the differential diagnosis of leukocoria, in addition to retinoblastoma, congenital cataracts (history of infection in pregnancy, such as toxoplasmosis, should be investigated) and Coats disease (retinal telangiectasia with deposition of intraretinal or subretinal exudates that affects younger children). Other symptoms and signs that should alert us include: strabismus, loss of visual acuity, eye pain or proptosis. In addition to retinoblastoma, other tumors that can manifest as proptosis include: neuroblastoma, rhabdomyosarcoma, lymphoma, and histiocytosis. The successful management of retinoblastoma depends on the ability to detect the disease while it still remains intraocular(32). Hence, it is very important to test for the red reflex in all newborns and in each programmed child health visit. An abnormal result of the red reflex examination is an indication for preferential referral (in less than two weeks) to the ophthalmologist(8). Patients with a family history of retinoblastoma must be referred from birth for close ophthalmological follow-up(3).

Another ocular manifestation of cancer is the paraneoplastic opsoclonus-myoclonus syndrome, which is associated with neuroblastoma in 50% of cases. It is characterized by multidirectional, involuntary and chaotic rapid eye movements, persistent during sleep, myoclonus, ataxia, and behavioral disturbances.

Time lapse to childhood cancer diagnosis

Decreasing the time to diagnosis has prognostic implications in some childhood tumors.

The most effective strategy to reduce the morbidity and mortality of childhood cancer is to focus, both on the reduction of the time to diagnosis (TD), understood as the time elapsed from the onset of symptoms to the diagnosis of cancer(33) (Fig. 6), as in the early initiation of treatment based on scientific evidence.

Therefore, the recognition of alarm symptoms by families and Primary Care professionals, as well as easy access to the latter, is a priority. Screenings in childhood are usually not helpful, unless the child has a high risk of cancer associated with hereditary disorders. Among factors that have been related to TD, the following stand out: the patient’s age (the older, the greater the TD); the type of tumor (CNS, bone, germ cells and retinoblastomas have longer TD compared to leukemia and kidney tumors); and tumor biology(33-35). The relationship of TD with survival is complex. Thus, some authors(35,36) indicate that it is precisely the biology of the tumor, the factor that most influences TD and survival. In any case, there is extensive literature supporting a positive correlation between improved survival and early diagnosis in tumors such as retinoblastoma(35), being this correlation more ambiguous for CNS and other solid tumors, probably in relation to high-grade tumors having a more abrupt onset of prediagnostic symptoms and, therefore, a shorter TD(37). In the group of adolescents and young adults, although females more frequently consult physicians, they have more prolonged TD. Bone tumors and lymphomas have longer TD, probably due to the non-specific clinical presentation of these types of cancer(6).

It should be noted how, in the COVID-19 pandemic situation, several publications have warned of the increase in TD of childhood cancer in neighboring countries(38,39).

Role of the Primary Care pediatrician

The Primary Care pediatrician shares the responsibility of reducing TD, identifying those patients suspected of cancer and making an early referral to specialized care. This decrease in TD may have a prognostic role for some tumors and, in addition, contributes to the reduction of anxiety and stress experienced by patients and their families during the difficult period prior to the diagnosis of childhood cancer(5).

Bibliography

The asterisks show the interest of the article in the opinion of the authors.

1. Pardo Romaguera E, Muñoz López A, Valero Poveda S, Porta Cebolla S, Fernández-Delgado R, Barreda Reines MS PBR. Cáncer infantil en España. Estadísticas 1980-2017. Registro Español de Tumores Infantiles (RETI-SEHOP). Valencia: Universitat de Valéncia, 2018 (Preliminar edition, CD-Rom).

2. Ministerio de Sanidad, Servicios Sociales e Igualdad. Portal Estadístico (sede Web). Accessed february 28, 2021. Available at: https://pestadistico.inteligenciadegestion.mscbs.es/publicoSNS/S.

3.*** Coury SA, Schneider KA, Schienda J, Tan WH. Recognizing and managing children with a pediatric cancer predisposition syndrome: A guide for the pediatrician. Pediatr Ann. 2018; 47: e204-16.

4.*** Fragkandrea I, Nixon JA, Panagopoulou P. Signs and symptoms of childhood cancer: a guide for early recognition. Am Fam Physician. 2013; 88: 185-92.

5.*** Dixon-Woods M, Findlay M, Young B, Cox H, Heney D. Parents’ accounts of obtaining a diagnosis of childhood cancer. Lancet. 2001; 357: 670-4.

6.** Herbert A, Lyratzopoulos G, Whelan J, Taylor RM, Barber J, Gibson F, et al. Diagnostic timeliness in adolescents and young adults with cancer: a cross-sectional analysis of the BRIGHTLIGHT cohort. Lancet Child Adolesc Health. 2018; 2: 180-90.

7.*** Clarke RT, Jones CHD, Mitchell CD, Thompson MJ. Shouting from the roof tops: a qualitative study of how children with leukaemia are diagnosed in primary care. BMJ Open. 2014; 4: e004640. doi:10.1136/bmjopen-2013-004640.

8.** NICE. Suspected cancer recognition and referral: symptoms and findings. Updated january 29, 2021. Accessed april 1st, 2021. Available at: https://www.nice.org.uk/guidance/ng12.

9.** Dommett RM, Redaniel T, Stevens MCG, Martín RM, Hamilton W. Risk of childhood cancer with symptoms in primary care: a population-based case-control study. Br J Gen Pract. 2013; 63: e:22-9.

10.** Pan American Health Organization. Early diagnosis of childhood cancer. Washington, DC; OPS. 2014.

11.** Wilne S, Collier J, Kennedy C, Koller K, Grundy R, Walker D. Presentation of childhood CNS tumours: a systematic review and meta-analysis. Lancet Oncol. 2007; 8: 685-95.

12. Wilne S, Collier J, Kennedy C, Jenkins A, Grout J, MacKie S, et al. Progression from first symptom to diagnosis in childhood brain tumours. Eur J Pediatr. 2012; 171: 87-93.

13. Chu TPC, Shah A, Walker D, Coleman MP. Where are the opportunities for an earlier diagnosis of primary intracranial tumours in children and young adults? Eur J Paediatr Neurol. 2017; 21: 388-95.

14. Shanmugavadivel D, Liu JF, Murphy L, Wilne S, Walker D. Accelerating diagnosis for childhood brain tumours: An analysis of the HeadSmart UK population data. Arch Dis Child. 2020; 105: 355-62.

15. Ansell P, Johnston T, Simpson J, Crouch S, Roman E, Picton S. Brain tumor signs and symptoms: Analysis of primary health care records from the UKCCS. Pediatrics. 2010; 125: 112-9.

16.*** Wilne S, Koller K, Collier J, Kennedy C, Grundy R, Walker D. The diagnosis of brain tumours in children: A guideline to assist healthcare professionals in the assessment of children who may have a brain tumour. Arch Dis Child. 2010; 95: 534-9.

17.*** Walker D, Wilne S, Grundy R, Kennedy C, Neil, Dickson A, et al. A new clinical guideline from the Royal College of Paediatrics and Child Health with a national awareness campaign accelerates brain tumor diagnosis in UK children – “headSmart: Be Brain Tumour Aware.” Neuro Oncol. 2016; 18: 445-54.

18. Chow A, Robinson JL. Fever of unknown origin in children: a systematic review. World J Pediatr. 2011; 7: 5-10.

19. Clarke RT, Van Den Bruel A, Bankhead C, Mitchell CD, Phillips B, Thompson MJ. Clinical presentation of childhood leukaemia: A systematic review and meta-analysis. Arch Dis Child. 2016; 101: 894-901.

20.** Del Rosal Rabes T, Baquero Artigao F. Adenitis cervical. Pediatr Integral. 2018; XXII(7): 307-15.

21. Nield LS, Kamat D. Lymphadenopathy in Children: When and How to Evaluate. Clin Pediatr (Phila). 2004; 43: 25-33.

22. Chiappini E, Camaioni A, Benazzo M, Biondi A, Bottero S, De Masi S, et al. Development of an algorithm for the management of cervical lymphadenopathy in children: Consensus of the Italian Society of Preventive and Social Pediatrics, jointly with the Italian Society of Pediatric Infectious Diseases and the Italian Society of Pedi. Expert Rev Anti Infect Ther. 2015; 13: 1557-67.

23.** Green K, Behjati S, Cheng D. Fifteen-minute consultation: Obvious and not-so-obvious mediastinal masses. Arch Dis Child Educ Pract Ed. 2019; 104: 298-303.

24. Chen C, Wu K, Chao Y, Weng D, Chang J-S, Lin C-H. Clinical manifestation of pediatric mediastinal tumors, a single center experience. Medicine. 2019; 98: 32.

25.** Saraswatula A, McShane D, Tideswell D, Burke GAA, Williams DM, Nicholson JC, et al. Mediastinal masses masquerading as common respiratory conditions of childhood: A case series. Eur J Pediatr. 2009; 168: 1395-9.

26.** Uzunova L, Bailie H, Murray MJ. Fifteen-minute consultation: A general paediatrician’s guide to oncological abdominal masses. Arch Dis Child Educ Pract Ed. 2019; 104: 129-34.

27. Potisek NM, Antoon JW. Abdominal masses. Pediatr Rev. 2017; 38: 101-3.

28. Steuber PC. Clinical assessment of the child with suspected cancer. UpToDate; 2021. p. 1-24.

29. Brix N, Rosthøj S, Herlin T, Hasle H. Arthritis as presenting manifestation of acute lymphoblastic leukaemia in children. Arch Dis Child. 2015; 100: 821-25.

30. Jones OY, Spencer CH, Bowyer SL, Dent PB, Beth S, Rabinovich CE. A Multicenter Case-Control Study on Predictive Factors Distinguishing Childhood Leukemia From Juvenile Rheumatoid Arthritis. 2006; 117: e840-4.

31. Sen ES, Moppett JP, Ramanan AV. Are you missing leukaemia? Arch Dis Child. 2015; 100: 811-2.

32. Parrilla Vallejo M, Perea Pérez R, Relimpio López I, Montero de Espinosa I, Rodríguez de la Rúa E, Terrón León JA, et al. Retinoblastoma: The importance of early diagnosis. Arch Soc Esp Oftalmol. 2018; 93: 423-30.

33.** Lethaby CD, Picton S, Kinsey SE, Phillips R, Van Laar M, Feltbower RG. A systematic review of time to diagnosis in children and young adults with cancer. Arch Dis Child. 2013; 98: 349-55.

34. Barr RD. “Delays” in diagnosis: A misleading concept, yet providing opportunities for advancing clinical care. J Pediatr Hematol Oncol. 2014; 36: 169-72.

35.*** Brasme JF, Morfouace M, Grill J, Martinot A, Amalberti R, Bons-Letouzey C, et al. Delays in diagnosis of paediatric cancers: A systematic review and comparison with expert testimony in lawsuits. Lancet Oncol 2012; 13: e445-59.

36. Brasme JF, Chalumeau M, Oberlin O, Valteau-Couanet D, Gaspar N. Time to diagnosis of Ewing tumors in children and adolescents is not associated with metastasis or survival: A prospective multicenter study of 436 patients. J Clin Oncol. 2014; 32: 1935-40.

37.** Ferrari A, Lo Vullo S, Giardiello D, Veneroni L, Magni C, Clerici CA, et al. The Sooner the Better? How Symptom Interval Correlates With Outcome in Children and Adolescents With Solid Tumors: Regression Tree Analysis of the findings of a prospective study. Pediatr Blood Cancer. 2016; 63: 479-85.

38. Soares Martins QC, Gomes de Morais Fernandes FC, Pereira Santos VE, Guerra Azevedo I, Góes de Carvalho Nascimento, LS, Dos Santos Xavier CC, et al. Factors associated with the detection of childhood and adolescent cancer in primary health care: A prospective cross-sectional study. J Multidiscip Healthc. 2020; 13: 329-37.

39. Chiaravalli S, Ferrari A, Sironi G, Gattuso G, Bergamaschi L, Puma N, et al. A collateral effect of the COVID-19 pandemic: Delayed diagnosis in pediatric solid tumors. Pediatr Blood Cancer. 2020; 67: 2-3.

Recommended bibliography

- Fragkandrea I, Nixon JA, Panagopoulou P. Signs and Symptoms of childhood cancer: A guide for early recognition. Am Fam Physician. 2013; 88: 185-92.

Article focused on the early diagnosis of childhood cancer in Primary Care, by focusing on those warning signs that should alert us of the possibility of neoplastic processes.

- Clarke RT, Jones CHD, Mitchell CD, Thompson MJ. Shouting from the roof tops: a qualitative study of how children with leukaemia are diagnosed in primary care. BMJ Open. 2014; 4: e004640. doi: 10.1136 / bmjopen-2013-004640.

Highly recommended. Qualitative methodology article that explores the presentation of childhood leukemia and the factors that influence its suspicion from the point of view of parents and Primary Care physicians.

- Wilne S, Koller K, Collier J, Kennedy C, Grundy R, Walker D. The diagnosis of brain tumors in children: a guideline to assist healthcare professionals in the assessment of children who may have a brain tumor. Arch Dis Child. 2010; 95: 534-9.

A must-read. Clinical guide for the suspicion and early diagnosis of tumors of the central nervous system.

- Walker D, Wilne S, Grundy R, Kennedy C, Neil, Dickson A, et al. A new clinical guideline from the Royal College of Paediatrics and Child Health with a national awareness campaign accelerates brain tumor diagnosis in UK children – “headSmart: Be Brain Tumor Aware.” Neuro Oncol. 2016; 18: 445-54.

Very interesting. Strategy launched in 2011 in the United Kingdom, aimed at healthcare professionals and the general public, with the aim of reducing the time interval from the onset of symptoms to the diagnosis of a CNS tumor in pediatric patients.