Chapter 13: Cancer in Children and Adolescents

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Okay, let's unpack this.

When we talk about cancer, our minds often jump to adult experiences.

But what about the youngest among us?

Childhood cancer is, thankfully, rare, but it's a really crucial area of medicine.

It's definitely a challenging topic,

yet understanding it deeply can lead to some incredible insights, wouldn't you say?

Especially in the development of disease.

Indeed.

It's challenging, but so important.

Despite its rarity, cancer tragically remains the leading cause of death from disease in children and adolescents.

But here's where it gets really interesting.

There's good news.

Over 80 % of children diagnosed with cancer today become long -term survivors.

That's a huge leap, a dramatic improvement since the 1960s, really a testament to decades of research and clinical advances.

That's amazing progress.

So today we're diving into what makes cancer in children and adolescents so distinct.

We'll explore its unique incidence patterns, the, well, often mysterious reasons behind its development, and the long -term outlook for these young survivors.

Think of this as your essential guide, you know, understanding the pathophysiology of childhood cancer straight from the experts without getting totally bogged down in jargon.

Exactly.

We'll focus specifically on the material from your chapter, painting a clear picture of the concepts, the mechanisms, clinical examples.

We'll even describe key data points and trends vocally so you can kind of visualize the information without needing the textbook right there.

Perfect.

So let's start with the big picture then.

How common is childhood cancer, really?

And how does it stack up against what we typically see in adults?

Well, numbers -wise, in 2018, an estimated 15 ,590 children and adolescents, that's up to age 19, were diagnosed in the U .S.

That works out to an overall incidence of about 18 .2 per 100 ,000.

What's particularly notable is this bimodal distribution.

We see two distinct peaks in incidence, one for the really young kids, under five, and another for adolescents aged 15 to 19.

That's interesting, two peaks.

Yeah, and it's slightly more common in boys.

The ratio is about 1 .2 males for every one female diagnosed.

Now, if you prepare that to adult cancer mortality, the contrast is stark.

The childhood cancer death rate is quite low, thankfully, around 2 .5 per 100 ,000 for males, 2 .1 for females.

That's significantly lower than adults, where the rate can be, you know, upwards of 158 per 100 ,000.

That bimodal distribution is really thought provoking.

Is it tied to specific developmental stages like rapid growth phases?

That's a fantastic question, and yes, it likely speaks to the underlying biology, the rapid cell division and growth in early childhood, and then again during the hormonal shifts and intense development of adolescents.

These probably create windows of vulnerability.

Right, and you said the types are really different too, not the ones we usually hear about in adults.

Very different.

Unlike adults, where you see prostate, breast, lung, colon cancers commonly, children are much more prone to leukemias, brain tumors, and sarcomas, and the key here really is their origin.

Most childhood cancers arise from the mesodermal germ layer.

Mesodermal.

Yeah, think of it like a foundational tissue layer in the very early embryo.

It gives rise to connective tissue, bone, muscle, blood, kidneys, lymphatic system, a whole array of things.

Okay, so it makes sense then that leukemia, sarcomas, these sorts of developing tissue cancers are more common.

Precisely.

And often, these cancers are fast growing.

They have a relatively short latency period.

The time from the first cell change to symptoms is often quite brief compared to many adult cancers.

And another layer here, it's not just the overall numbers.

Incidents also varies across different racial and ethnic groups.

If you were looking at, say, table 13 .1 from the chapter, you'd see that while non -Hispanic white children have a higher overall rate, around 20 .8 per 100 ,000.

There are specific variations.

For instance, leukemia rates are highest among Hispanic children at 6 .5 per 100 ,000.

Wow, okay.

That points to needing more research into why those differences exist, right?

Yeah.

Genetics, environment.

Absolutely.

It raises important questions.

So let's zoom in on those specific types then.

You mentioned leukemias, brain tumors, sarcomas.

Do they stay consistent across childhood or do they change with age?

They change quite dramatically with age.

Leukemia is the most frequent overall, but it peaks between ages two and five.

Brain and central nervous system tumors are second.

Their peak incidence is before age 15, but the specific types of brain tumors vary a lot within that range.

Lymphomas, Hodgkin, and non -Hodgkin are third.

They're actually quite rare in kids under five, but become much more frequent from age 10 onwards.

Okay.

And what about embryonal tumors?

You mentioned those earlier.

Ah, yes.

Embryonal tumors.

These are fascinating because they literally start developing during intrauterine life before the baby is even born.

They contain immature embryonic tissue that just hasn't matured properly.

So they're usually diagnosed very early, typically before age five.

The names often give it away.

They tend to include the root term blast, like neuroblastoma or retinoblastoma.

Blast, blast.

Embryonic blast cells.

Exactly.

Then you have sarcomas.

Rhabdomyo sarcoma is the most common soft tissue sarcoma.

It also has a sort of bimodal pattern.

Peaks under six, and then again in adolescents 10 and older.

And bone tumors like osteosarcoma and Ewing sarcoma are more typical in adolescents, say, 15 and older.

So if you imagined like table 13 .2 showing incidence rates, you'd see this shift.

The overall rate for birth to 14 might be 16 .9 per 100 ,000, but it nudges up to 19 .2 if you include up to age 19.

And that increase is driven by things like Hodgkin lymphoma, which more than doubles its rate when you include those older teens.

So tying this back, why don't we see these types as often in adults?

And why are adult type cancers, carcinomas, so wearing kids?

It really boils down to the underlying cause or etiology.

Most adult cancers, the carcinomas, arise from epithelial tissues, linings of organs, skin, etc.

And they're often linked to decades of environmental exposure.

Think smoking for lung cancer, UV radiation for skin cancer.

That's right, cumulative damage.

Exactly.

Children simply haven't had that length of exposure time.

That's why carcinomas are extremely rare in childhood.

You do see their incidents start to creep up a bit between 15 and 19, but it's nothing like in adults.

Childhood cancers are much more intertwined with developmental processes going awry, which naturally raises the big question.

If it's not primarily those long -term environmental factors, what does cause cancer?

And honestly, for most childhood cancers, the specific causes are largely unknown, but we have identified several crucial factors.

Okay, let's unpack that.

It definitely sounds like genetics and maybe things present from birth play a much bigger role here, given what you said about development.

You're absolutely right.

While some environmental factors can play a role or predispose a child, we often don't find those established causal links like smoking for lung cancer.

Instead, we focus heavily on what we call host factors.

Many of these are genetic risk factors or congenital conditions.

Like conditions someone's born with.

Exactly.

Think about table 13 .3, which lists some examples.

Down syndrome, for instance, dramatically increases the risk for acute leukemia maybe 10 to 20 times higher.

Or life -formany syndrome, LFS.

It's an autosomal dominant disorder, meaning you only need one copy of the faulty gene affecting the crucial TP53 tumor suppressor gene.

This puts individuals at a really high risk for sarcomas, leukemia, brain tumors, multiple cancers throughout their life.

Wow.

TP53 is a big one in cancer research, generally, isn't it?

It is a major guardian of the genome.

Another example is Wilms tumor, a kidney cancer.

It's often associated with other congenital anomalies like aniridia, which is the absence of the iris in the eye, or hemihypertrophy, an overgrowth of one side of the body.

Now, because these cancers often develop quickly, population -wide screening, like we do for some adult cancers, isn't generally effective.

But for children with a known strong family history or a known mutation, like in TP53, they do receive extra targeted screening.

So it's targeted surveillance for those high -risk kids.

Precisely.

And it's rarely just one single thing.

It's often what we call a multiple causation model, an interplay between these host factors and potentially some environmental triggers.

So it's complex, not just one gene, usually.

Can you tell us a bit more about those specific genetic and genomic factors involved?

Absolutely.

Research has linked mutations, either acquired or inherited, in over 150 different oncogenes and tumor suppressor genes to various childhood cancers.

We find that children who develop cancer tend to have a higher frequency of these germline cancer predisposition genes, the inherited ones, compared to kids without cancer.

Think about table 13 .4, which lists some key players.

For instance, the RB1 gene, a tumor suppressor, is famously linked to retinoblastoma, that eye tumor.

Right, the retinoblastoma gene.

Exactly.

Or MYCN, that's an oncogene, and it's strongly associated with neuroblastoma.

These are just examples, but they show specific genetic drivers.

Beyond single gene mutations, certain genetic conditions that affect DNA repair are big risk factors.

Fanconi anemia and Bloom syndrome are examples.

They're recessive conditions that impair the cell's ability to fix DNA damage,

significantly boosting leukemia risk.

So problems with the basic DNA repair kit.

That's a good way to put it.

And while leukemia itself isn't usually directly inherited in a simple way, we do see familial clustering.

Siblings of a child with leukemia have a 2 -4 times higher risk, and identical monozygous twins show up to 25 % concordance, meaning if one twin gets it, the other has a 1 in 4 chance.

Suggests a strong genetic component interacting with other factors, maybe even prenatal events.

Okay.

And what about bigger changes like chromosomal abnormalities?

Yes, those are definitely important too.

We see changes in chromosome number aneuploidy, or structure,

like deletions, bits missing, or translocations, where pieces of chromosome swap places.

A classic example is the BCR -ABL fusion gene.

This results from a specific translocation between chromosome 9 and chromosome 22, the Philadelphia chromosome.

And it's strongly associated with certain pipes of leukemia, including acute lymphocytic leukemia, ALL.

Got it.

So we have single gene issues, DNA repair problems, and these larger chromosomal changes all playing a role.

What about environmental factors then?

You said they're less established as primary causes, but do they contribute at all?

They do contribute, yes.

It's definitely a multifaceted picture.

As outlined in box 13 .1, environmental factors interact with genetic, genomic, epigenetic factors, diet, immune function, a whole host of things.

We can think about exposures before birth, prenatal, and during childhood.

Okay, like prenatal exposures, what kind of things?

Well, some drugs taken during pregnancy have been implicated.

The most infamous is probably

Dithylstilbestrol, or DES.

It was given to women decades ago, supposedly to prevent meal carriages, but it was later linked to a rare type of vaginal cancer, adenocarcinoma, in their daughters.

Oh, I've heard of DES.

A cautionary tale.

Definitely.

Ionizing radiation is another one.

Even relatively low levels of x -rays during pregnancy have been associated with a slightly increased risk of childhood leukemia,

and an emerging area is epigenetics, how prenatal exposures might change gene expression without actually altering the DNA sequence itself.

That's still being actively researched.

Okay, and what about exposures during childhood itself?

Again, ionizing radiation is a significant factor here.

There's a well -established correlation between radiation exposure and later malignancies.

This includes radiation used for cancer treatment itself, radiotherapy, but also from diagnostic imaging.

You mean like CT scans.

Exactly, and this brings up a really important point highlighted in the Did You Know box about pediatric CT scans.

CT scans are actually the largest single contributor to medical radiation exposure for the U .S.

population overall, and children are inherently more sensitive to radiation than adults.

They also have a longer lifespan ahead of them for any potential damage to manifest.

Plus, they might get higher doses if the machine settings aren't adjusted for their smaller size, right?

That's a crucial point.

The dose needs to be pediatric specific.

Now, the absolute lifetime risk from a scan is generally small, estimated around one extra cancer case per 1 ,000 children scanned, maybe up to 1 in 500 at the higher end.

So the benefit of a medically necessary CT scan should absolutely outweigh this small risk.

But the key is minimizing unnecessary exposure using other imaging like ultrasound or MRI when possible, and always using the lowest effective dose, as low as reasonably achievable or ALERA.

ALERA.

Got it.

That's really important for parents and clinicians to be aware of.

Absolutely.

Interestingly, on the flip side of exposures, some research suggests that early exposure to common childhood infections might actually offer some protection.

Protection?

How would that work?

The idea is that these infections might help prime or mature the developing immune system in a way that makes it better at recognizing and eliminating pre -leukemic cells, potentially reducing the risk of acute lymphoblastic leukemia.

It's called the hygiene hypothesis in some contexts.

Still debated, but interesting.

Huh.

Okay, what about drugs taken during childhood?

Certain drugs can increase risk.

Table 13 .5 gives examples.

Anabolic androgenic steroids have been linked to liver cancer, hepatocellular carcinoma.

Some chemotherapy drugs used to treat a primary cancer can unfortunately increase the risk of developing a secondary leukemia later on.

And immunosuppressive drugs, often used after organ transplants, can increase the risk of developing lymphomas.

Right.

Suppressing the immune system might let cancer cells get a foothold.

That's the thinking.

There have also been concerns raised about environmental exposures like low -frequency magnetic fields, maybe from power lines.

There was a large meta -analysis, discussed in another Did You Know box, that pooled data from many studies.

It did find an

high levels of magnetic field exposure, .4 microteslas or more, and an increased risk of childhood leukemia.

High levels, okay.

Yes, emphasis on high.

It's important to note that less than 1 % of children in those studies actually experience that level of exposure.

And crucially, association doesn't prove causation.

There could be other confounding factors.

So research is ongoing, but widespread panic isn't warranted based on current evidence.

Good context.

And finally, viruses.

Do they play a role?

Yes, certain viruses are definitely linked.

Epstein -Barr virus, EBV, which causes mono, is associated with Burkitt lymphoma, especially in certain regions of Africa, as well as nasopharyngeal carcinoma and some types of Hodgkin disease.

And HIV -AIDS significantly increases the risk for non -Hodgkin lymphoma and Kaposi sarcoma, although thankfully, modern, highly active antiretroviral therapy, HART, has dramatically reduced those risks for people living with HIV.

Okay, so it's a real mix of genetics, developmental factors, and some environmental influences, including radiation, drugs, and viruses.

Now, let's connect this back to the bigger picture.

You said earlier the survival rates are over 80%, which is fantastic news.

But what does that survival actually look like long term?

That's the critical next phase of understanding and care.

Yes, over 80 % cure rates are a major triumph.

This is thanks to huge advances.

Combination chemotherapy, using multiple drugs, multimodal treatment for solid tumors, combining surgery, radiation, and chemo, newer biotherapies, and just massive improvements in supportive care, managing side effects, infections, etc.

Cooperative study groups, where hospitals pool data and refine protocols together, have been absolutely essential to this progress.

That's incredible.

Real progress through collaboration.

But I think I read somewhere, or maybe you mentioned it, a difference in cerebral improvements for adolescents.

Is that right?

Yes, unfortunately, that's true.

There's what's often called the adolescent and young adult gap, or AYA gap, while survival rates for younger children under 15 have been steadily increasing by about 1 .5 % per year.

For adolescents and young adults, say 15 to 24, the improvement has been much slower, less than 0 .5 % per year.

Wow, that's a significant difference.

Why?

Is it biology or access to care?

It seems to be multifactorial, but a huge contributing factor is lower participation in clinical trials.

Between 1997 and 2005, for instance, only about 10 -15 % of 15 -19 year olds with cancer were enrolled in trials.

Compare that to younger kids, where the rate was roughly four times higher.

Four times?

Why such low participation?

Several reasons.

They might be treated in adult cancer centers, where pediatric trials aren't offered or aren't the default.

Sometimes trial eligibility criteria historically excluded them.

Or there just might be fewer trials specifically designed for the cancer types common in that AYA age group.

The National Cancer Institute is very aware of this and has specific initiatives trying to bridge this gap, increase trial access, and enrollment for AYA's.

That's good to hear they're working on it.

So for those who are cured, and that's most kids now,

what are the long -term implications?

You mentioned treatment happens during critical growth periods.

Yes, and this is where the perspective shifts.

We increasingly need to view childhood cancer not just as an acute, potentially fatal illness, but as a chronic disease for survivors.

Treatment focus now rightly includes quality of life, symptom management, and even palliative care principles integrated early on, even for those with curable cancers, to manage suffering.

But the downside of successful, intensive treatment during childhood is the risk of late effects.

Late effects, meaning problems that show up years later.

Exactly, and they tend to be more significant in childhood cancer survivors than adult survivors, because the treatments chemo, radiation were giving while their bodies were still growing and developing.

These late effects can be really wide -ranging.

Physical impairments, problems with growth and development, reproductive dysfunction, infertility later in life, soft tissue and bone atrophy, meaning wasting or thinning, learning disabilities, cognitive challenges.

That's a lot to deal with long after the cancer is gone.

It is, and perhaps one of the most concerning is the increased risk of secondary cancers.

Different cancers developing later in life, sometimes related to the original genetic predisposition, like with life from any,

or as a direct result of the radiation or chemotherapy used to treat the first cancer.

For example, survivors of familial retinoblastoma have a known increased risk for osteosarcoma, that bone cancer later on.

And of course, there can be significant psychological sequel anxiety, depression, PTSD related to the cancer experience.

So lifelong follow -up and support are crucial.

Absolutely critical, which points to future needs.

We need much more research into the genetic and genomic factors driving these cancers and the long -term genetic and genomic consequences of the treatments themselves.

And for families where there's a known inherited risk, referral to genetic counseling services is really important, both for the child and potentially other family members.

Okay, so wrapping this up, what does this all mean?

We've taken quite a deep dive here into the unique world of cancer in children and adolescents.

We really have.

I think the key takeaways are, while it's rare compared to adult cancer, it's still a leading cause of disease -related death in kids.

But T survival rates are now very high, over 80%, thanks to decades of treatment advances.

We've seen how fundamentally different these cancers often are from adult ones originating from those mesodermal tissues, driven more by genetics, congenital factors, chromosomal issues, rather than long -term lifestyle exposures.

And we talked about the main types leukemias, brain tumors, sarcomas, embryonal tumors, and how their frequency shifts with age.

And we can't forget those insights into why they happen, the etiology, from prenatal factors like DES and radiation, to the complex role of childhood radiation, like with CT scans, even the potential protective effect of infections, the risks from certain drugs, the ongoing questions about magnetic fields, and the known links to viruses like EVV and HIV.

And then looking forward, celebrating the huge progress in prognosis, but also recognizing the real challenges of that adolescent gap in survival gains, and especially the significant burden of long -term late effects for survivors,

plus the need for more AYA trial participation.

Exactly.

It paints a picture of a field with incredible progress, but also significant ongoing challenges.

It really underscores the dynamic nature of health and disease, especially when we're talking about growth and development in our youngest patients.

Well, thank you for walking us through all of that.

We hope this deep dive into childhood cancer pathophysiology has given you, our listeners, a clear, concise, and thorough understanding, hopefully some aha moments, without feeling completely overwhelmed.

And maybe a final thought to leave you with.

Consider how reframing childhood cancer as a potential chronic disease for survivors really changes things.

How does that shift our approach, not just to the initial treatment, but to lifelong surveillance, support systems, public health policy?

What does that truly mean for the futures of the next generation of survivors?

And how can the research we've talked about continue to shape and improve those futures?