Pediatric Liver Tumors Power Notes [1]

What is the age range of children with hepatoblastoma (HB) vs. hepatocellular carcinoma (HCC)?
HB is most common between the ages of 6 months and 3 years, while HCC occurs in older children and adolescents.

What is the origin of HB?
HB arises from pluripotent hepatic stem cells or oval cells that can differentiate into hepatocytes or biliary epithelial cells.

What conditions is HB associated with?
Beckwith-Wiedemann syndrome
Hemihypertrophy
Low birth weight
FAP

What proportion of liver tumors are malignant?
2/3

What % of patients with HB have thrombocytosis?
60%

What is the most sensitive blood test to evaluate for HB and HCC?
AFP: produced by fetal liver cells and yolk sac. In neonates, levels are normally elevated and then drop to adult levels by age 6 months.
AFP is elevated in 90% of children with HB, and 70% of those with HCC
AFP levels are not associated with the level of maturity of HB

What other conditions cause elevated AFP levels?
Liver cirrhosis
Hepatitis
Germ cell tumors
Hemangioendothelioma
Testicular tumors
Gall bladder CA

Which variant of HCC is not associated with elevated AFP levels?
Fibrolamellar HCC

What should we look for when imaging for liver tumors?
Size/location of tumor
Metastatic disease
Vascular invasion to PV, HV, and VC

What is the advantage or MRI?
MRI is accurate in determining the relationship of the tumor to vascular and biliary structures.
Tumors appear homogenous and hypointense on T1 sequences, and hyperintense on T2 sequences.

Is FNA biopsy an option with liver tumors.
Yes, FNA may be sufficient to confirm the diagnosis.

What are the benign liver tumors?
Benign vascular tumors
Mesenchymal hamartoma
Adenomas
FNH

What is the role of HB histology in prognosis?
The histology of HB has minimal impact on prognosis.

What is the histologic classification of HB?
Epithelial vs. mixed (epithelial + others)
Epithelial divided into: Fetal, embryonal, macrotunular, and small cell undifferentiated.

What from of HCC has a better outcome than the typical variants?
Fibrolamellar variant

What is the COG staging system based on?
Post resection extent of disease.
Stage !: completely resected. Purely fetal histology (PFH) with minimal mitotic figures is unique group
Stage 2: microscopic residual disaese
Stage 3: gross residual disease
Stage 4: metastatic disease

What is unique about the PFH group?
When completely resected, patients with PFH and low mitotic figures (<2/10 mitotic figures) have excellent outcomes and do not require adjuvant chemotherapy. This situation occurs in 5% of patients with HB. What are factors that can compromise surgical resection?
Multifocality, bilobar involvement, portal vein or vena cava thrombosis, para-aortic lymphadenopathy, extension into liver hilum, and metastatic disease.

Why should a smaller incision be used initially?
A smaller incision should be used first to assess resectability before committing to a larger incision.

How should microscopically positive margins be managed?
Re-excision if possible.

Why should intraoperative U/S be used?
Intraoperative U/S should be used to better assess vascular involvement.
The most common cause of complications such as positive resection margins, severe intraoperative hemorrhage, and post operative liver failure secondary to Budd Chiari syndrome is unrecognized involvement of the remaining solitary hepatic vein.

What are options for anatomic resection?
R or L hepatic lobectomy
Extended R or L hepatic lobectomy
Central resection
Segmental based anatomic resection (rare)

What are the basic steps for resection?
Check for metastatic disease
Mobilize liver
Dissect poratal structures
Ligates structures supplying intended segment of liver to create line of demarcation
Dissect VC off the liver towards the VC, leaving hepatic veins as only attachment
Ligate hepatic veins within parenchyma of liver vs. extra-hepatic segments.
Perform parenchymal dissection

What is the max time allowed for clamping of portal structures?
60 minutes total, 15 minutes at a time.

What is the name of the imaginary line between GB and IVC?
Median portal fissure.

How much of the liver is removed with a L lobectomy vs a R lobectomy?
A L lobectomy removes 35% of liver parenchyma while a R lobectomy removes 65%.

What are potential postoperative complications?
Bleeding, subphrenic abscess, biliary fistula, wound infection, and biliary obstruction.
Perioperative mortality is 5%.

Why are neonates more susceptible to complications of liver resection and how is that counteracted?
Neonates have immature livers and are susceptible to postoperative hypoalbuminemia, hypoglycemia, and hypothrombinemia.
Perioperative administration of vitamin K, albumin, and vitamin K can counteract these deficiencies.

what % of HB will require liver transplant?
6%

What is the contra-indication to liver transplant in HB?
Extrahepatic disease

What are 10-year survival rates after primary transplant vs. rescue transplant (after attempted resection)?
Primary transplant has 85% 10-year survival, vs. 30-50% with rescue transplant.

When is transplant indicated for HCC?
Single lesion <5cm or up to three nodules < 3 cm. What are the disadvantages of neo-adjuvant chemotherapy?
Non-responders may experience disease progression.

What are agents used for initial therapy vs therapy for non-responders/recurrent disease?
Baseline therapy is with Cisplatin/Vincristine/5-FU or Cisplatin/Doxorubicin.
Resistant or recurrent disease is treated with etoposide/carboplatin or irinotecan

How often are unresectable tumors rendered resectable by neo-adjuvant therapy?
up to 70% of stage 3 tumors become resectable with neo-adjuvant therapy.
Only 30% of HCC are rendered resectable with neo-adjuvant therapy.

What is the role of radiation in liver tumors?
Radiation has a limited role. Not very effective.

What is suicide gene therapy?
Therapy that selectively targets tumor cells, where a non-toxic, cell permeable pro-drug, is converted to a toxic drug inside tumor cells only.

What are available options for ablative therapy?
Patients who are not candidates for transplant or resection can undergo ablative therapy.
Options incllude:
1. Chemo-embolization
2. RFA: Needle electrode delivers heat through an alternating current
3. Percutaneous injection of alcohol
4. Cryoablation: direct freezing then thawing results in cell death.

What are U/S findings that help guide ablative therapy?
RFA: echogenic micro-bubbles delineate the zone of therapy
Cryoablation: echogenic expanding rim

What is 5 year survival of HB vs HCC?
75% for HB vs 30% for HCC

What is 5 year survival with successful resection?
up to 100% for HB vs 54% for HCC

What is the primary predictor of poor prognosis?
Metastatic disease

What is the role of lung metastectomy?
Only lung lesions that do not respond to neoadjuvant chemotherapy should be resected

Reference:
1. Grosfeld's Pediatirc Surgery. Sixth edition. Chapter 30. Liver Tumors

Is this neonatal small left colon syndrome (NSLCS) and what's the next step?

This kiddo read the book before
he was born!

Mom with maternal diabetes. 24 hour old baby born term, had bowel movement only with stimulation, and then started having bilious emesis. Exam and AXR were consistent with a distal bowel obstruction. UGI to r/o malrotation showed a normally located ligament of Trietz, while the contrast enema showed a small left colon with a transition point at the splenic flexure (above).

Dilemma!... Given the kid's history and the imaging findings, this is very likely NSLCS. But do we not need to be sure we're not missing Hirschsprung's disease?

Time for some PubMed action and an article titled: "Neonatal small left colon syndrome in the offsprings of diabetic mothers-an analysis of 105 children". Perfect!

In this article by Ellis et al, the authors looked at 105 patients born to mothers with diabetes in pregnancy (pregestational or gestational). Of these neonates, 6 had intestinal obstruction. 5 had NSLCS and one had Hirschsprung's disease (recto-sigmoid transition zone). The obstructive symptoms in the neonates with NSLCS resolved after a contrast enema.

The authors emphasized that 50% of infants born with NSLCS are born to mothers with diabetes during pregnancy. Additionally, when such infants are born with distal intestinal obstruction, the chance of having NSLCS vs. Hirschsprung's disease is >10:1. Given that NSLCS is a self limited disease that resolves with a diagnostic/theraputic contrast enema, it would seem reasonable to treat this baby expectantly, and perform a rectal biopsy if he does not resume a normal pattern of bowel function.

Reference:
Ellis H, Kumar R, Kostyrka B. Neonatal small left colon syndrome in the offsprings of diabetic mothers-an analysis of 105 children. Journal of Pediatric Surgery (2009)44,2343-2346

Cervical seat belt sign in kids. What are the implications?

Three trauma alerts. Three kids in an MVC.
Three cervical seat belt signs. Now what?

After obtaining a CT-arteriogram on all three (no injuries) it was time to dig up that paper I came across a couple of years ago.

This paper, out of Emory University, looked at cervicothoracic seatbelt signs (SBS) and their association with vascular injury. The authors prospectively studies the results of their workup algorithm for SBS's, which consisted of an arteriogram or CTA for all patients with cervical SBS and those with a thoracic SBS who were symptomatic or suspected of having an aortic injury.

They identified 131/797 (16.4%) of trauma patients with a cervical and/or thoracic SBS, 3% of whom were found to have a vascular injury (mortality 50%).

Of the pediatric patients in that study, all of whom were appropriately restrained, 18.8% had a SBS. None of those patients had a vascular injury.

This study basically validated the safety of an algorithm where all patients with a cervical SBS undergo either a CTA or arteriogram (emergently in the presence of an abnormal neurovascular exam or GCS<14), while only those with a thoracic SBS and an abnormal neurovascular exam need further imaging (the rest should be ovserved and reexamined).

Interestingly, 2 of the 4 patients with carotid injury had an isolated thoracic SBS, suggesting the importance of shearing forces related to deceleration and hyper extension/flexion in carotid injury.

The absence of vascular injury in the pediatric population in this study should obviously not be considered a reason not to continue to image these patients, given that the number of pediatric patients in this study was small, and the potential consequence of missing an injury (rare as it is) is catastrophic.

Reference:
Rozycki et al. A prospective study fro the detection of vascular injury in adult and pediatric patients with cervicothoracic seat belt signs. The Journal of Trauma injury, infection, and critical care (2002) 52:618-624

Wilm's Tumor Power Notes [1]

What was Sidney Farber's contribution to the field of oncology?
Sidney Farber was the first to us adjuvant chemotherapy (Actinomycin D) to treat cancer (Wilm's tumor).

What syndromes is WT associated with and how often?
In 10% of cases, WT is associated with:
1. sporadic aniridia
2. isolated hemihypertrophy
3. Denys-Drash syndrome
4. genital anomalies
5. Beckwith-Wiedemann syndrome
6. WAGR (60% develop WT)

What are the main genes associated with WT, and what is the role of the protein produced by those genes?
WT1 and WT2 (reside on chromosome 11) are tumor suppressor genes that code for proteins that suppress growth inducing genes. Deletions in WT1 and WT2 predispose to WT.
WAGR is associated with WT1 and Beckwith-Wiedemann syndrome is associated with WT2

How often is WT bilateral in WAGR?
60% of patients with WAGR develop WT which is bilateral in 17% of cases

What is the relationship between Beckwith-Wiedemann syndrome and WT?
Kids with BW syndrome have a 40% chance of developing WT

How often is WT familial?
in up to 2% of cases

How does loss of heterozygosity (LOH) affect prognosis?
LOH (of chromosomes 1 or 16) is associated with increased risk of relapse and mortality.
LOH-16 present in 15-20% of WT, LOH-1 present in 10%

What is screening protocol for patient with syndromes associated with WT?
Ultrasound of kidneys every three months until the age of 5 YO

What are nephrogenic rests (NR) and what are their two distribution patterns?
NRs are persistent metanephric tissue beyond 36 weeks of gestation. The vase majority of NRs involute. They are found in two main distribution patterns.
1. Perilobular (PLNR): more common
2. Intralobular (ILNR)

What is the autopsy incidence of NRs?
~1%
PLNR: 0.9%
ILNR: 0.1%

What are the three histologic groups of NRs?
1. Incipient (infants)/Dormant (Older children): composed of blastemal and primitive epithelial cells that resemble embryonic kidney tissue and WT, but are microscopic and have sharp margins.
2. Regressing/Sclerosing (most common): show maturation of cellular elements. Progress to become obsolete rests composed of hyaline stromal elements (acellular proteinaceous material).
3. Hyperplastic: These are difficult to distinguish from WT, except based on architecture. They have uniform growth components that result in enlargement of the entire rest (preserving it's shape), as opposed to the neoplatic growth (WT) that results in a spherical expanding nodule within a rest.

How are hyperplastic NRs differentiated from WT?
The shape of the NR is preserved in hyperplastic NRs, and there is now surrounding pesudocapsule (which is found in WT). The importance of architectural characteristics makes a needle biopsy insufficient for differentiation unless they contain a part of the lesion's margin.

What is the association between WT and NRs?
41% of unilateral WT have NRs vs 99% of bilateral WT. NRs are increased in patients with WT associated with syndromes.

What is diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) and what is it's radiologic characteristic?
DHPLN is an entity that can be confused with WT. Infants with DHPLN have unilateral or bilateral enlarged kidneys that maintain their their normal shape and lack necrosis. DHPLN can become WT (in ~50% of cases despite neoadjuvant chemotherapy) so they should be monitored closely. Changes in CT/MRI characteristics or evidence of growth of DHPLNs should raise concern for WT.

what is the treatment and prognosis of DHPLN?
Chemotherapy is used to decrease the size of DHPLNs, which may cause respiratory compromise by virtue of their size, but has not been shown to decrease the risk of malignant transformation. 100% transformation to WT in the absence of chemotherapy, vs 55% when biopsy/chemotherapy performed.
A high proportion of patients with DHPLN and WT will have anaplastic WT

Is nephrectomy justified in multicystic dysplastic kidneys?
No. Only 4% of these patients will have NRs and the risk of WT too low to justify prophylactic nephrectomies

What defines unfavorable histology WT (UH)?
Presence of focal or diffuse anaplasia. Anaplastic cells have large, pleomorphic, hyperchromatic nuecleii with abnormal mitotic figures. Focal anaplasia confers a better prognosis than diffuse anaplasia. Anaplasia is aassoicated more with respnse to therapy than tumor aggressiveness.

What are the two tumors that were considered WT UH and where split into a different category?
Clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumors

What is the main difference between NWTSG and SIOP classifications?
NWTSG is a pre-treatment staging system while the SIOP assesses post treatment characteristics of the tumor.

What difference between Stage II and Stage III in terms of spillage?
Spillage is now considered Stage III regardless of whether it is local or diffuse, from a biopsy or tumor rupture. The extent of spillage affects the field of radiation given. Local spillage in the renal fossa is treated with local flank radiation; spillage outside the tumor bed mandates total abdominal radiation [2]

Is there a difference in terms of gross or microscopic post resection residual tumor in terms of staging?
No. Both are considered Stage III

How are tumors classified into risk groups based on neoadjuvant chemotherapy?
Based on histology at resection AFTER neo-adjuvant chemotherapy.
Low risk tumors are those that are completely necrotic (>99%)at time or resection
Blastemal predominant tumors (high risk) are those with more than 1/3 of tumor viable, and at least 2/3 of the viable tumor consists of blastemal cells.
Intermediate risk tumors are those with a variety of histologic charactaristics in between the low and the high risk categories.

What are the main pathologic characteristics of WT and how are they related to outcome?
WT is an embryonal neoplasm with blastemal, stromal, and epithelial components. Each of these can have variable levels of differentiation, including anaplasia.

What is particular about fetal rhabdomyomatous nephroblastoma and diffuse blastemal type WT?
Both these subtypes of WT. Fetal rhabdomyomatous nephroblastoma has poor response to chemotherapy, but excellent prognosis. Diffuse blastemal type has rapid response to chemotherapy, but characteristically presents with advanced disease

Which kids are at risk for anaplastic WT?
Kids older than 2 YO. Mortality from anaplastic WT ~ 60%. Outcome better for focal vs diffuse anaplasia.

What is the rate of metachronous contralateral disease and what are risk factors?
The rate of metachronous disease is 1% (synchornous is 5%). This is increased:
1. In the presence of NRs
2. Kids younger than two years
3. associated syndromes

What are the main characteristics of clear cell sarcoma of the kidney?
metastasis to bones and brain. Unclear cell origin

What are the main characteristics of malignant rhabdoid tumors of the kidney?
average age 11 months
characteristic involvement of perihilar renal parenchyma
second primary neurglial tumor in the brain

What are the main chemotheraputic agents used with WT?
Dactinomycin, vincristine, doxorubicin

When is doxorubicin added?
Stage III disease or in the presence of anaplasia

What are the aims of the main SWTS studies?
SWTS3: Use of Dox for Stage III dz
NWTS4: Dose intensification (less frequent) adequate with less hematologic toxicity
NWTS5: Effect of LOH on outcome in stage 1 and 2: decreased EFS
looked at management of relapse

What chemotheraputic agents are used for anaplasia?
Focal anaplasia: Vincristine/Dactinomycin/Doxorubicin
Diffue anaplasia: add cyclophosphamide +/- etoposide


What agents are used for CCSK and malignant rhabdoid tumors?
CCSK: Doxorubicin
Malignant rhabdoid: cyclophos/carbaplatin/etoposide (non of the basic WT agents)

What are the disadvantages of the routine use of neoadjuvant chemotherapy (SIOP)?
1. risk of losing staging information
2. risk of treating benign disease
3. modification of tumor histology by chemotherapy
4. Clear cell/rhabdoid will not respong
up to 10% rate of benign or altered malignant diagnosis in kids with pre-nephrectomy diagnosis of WT

What are the complications of doxorubicin?
1. cardiomyopathy in 1.2%
2. secondary malignancies (AML) in 1.6%

What are risk factors for a secondary malignancy?
1. doxorubicin
2. irradiation
3. prior treatment for relapsed tumor

What are the current guidelines for radiation therapy to lungs?
low dose radiation if lunges involved.

What is the significance of CT only lung lesions? [3]
Up to a third of lung lesions found on CT in patients with WT are not malignant.
Patients who are stage I or II FH WT should undergo biopsy of CT only lesions to gauge therapy. Those who are FH stage III or IV who are on AREN0533 protocol trial receive chemotherapy and then are reevaluated after 6 weeks. At that time, any residual lesions will get radiation, preferably after biopsy

What are guidelines for abdominal irradiation? [2]
Local Stage III disease. 10cGy


What are the main things that need to be assessed on imaging?
1. contralateral kidney involvement
2. two functioning kidneys
3. vascular involvement

What is the incidence of synchronous contralateral lesions?
5%

Is there a need for contralateral exploration and why?
No. Although 10% of lesions on the other side may be missed by imaging, these lesions do not affect outcome and recurrence, especially that some are NRs and not WT.

What are the false positive and false negative rates of clinical assessment of LN involvement?
The false positive rate of clinical assessment is ~20% and a false negative rate is 30%. Thus routine sampling of LN's (even when not suspicious) is mandatory for proper staging.

Why is cystoscopy important in the presence of hematuria?
Cystoscopy is important to rule out tumor extension into the bladder, where cutting through the ureter would result in cutting through the tumor, thus upstaging the patient.

What are factors related to increased risk of tumor recurrence?
Stage III
Intraoperative rupture
Anaplasia

What are indications for neoadjuvant chemotherapy (NWTSG)?[2]
1. solitary kidney
2. bilateral tumors: all bilateral tumors are treated with upfront chemotherapy. Any attempts at partial nephrectomy should be with held until week 6 or 12 [2]
3. horseshoe kidney
4. unresectable tumor
a.intravascular extension of tumor thrombus above hepatic veins
b.involvement of contiguous structures that would need to be sacrificed
c.if resection risks unnecessary morbidity and mortality per surgeon judgement
d.pulmonary compromise due to extensive pulmonary metastasis
5. respiratory distress form mass

Should both kidneys be biopsied in bilateral WT? [2]
No. Initially, and because of the risk of discordant pathology between the two kidneys, it was recommended that both kidneys be biopsied.
Per new COG protocol, renal biopsy is not necessary in stage V disease. Protocol calls for upfront 3 drub chemotherapy followed by possible OPEN biopsy (<50% reduction in size which may suggest presence of anaplastic tumor) or resection (tumor rendered resectable) or continued chemotherapy and resection at 12 weeks When is a core needle biopsy vs an open biopsy acceptable?
A core needle biopsy is acceptable to obtain a tissue diagnosis when a suspected WT tumor is deemed unresectable. An open biopsy is mandatory in the setting of bilateral WT that does not decrease in size by more than 50% after 6 weeks of chemotherapy.

How often is intravascular extension identified?
The renal vein is involved in 11% of children, the vena cava in 5% [2]. The Renal vein and VC should be palpated for the presence of tumor intraoperatively, even when preoperative imaging studies are normal.

Which patients are candidates for resection alone without adjuvant chemotherapy?
patients who are younger than two years, stage I, and <550 grams. LN's MUST be sampled and found negative for children to qualify. If LN's are not sampled, the child does not qualify for the surgery only protocol [2]
90% 4 year disease free survival

References: Ashcraft unless otherwise specified
1. Ashcraft's Pedatric Surgery. 5th edition. Chapter 67: Renal Tumors
2. COG renal biology protocol handbook. Accessed July 2011. Available at http://www.childrensoncologygroup.org/_files/disc/Surgery/RenalTumorsHandbook.pdf
3. Ehlrich et al. The value of surgery in directing therapy for patients with Wilm's tumor with pulmonary disease. A report from the National Wilm's Tumor Study Group (NWTS-5). Journal of Pediatric Surgery (2006);41:162-167