From index of suspicion to managing survivorship: A primary care toolkit for childhood cancer

Primary care providers (PCPs) play a critical role from early recognition of childhood cancer to ongoing surveillance and long-term care of survivors and families after cancer treatment. In the United States, we see around 15,000 new cases per year in patients under 20 years of age.¹ To put that into perspective, while PCPs will see hundreds, if not thousands, of kids with viral fever, sore throat, headache, limp, or swollen lymph nodes, only a handful of patients in the course of a career may ever have cancer. And yet, when that one child with cancer walks through the door, the stakes are incredibly high.

Part of the challenge is that the presenting symptoms of pediatric malignancies overlap so heavily with normal childhood illnesses. Fatigue, fever, bruising, bone pain, swollen lymph nodes, and abdominal pain are commonly caused by colds, injuries, or constipation. But every so often, it is not just “growing pains” or a “stress-induced headache”; it is leukemia, lymphoma, a bone tumor, or a brain mass. Therefore, it is important to keep cancer somewhere on the differential diagnosis, especially when symptoms do not add up, when they persist, or when they present with certain red flags.

Why reducing diagnostic delay matters

Most of the time, reassuring a worried parent that their child’s fatigue or cough is probably viral is an appropriate clinical response. However, those reassuring words need to be balanced against an index of suspicion with follow-up, to avoid inadvertently delaying the recognition of a cancer diagnosis. From a strict medical standpoint, diagnostic delay can change short-term and long-term outcomes.

When cancer is on the differential earlier, there is an opportunity to order the complete blood count, to pause before prescribing steroids, or to obtain the imaging that might reveal the cause of seemingly common symptoms. This helps to reduce acuity of illness and severity of disease at initial presentation.² Brain tumors can herniate; bone tumors can result in a fracture; and neuroblastomas can compress the spinal cord. A child with leukemia or lymphoma can spiral into renal failure from hyperleukocytosis or tumor lysis if they have received steroids to allay symptoms. Likewise, diagnosing a mediastinal mass before a child is placed supine under anesthesia can be the difference between life and death.

Lower tumor burden at diagnosis often means less intense treatment and thereby fewer long-term sequelae.³ Diagnosing leukemia after steroids are prescribed can mean the difference between a standard-risk and a high-risk treatment pathway based on the risk stratification for acute lymphoblastic leukemia (ALL).⁴ Diagnosing an osteosarcoma when it is localized instead of metastasized impacts treatment course and prognosis.

Beyond the physiologic impacts of delayed diagnosis, there can also be a loss of trust with families, which negatively affects the lifelong relationship between the PCP and the family, especially if there are other siblings who may be in the practice. When a child is seen multiple times with persistent or evolving symptoms such as fever, it is important to broaden the differential diagnosis to include cancer.⁵While it is easier to see missed opportunities in hindsight, it is still critical to try to get to the correct diagnosis as quickly as possible (Table 1).

Notably, certain patients are more at risk for potential delays in diagnosis. In the United States, studies have shown that Medicaid enrollment, particularly when coverage is discontinuous, is associated with more advanced stage at diagnosis and increased mortality.^6,7Teenagers and those with isolated pain complaints also tend to have longer diagnostic intervals.⁸ There is increasing recognition that disparities in pediatric cancer survival are associated with socioeconomic disadvantage, racial and ethnic inequities, and geographic barriers to care.⁹ However, tumor biology is also a factor that may contribute both to time to diagnosis and overall outcomes. This is a reminder that while early detection and prompt treatment are important, despite our best efforts, there are disease characteristics outside of our control when it comes to treating children with cancer.

The challenge for every PCP is the balance of over-testing every child with a bruise or stomachache. So having the appropriate index of suspicion and good follow-up is critical. Future efforts incorporating clinical decision tools and even artificial intelligence guidance into electronic medical records could support PCPs in appropriate detection and referral of patients with suspected malignancy, but these tools have not yet been developed and tested in pediatrics.¹⁰ Keeping the possibility of a cancer diagnosis in the back of your mind, being willing to ask that extra question, setting follow-up systems, and resisting the urge to give steroids without a clear diagnosis are tenets to shorten time to diagnosis and protect both outcomes and trust.

Case reviews

Case 1: The mediastinal mass that presented like asthma

A 13-year-old boy presented to urgent care with a week of cough, no fever, and puffiness around his eyes. His symptoms were attributed to a viral URI. A few days later, he was still coughing, had facial petechiae, and was wheezing, despite no prior history of reactive airway disease. Steroids and albuterol were prescribed for presumed asthma.

On return to urgent care 2 days later, he was anxious, struggling to breathe when lying flat, and had retractions; the serum creatinine was 3.4. A chest X-ray (CXR) revealed a large anterior mediastinal mass compressing his airway and major vessels.

Airway compression and superior vena cava syndrome, associated with large mediastinal masses, are medical emergencies. Mediastinal masses can collapse airways under anesthesia, disrupt venous return, or trigger sudden cardiovascular collapse at the extreme. The correct approach is to keep the child upright, avoid sedation if possible, and get oncology and critical care involved immediately. A biopsy, performed with a team prepared for controlled anesthesia, diagnosed T-cell lymphoblastic lymphoma.

Take-home message: If there is concern for new-onset wheezing, obtaining a CXR is a quick way to make sure there is no anterior or posterior mediastinal mass. A PA and lateral X-ray give the most complete information. While steroids may alleviate symptoms briefly, they could complicate the diagnosis of leukemia or lymphoma, including leading to tumor lysis in some cases.

Case 2: Lymphadenopathy that did not improve with antibiotics

A 16-year-old girl noticed a non-painful, non-erythematous lump above her clavicle. She was initially treated for lymphadenitis with antibiotics. Two weeks later, the lump was bigger, and she had developed fevers; an ultrasound confirmed a supraclavicular mass. An excisional biopsy revealed Hodgkin lymphoma.

Although enlarged lymph nodes are a common presentation of viral, bacterial, or tuberculous infection, and an initial approach with antibiotics or careful observation is appropriate, there are hallmark features that warrant additional evaluation:¹¹

• Lymph node Size >2 cm
• Firm, non-tender, or fixed nodes
• Supraclavicular location
• Systemic symptoms like fever, weight loss, cough, or night sweats
• Persistence despite antibiotics

Workup includes a complete blood count (CBC), CXR, erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), uric acid, and Epstein-Barr virus (EBV) studies. If a node does not resolve in 6 weeks or grows, excisional biopsy is warranted.

Take-home message: Lymph nodes with certain features deserve careful short-term follow-up. Discussing return precautions with families, especially adolescents, is critical so that if signs do not improve as expected they return for additional testing.

Case 3: Persistent fever and leg pain

A 4-year-old girl presents with fever and sore throat of 10 days’ duration. The rapid strep test is negative. Due to concern for croup with stridor, she received a dose of dexamethasone and was sent home. Over the next week, she returned twice with fever, new-onset leg pain, and bruising. A CBC at that time showed severe anemia and thrombocytopenia, and upon referral to pediatric oncology, peripheral blood flow cytometry confirmed B-cell ALL.

Although viral illness is the most common association with fever in children, there are co-occurrences with malignancy. While many signs and symptoms of leukemia overlap with common childhood illnesses (fever, infection, lymphadenopathy) and normal findings (bruising), persistent or severe findings warrant additional evaluation.

Symptoms to ask about: bone pain, fatigue, pallor, anorexia, mucous membrane bleeding with tooth brushing, weight loss

Signs to look for: petechiae, bruises above the belt line, pallor, lymphadenopathy, hepatosplenomegaly

CBC findings of concern include:

Abnormalities of 2 or more cell lines (platelet count, hemoglobin, white blood cell count)

Anemia with elevated mean corpuscular volume (MCV)

Blasts or “other” or “atypical lymphocytes” on CBC

Take-home message: While the differential diagnosis for persistent fever is broad, accompanying symptoms of bruises or petechiae above the beltline, bone pain, excessive fatigue leading to school absences, or recurrent bleeding warrant a CBC.

Case 4: A hidden tumor in a teen with back pain

A 15-year-old boy presents with back pain. He was diagnosed with muscle strain. Weeks later, he still had pain and received NSAIDs and muscle relaxants. Eventually, he presented to the emergency department (ED) with cough, weight loss, and ongoing back pain. Imaging revealed massive lymphadenopathy, and exam found a large testicular mass. Biopsy indicated a germ cell tumor.

Testicular cancer in adolescents often presents late because boys frequently do not volunteer symptoms. By the time back pain appears, there is often metastatic retroperitoneal disease.

Take-home message: Back pain in adolescents deserves a careful neurologic and genital exam. Encourage boys to speak up about testicular changes. X-rays are not sufficient in pediatric cases to rule out a malignancy; magnetic resonance imaging (MRI) is recommended for further evaluation. A need for escalating pain medication warrants consideration for broadening the differential.

Case 5: School avoidance due to a brain tumor

A 7-year-old boy had declining academic performance and was missing many days of school. He had headaches, abdominal pain, and trouble focusing in class; his teacher noted he would cover one eye when trying to read the board. He was referred to optometry and recommended for an Individualized Education Plan. Several days later, he presented to the ED sleepy and vomiting, with a fixed dilated pupil. Imaging revealed a brain tumor found on biopsy to be a glioblastoma.

Brain tumors can present with a loss of developmental milestones, behavior problems, and school refusal. Symptoms like persistent headache, visual changes, or vomiting warrant imaging.

Consider imaging or urgent specialty input when a new/recent headache pattern is:

• Worsening in severity or frequency
• Worse in the morning or wakes the child from sleep
• Associated with vomiting, focal neurologic deficits (e.g., diplopia, facial weakness, ataxia), behavior change, loss of developmental milestones, or school performance decline

Take-home message: Neurologic red flags should lead to considering imaging sooner rather than later. A CT scan of the brain can be an initial start, but often an MRI may be necessary, given that many central nervous system tumors in children are in the posterior fossa.

Case 6: The lazy eye that was retinoblastoma

A 17-month-old girl was noted to have strabismus. It was brushed off as a “lazy eye.” Months later, an optometrist saw leukocoria. She was ultimately diagnosed with retinoblastoma, requiring enucleation.

A simple red reflex exam might have caught this earlier, potentially saving her vision. Strabismus beyond 4–6 months of age deserves ophthalmology referral.

Take-home message: Never skip the red reflex exam and evaluate persistent strabismus carefully.

Case 7: When Wilms tumor presents as constipation

A 3-year-old girl with a history of constipation was found to have a firm abdominal mass. Despite achieving clear stools, the mass persisted. Imaging showed a left-sided intra-renal mass, and she was diagnosed with Wilms tumor.

Abdominal masses in kids always deserve imaging. The location in the abdomen and the age of the child often provide the clue to the underlying diagnosis.

Take-home message: A palpable abdominal mass in a child is cancer until proven otherwise. An initial evaluation with an abdominal ultrasound can be revealing.

Cancer predisposition syndromes

Most childhood cancers arise sporadically, but about 1 in 10 can be traced back to an inherited predisposition syndrome.¹² In the primary care setting, it is not essential to memorize the different syndromes but rather to identify anatomic abnormalities and consider if there may be an underlying syndrome. It is important to recognize when a child or family’s history points toward a syndrome and know when it is time to bring genetics and oncology colleagues into the conversation. Table 2 summarizes some of the most common cancer predisposition syndromes, clinical features, and associated childhood cancers. Next-generation sequencing and multigene panel testing are becoming more cost-effective and allow simultaneous analysis of multiple cancer predisposition genes, increasing the detection rate of pathogenic variants beyond what single-gene testing can achieve.¹³ However, genetic testing needs to be done in the context of a program with a genetic counselor.

Data now shows that cancer surveillance and early detection in those with identified cancer predisposition syndrome impacts overall survival.¹⁴ A child with Beckwith-Wiedemann who gets regular ultrasounds may have their Wilms tumor detected at 2 cm instead of 10 cm. That means simpler surgery, less intensive chemotherapy, and better long-term survival. Oncologists and specialized predisposition clinics can work with PCPs to establish the most appropriate surveillance schedules for patients at risk.

Oncologic emergencies

Although there is often time to methodically evaluate a child with a possible malignancy, occasionally a child will present emergently from an undiagnosed malignancy. In those moments, it is critical for PCPs to recognize the pattern and help rapidly stabilize the child while getting them to the hospital. Avoiding harmful interventions such as laying a child flat when a mediastinal mass is suspected or giving a child steroids if leukemia is suspected, unless there is concern for impending respiratory compromise, is crucial.

Survivorship care

Following treatment for cancer, patients are encouraged to reestablish and transition care from their oncologist to their PCP, who has served as a constant partner throughout their journey (Figure). Surveillance and follow-up care should be individualized and risk-based based on the treatment they received; this is often detailed in a survivorship care plan from the pediatric oncology team.³ The Children’s Oncology Group (COG) long-term follow-up guidelines provide detailed, exposure-based recommendations for screening and management of late effects.¹⁵ Oncologists and specialized survivorship programs should take the lead on recommending necessary follow-up screening, but management of late effects is best carried out in partnership with PCPs.¹⁶

Often independent of side effects during treatment, late effects include endocrine disorders, cardiovascular disease, secondary neoplasms, neurocognitive impairment, and psychosocial challenges. Primary care providers should screen for these conditions and promote health through routine immunizations, or re-immunization (after clearance from the oncologist), healthy lifestyle counseling, and preventive care.^3,15-17

Conclusion

Childhood cancer hides in common symptoms. As pediatricians, the task is not to see cancer everywhere, but to keep it on the list just long enough to be sure it does not belong there. Watching for patterns, respecting red flags, utilizing basic labs or imaging, and listening to parents and teens all contribute to identifying the few patients in one’s practice who need additional diagnostic testing and emergent referral. Never hesitate to call pediatric oncology if there are concerns. These practices save lives, lighten treatment burdens, and preserve family trust in the healthcare system. While there have been incredible gains and advances in therapy for childhood cancer,⁹ early detection matters, and survivorship care is an important component of overall survival and optimal quality of life.

References

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