Epithelial ovarian tumors in children: some high yield points

Ovarian germ cell tumors are the most common neoplastic tumors of the ovary in children. Less common are tumors derived from the ovarian surface epithelium, accounting for 15% of ovarian neoplastic tumors. These epithelial tumors are rarely seen in premenarchal patients.

Ovarian epithelial tumors in children are either mucinous or serous. Each one of these two categories can be divided into a benign subgroup, malignant subgroup, or subgroup of tumors of low malignant potential, also known as borderline tumors (where the lack of invasion into the ovarian stroma is characteristic, despite varying levels of nuclear atypia). Thus a patient may have a mucinous cystadenoma, mucinous cystadenocarcinoma, or mucinous tumors of borderline malignancy.

The overall intraoperative management of this group of tumors is based on adult protocols. At minimum, thorough staging of the abdomen is required, with focus on careful examination of the contralateral ovary, as bilateral disease is common with these tumors.

What is the value of tumor resection in kids with high risk neuroblastoma?

In a recent review of available literature on the subject of the impact of surgical resection on the outcome of patients with high risk NB, I came across this report by Englum et al in Pediatric Blood and Cancer.  

The authors looked at the impact of gross total resection (GTR) vs less than gross total resection on overall survival in 87 patients operated on in 14 different institutions.  Although no significant difference in OS (~50%) between the two groups could be found, the data did show a significant improvement in OS when more than 90% resection of the tumor was performed.

When the data was broken down by subgroups based on extent of resection, the results were as follows: 5-year survival was 53% after GTR, 64% after more than 90% resection , 35% after less than 90% resection, and 14% after biopsy only or no surgery.

As with all retrospective studies, it is difficult to tease out potential confounding variables that determine outcome in these patients, especially with a condition as complex as neuroblastoma.  This study does, however, add some more information that can help us when deciding how hard to continue to push when that last bit of tumor just will not come off that IVC safely!

1.7 cm carcinoid in the appendectomy specimen, now what?

I have yet to walk away from a conversation about the management of incidentally found carcinoid tumors of the appendix satisfied.  Today, I was determined to find some kind of an answer.

My basic understanding is that an incidentally found lesion which is < 2 cm and with negative margins is essentially treated with the appendectomy.  Otherwise, a hemicolectomy is needed.

If we were to extrapolate form the adult literature, the simplest recommendation is that of the NCCN version 2.2014 (National Comprehensive Cancer Network). Simply stated, a tumor < or = 2cm completely removed with the specimen is essentially cured with no further operative management needed.  Surveillance is performed "as clinically indicated". The document does acknowledge the fact that the management of tumors between 1 and 2 cm with poor prognostic factors such as mesoappendiceal invasion, lymphovascular invasion, or atypical histologic features, is controversial.

The NANETS (North American Neuro Endocrine Tumor Society) guidelines officially take into account local invasion.  They recommend right hemicolectomy for patients with evidence of tumor invasion to the base of the appendix, if the tumor is >  2 cm, if tumor size cannot be determined, if tumor is incompletely resected, if there is lymphovascular invasion or invasion of the mesoappendix, in patients with intermediate or high grade tumors, and in patients with mixed histology tumors.

A recent paper, Kim et al reported their experience with the management of incidentally found carcinoid tumors. The authors noted that out of their 13 cases, only one tumor was larger than 2 cm (2.1 cm) and that was the only patient, out of three who had a right hemicolectomy, who was found to have regional metastatic disease.

As is the overall case with carcinoid of the appendix, the numbers are just too small to make solid recommendations, especially for tumors in the 1 to 2 cm range. A good conversation with the patient and family about the numbers and management options is central to decision making.

So much for finding an answer today.

GIST tumors in kids

Looking down at the path report that read "Wild type gastrio-intestinal stormal tumor", I had to reach deep into my memories of adult general surgery training, and all I could come up with was Gleevec. Clearly not enough to formulate a management plan for my 12 year old patient.

Off to Pubmed...

Talk about children not being just small adults!  Pediatric GISTs, it turns out, are a whole different animal.

Adult GISTs are tumors of mesenchymal origin that carry a tyrosine kinase receptor activating mutation. 85% of tumors in adults will have a mutation in either oncogenic KIT, PDGRRA, or (less commonly) BRAF. The presence of a tyrosine kinase mutation is the basis for tumor response to tyrosine kinase inhibitors such as Imatinib (Gleevec).

The pediatric counterpart, a rare entity, differs in a critical way; namely the absence of a tyrosine kinase mutation in the majority (>90%) of cases. Gastrointestinal stromal tumors with no tyrosine kinase mutation are referred to as wild type GISTs.  The absence of these mutations translates to the lack of efficacy of tyrosine kinase inhibitors such as Imatinib. Essentially, no effective neo-adjuvant or adjuvant therapy is available for WT GISTs.

Because of the rare nature of GISTs in children, we do not have a clear idea about behavior. The general impression is that these are insidious lesions, that grow slowly and have a high recurrence rate, even in the setting of complete surgical resection.

What does this mean for us, the pediatric surgeons faced with the responsibility of primum non nocere?  this is a chronic disease that needs management and not cure; more like hypertension that appendicitis.  So avoid big morbid resections if possible, and plan for this disease coming back.

Reference:
Pediatric Gastrintestinal stromal tumor

Bilateral Wilm's Tumor

Now that the dust has settled on the move to the west coast... back to some reading.

A recent discussion about an infant with bilateral renal masses prompted a review of the COG recommendations and protocols for the management of patients with bilateral Wilm's tumor.

Obviously, the basic impetus behind the special consideration for this group of patients is the the need for preservation of functional renal tissue.  Kids with bilateral WT have several factors that contribute to potential renal failure.  These include  intrinsic disease in predisposed kidneys, loss of functional renal tissue after surgery, and injury from chemo and radiation therapy.

Historically, all pediatric patients with bilateral renal tumors have been found to have Wilm's tumor. This, along with the fact that biopsy upstages patients, increases the risk of local recurrence, and can not effectively rule out anaplasia, contributed to the current COG recommendation to proceed with chemotherapy without tissue biopsy.

Once chemotherapy is started, the pattern of tumor response after 6 and 12 weeks determines whether and how therapy is adjusted.

The COG protocol for bilateral renal masses calls for upfront three drug chemotherapy (no biopsy), with re-imaging in 6 weeks.  If, after 6 weeks, there is good response (>30% decrease in size), and the tumor is now resectable with partial renal preservation, then the surgeon proceeds with nephron sparing surgery.

For patients with partial response, but not enough for nephron sparing surgery after 6 weeks, three drug chemotherapy is continued.  At 12 weeks, all patients undergo operative resection; partial nephrectomy if made possible by further reduction in tumor size, or radical nephrectomy.

If there is no good response, then resection is needed to rule out an anaplastic component (chemotherapy needs to be adjusted) or to make sure this is not a benign lesion (further chemotherapy is unnecessary and surgical resection is curative)

Reference:
COG AREN 0534 Protocol: Treatment for Patients with Bilateral, Multicentric, or 
Bilaterally-Predisposed Unilateral Wilms Tumor

Neo-adjuvant chemotherapy for hepatoblastoma: Do tumors shrink away from major vascular structures?

No.

This was an eye-opening study by Murphy et al who looked at patterns of response of hepatoblastoma (both volume reduction and regression away from major vascular structures)  treated with neo-adjuvant chemotherapy.

It was eye opening for two reasons.

The first reason is that one would assume that substantial shrinkage of tumor would translate into substantial regression away from major vascular structures (and subsequently facilitate resection).  It turns out that although these tumors respond well to neo-adjuvant chemotherapy, they shrink towards major vascular structures (as if anchored to their main blood supply), and not centripetally.  In fact, the authors noted that the tumors, at most, regressed an average of 1 mm from major vascular structures.

The second, and more important eye opener, was the remark made by Dr Meyers in the discussion section of the paper.  The authors were addressing the recommendation by the COG protocol (AHEP0731) that patient with margins less than 1 cm from major vascular structures not undergo attempts at primary resection but receive neo-adjuvant chemotherapy.  The authors conculded that chemotherapy brought only a few patients closer to respectability  (because it brought only a few patients to this 1 cm level)

The misinterpretation of COG recommendations lies in the following:  The 1 cm recommended margin away from major vascular structures is intended to encourage neoadjuvant chemotherapy and avoid positive margins with attempts at primary resection.  So really, the < 1 cm margin is more an indication for neo-adjuvant chemotherapy than a contraindication for surgery.

Subsequently, once a patient has received neo-adjuvant chemotherapy, the entire < 1 cm business is out the window, and resection should be attempted if deemed possible and safe regardless of radiologic vascular margins.

Which kids with Wilm's tumor qualify for no post op adjuvant chemotherapy?

Adjuvant chemotherapy for favorable histology Wilm's tumor consists of either regimen EE-4A (vincristine and dactinomycin) or DD-4A (vincristine, dactinomycin, and doxorubicin) based on staging and the status of loss of heterozygosity (1p and 17q).

One special subset of patients with Wilm's tumor has been found to have a good outcome without chemotherapy.  Specifically, patients younger than 2 years of age, with stage I FH Wilm's tumor that weighs less than 550 g have an estimated 5-year EFS of 84% (compared to 97% for those receiving EE-4A).  Of the patients who receive no adjuvant therapy and relapse, the salvage rate (using DD-4A) exceeds that of those who are treated with EE-4A and relapse.

This protocol underlines importance of lymph node sampling (irrespective of gross appearance) as part of the surgical management of Wilm's tumor.  In this case, if nodes are not sampled, the patient would not qualify for the no-chemotherapy option.

Reference:
Coran, A.G (2012) Pediatric Surgery. Philadelphia, PA. Elsevier

Encephalitis associated with ovarian tumors

It is one thing to learn something new every day, but another to come across something you have never heard of.

Enter anti-NMDAR encephalitis secondary to ovarian teratomas.

Anti-NMDAR encephalitis syndrome is a constellation of psychiatric symptoms, memory changes, altered level of consciousness, and/or central hypoventilation due to the interaction of antibodies to NMDAR (receptor in brain tissue) with the hippocampus.

This condition can present at any age group, and can be associated with teratomas (in 50% of females above 12 years of age with anti NMDAR encephalitis); mainly the ovarian type.  It is the second most common type of autoimmune encephalitis, and is believed to be the result of interaction of auto antibodies to NMDAR (generated in response to ectopic neuronal tissue in the teratoma) with the hippocampus.  The diagnosis is confirmed with anti-NMDAR antibodies in the blood or CSF.

The treatment for this condition consists of immune therapy (steroids/plasmapharesis/IV immunoglobulin), tumor resection, and possible need for immune suppression.

80% of patient have substantial improvement of symptoms within 24 months of initiation of therapy.  During this time, the risk of relapse is 12%.

News to me.

Reference:

Tiltulaer et al.  Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis Lancet Neurol (2013) 12:2-157

Staging ovarian masses intra op... what are we responsible for as pediatric surgeons?

Managing ovarian masses in children can be quite challenging. This is more of a decision making challenge than a technical one.

The fact that we usually have little information preop that is useful in helping to risk stratify a lesion and answer the question 'is this malignant or not' makes many of the decisions we make difficult: Laparoscopic or open resection? shall we try to save any remnant ovarian tissue or do a complete oopherectomy?...

Occasionally some intraoperative findings guide that decision, but more frequently we are faced with an ovarian mass, normal preop AFP/BHCG (whatever the diagnostic implications of those are), and no evidence of local or distant spread.

Regardless of different approaches to that scenario, one thing we are responsible to do as surgeons is clearly document intraoperative findings (including pertinent negatives) so that the information is available if the mass does turn out to be malignant.

Per COG recommendations, intraoperative documentation of the following should be made (including pertinent negatives)

1. Collection of ascites or washings on entering the peritoneum

2. Examination of peritoneal surface with biopsy of any nodules

3. Examination and palpation of retroperitoneal LN's and biopsy of firm or enlarged ones

4. Inspection and palpation of the omentum with excision of any abnormal or adherent areas

5. Inspection and palpation of the contralateral ovary and biopsy any abnormal areas

6. Complete resection of the tumor and ovary with sparing of the fallopian tubes if not involved.

Clearly, if a totally laparoscopic approach is used, palpation of the peritoneal lining and omental lesions is not possible, which makes it impossible to perform the complete staging mentioned. In some situations, however, the contralateral ovary and retroperitoneal lymph nodes may still be palpated if a small Pfannenstiel incision is used to extract the ovarian mass.

Reference:
Oltmann S et al. Pediatric ovarian malignancies: how efficacious are current staging practices? JPS(2010)45,1096-1102

Sketchnotes: Differential diagnosis of mediastinal masses

Lung metastectomy in osteosarcoma: thoracotomy or VATS?

Osteosarcoma, which presents with metastatic lung disease in 15-20% of cases, is one of the few malignancies (along with non-rhabdo soft tissue sarcoma and hepatoblastoma) where resection of metastatic disease to the lung can improve survival.

Although lung metastectomy has been shown to be beneficial in this group, the optimal modality of resection, whether by open thoracotomy or VATS, is not clear. The argument for the use of an open thoracotomy in the management of lung mets has to do with the ability to palpate lesions, whereas VATS relies on imaging for detection of lung nodules. Studies have shown that a CT scan that detects a nodule(s) in the lung can miss additional palpable ones in 50% of patients, approximately half of which contain viable malignant tissue. So, in essence, VATS would likely miss additional malignant nodules, and thus leave behind otherwise palpable malignant lesions, in 25% of patients.

So it seems obvious that an open thoracotomy is the way to go, except that we don’t really know if a VATS followed by close monitoring to detect the 25% of patients with missed nodules that can be salvaged by a second VATS (and thus spare a number of kids a thoracotomy) changes the outcome in terms of long term survival when compared to primary resection of all the palpable nodules with an open thoracotomy.

Reference:
1. St Jude Oncology Review Course
2. Kayton ML et al. Computed tomographic scan of the chest underestimates
the number of metastatic lesions in osteosarcoma (2006);41:200

Vascular lesions: time to abandon the nomenclature of edibles!

After a long conversation discussing the management plan for a “giant cavernous hemangioma” of the liver, and although I had just recently brushed up on the subject of vascular lesions, I had to go back and look it up again. I was pretty sure the term “cavernous hemangioma” was as antiquated as “strawberry hemangioma” or “port wine stain”; the generalized agreement around me on the diagnosis made me doubts myself. Back to the books.

Sure enough, as of 25 years ago, the International Society on the Study of Vascular Lesions adopted the Mulliken system of classification, which divides vascular lesions into tumors (mainly infantile hemangiomas) and malformations (capillary, venous, lymphatic malformations etc…). This division is based on clinical and histologic characteristics; vascular tumors display endothelial proliferation and usually regress with time, while vascular malformations have a quiescent epithelium, result from dysmorphogensis of vessels, and tend to enlarge with time.

No more should the term lymphangioma, which by vertue of the –oma suffix suggests a tumor, be used to describe a lesion that is a malformation (lymphatic malformation). Nor should the term cavernous hemangioma be used to describe what could either be a deep visceral hemangioma or a venous malformation (two distinct entities, treated in very different ways).

A study by Hassanein et al reviewed articles on vascular lesions and noted a 70% incidence of incorrect nomenclature and a subsequent 20% incidence of incorrect treatment based on erroneous classification. They commented that this is probably an underestimation of the incidence of incorrect diagnosis and treatment in clinical practice, given that experts had probably edited many of these articles for accuracy.

Another reason we should continue to read, read, and read some more.

Reference:
Hassanein et al. Evaluation of terminology for vascular anomalies in current literature. Plastic and Reconstructive Surgery (2011);127(1):347

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

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

Tumor spillage and Wilm's tumor: types and implications

Tumor spillage during resection of a Wilm's tumor has substantial implications on prognosis and therapy. Spillage immediately upstages a patient to Stage III, and depending on the type of spillage, commits the patient to either flank (local spillage) or total abdominal radiation (diffuse spillage).

Intraoperative recognition and documentation of spillage, whether pre-exiting or secondary to manipulation, thus has substantial implications on adjuvant therapy. With that in mind, it is important understand the different types of spillage or peritoneal soilage by tumor.

Based on the COG's AREN03B2 Renal Biology Protocol handbook (2010), the peritoneum is concidered soiled (tumor spill) when:

1. There is intraoperative tumor spillage
2. The tumor is biopsied
3. The tumor has ruptured

Spillage occurs whenever the tumor capsule is violated. If adherent organs (eg. diaphragm) are resected without violation of the capsule, this is not considered spillage. Whenever one cuts across tumor, including tumor present within vessels, or the tumor is removed in more than one piece, spillage is assumed to have occurred.

Tumor biopsy, whether done through a percutaneous anterior or retroperitoneal approach, or using an open approach, is considered local spillage unless indicated otherwise by the surgeon.

Tumor rupture can be spontaneous or post-traumatic with subsequent tumor cell dissemination in the peritoneal cavity. Tumor rupture is usually considered diffuse soilage, though in some cases it may be clearly isolated to the retroperitoneal space and considered local spillage. The presence of a hematoma implies tumor cell spread and diffuse soilage.

Because of the various types of soilage, and their different implications (either flank or total abdominal radiation), the surgeon should completely and clearly document how the soilage occurred and whether it was thought to be diffuse or local. If tumor thrombus is encountered, the surgeon must clearly describe whether it was removed en bloc, in more than one piece, and if residual thrombus was thought to be left behind.

Neuroblastoma Power Notes [1]

Where do neuroblastic tumors (NBT) arise from?
They arise from the sympathetic cells of the neural crest. Thus NB can occur in sympathetic ganglia, sympathetic para-ganglia, or adrenal gland.

How is NB differentiated from other small round blue cell tumors?
The histopathologic findings characteristic of NB are:
1. Rosettes: NB cells surrounding neural fibrils
2. Neuropil: neuritic processes
3. Schwannian cell stroma: reactive/non-neoplastic tissue, recruited by tumor cells, and composed mostly of sheets of spindle cells. Schwannian stroma has an antineoplastic/anti-angiogenic/pro-differentiating effect on NB cells. The amount of stroma present is the major factor that divides neuroblastic tumors into NB vs. ganglioneuroblastoma and ganglioneurooma. More Shwannian stroma imparts better prognosis

What is the Shimada classification and what is it based on?
The Shimada classification is an age-linked histopathologic classification that is used to divide neuroblastic tumors in to favorable and unfavorable histology groups. It depends on
1. Degree of cellular differentiation
2. Mitotic-Karyorrhectic index: Number of cells in mitosis or Karyorrhexis (cell death) per 5000 cells. MKI can be low (<100), intermediate (100-200), or high (>200).
3. age
4. Amount of Shwannian stroma
The Shimada classification has independent prognostic value, where FH tumors have a 90% 5 year EFS, and UH tumors have a 30% 5 year EVS.

How is the International Neuroblastoma Pathologic Classification (INPC) different from the Shimada classification?
The INPC is based on the Shimada classification. It divides neuroblastic tumors into 4 tumor categories under 2 distinct prognostic groups: favorable subgroup (FS) and unfavorable subgroup (US).
FS:
Ganglioneuroma differentiating
Ganglioneuroblastoma intermixed type
Ganglioneuroblastoma nodular (with specific favorable features)
US:
Ganglioneuroblastoma nodular (unfavorable features)
Neuroblastoma

What is the histopathologic definition of NB?
NB is a Shwannian poor neuroblastic tumor (<50% Schwannian stroma) divided into three main types 1. Undifferentiated: No neuropil present 2. Poorly differentiated: <5% cells showing signs of differentiation into ganglion cells and neuropil present 3. Differentiating: >5% cells showing signs of differentiation and neuropil present

What defines Ganglioneuroblastoma (GNB) and Ganglioneuroma (GN)?
GNB and GN are both Schwannian stroma rich neuroblastic tumors (>50%)

What are the characteristics of GNB?
GNB cells are progressing into mature ganglion cells with >50% of cells in the maturing form (not completely mature, otherwise would be ganglioneuroma). GNB has residual foci (vs scattered) of neuroblastic cells that constitute <50% of cells. GNB is divided into the intermixed type (GNB-I) (where the foci of neuroblastic cells are microscopic) and the nodular type (GNB-N) (where foci are macroscopic) The GNB-I type are considered under the favorable subgroup while the GNB-N can be either favorable or unfavorable subgroup based on INPC factors [2] What are the characteristics of GN?
GN divided into GN mature (composed of mature cells and no neuroblastic elements) and GN maturing. The GN-maturing contains scattered (vs. foci) differentiating neuroblastic cells. Unlike GNB, these cells do not form distinct foci.

What is Horner's syndrome?
Horners syndrome results from loss of sympathetic innervation to part of the face. It consists of:
1. Ptosis: drooping of the eyelid due to loss off innervation of the upper tarsal muscle
2. Mioisis: small pupil
3. Anhydrosis: Decreased sweating on the affected side of the face
4. Enphthalmos: Impression that the eye is sunken
5. Heterochromia (in children): due to decreased melanin pigment deposition in the pupil on the effected side, secondary to loss of sympathetic innervation

What is acute cerebellar ataxis?
Also referred to as the 'dancing eyes syndrome', usually occurs in infants with mediastinal masses and results from excessive catecholamine production
It consists of:
1. Myoclonus: brief, involuntary twitching of muscles
2. Opsoclonus: uncontrolled eye movement
3. Nystagmus

Where are NB's usually found?
Adrenal gland (50%), Paraspinal ganglia (25%), Thorax (20%), pelvis (4%), and neck (1%)

Where does NB metastasize to?
40% of NB are stage 4 (metastatic) at time of diagnosis. Metastasis is most frequently to bone (bone pain), Bone marrow (anemia), and lymph nodes.
Raccoon eyes result from retrobulbar venous plexus spread.

What is stage 4S NB?
A specific type of metastatic NB found in infants (<1 year). Primary tumor is localized (stage 1, 2A, or 2B) and spread is limited to: 1. Skin: blueberry muffin lesions 2. Liver: can cause respiratory distress from hepatomegaly 3. Bone marrow: malignant cells should be limited to <10% nucleated cells. Can cause anemia. What are the different options for diagnosis of NB?
1. Histopathology of primary tumor OR
2. Tumor cells in bone marrow + elevated urine catecholamines

What laboratory values correlate with NB tumor burden?
1. LDH
2. Catecholamines
3. Neuron specific enolase
4. Ferritin

How often are calcifications found on CT scan?
85% of cases

In what setting is MRI better than CT scan for NB imaging?
1. evaluation of stage 4 disease: Bone and bone marrow metastatic disease
2. evaluation of encroachment into neural foramen
3. evaluation of vessel encasement

What is MIBG scan and how does it work?
MethIodoBenzylGuanine is taken up by the storage granules in chromaffin cells, in the same way catecholamines are. Detects the primary tumor, involved LN's, and metastatic disease.

What is the main drawback of INSS and how is that counteracted?
The main drawback is the the staging and thus the prognosis is dependent on extent of resection, and thus the skill and aggressiveness of the surgeon. Image defined risk factors, those that preoperatively predict worse prognosis, can help provide a more uniform system for staging disease at presentation.Such factors include vessel encasement, extension into neural foramena etc...

What are the two main categories of determinants of prognosis?
1. Clinical factors: age and stage
2. Biological factors: NMYC, DNA plyody (in infants), histopathologic classification (Shimada)
additional variables include LOH: 1p or 11q deletions. Loss of tumor suppressor genes. Used to define duration of chemotherapy in some situations.

What is the probability of 5 year disease free survival?
Low risk group > 95%
Intermediate risk group > 90%
High risk group < 30% What role does partial tumor resection play in NB?
As long as there is no N-MYC amplification, >50% resection of localized tumors (including stage 2 disease) keeps patients in the low risk group.

What is the adjuvant therapy for low risk disease?
Low risk disease is observed after resection, except in the situation where less than 50% of the tumor was resected or in the presence of organ or life threatening symptoms.

When is 4S disease considered intermediate risk?
when symptomatic, has unfavorable biologic characteristics (by Shimada/INPC) or DNA index=1, or when no tissue is obtained for evaluation.

What chemotheraputic agents are used for intermediate risk disease?
cyclophosphamide, doxorubicin, carboplatin, etoposide.
Patients with favorable histology receive 4 cycles, unfavorable histology receive 8 cycles (each three weeks apart).

What is the current COG protocol goal for intermediate risk NB?
Protocol ANBL0531: Aims at reducing chemotherapy by decreasing the number of cycles.

What are the main chemotherapy strategies for high risk NB?
1. combination of agents to decrease resistant tumor growth and improve synnergy
2. use of maximal tolerated dose/high dose intensity
3. Target therapy for minimal residual disease
for autologous BM transplant, cells are harvested after second cycle of chemotherapy.
after neo-adjuvant therapy, resection re-evaluated after 5th cycle

What is the current COG protocol for high risk NB?
Protocol ANB0532: looks at role of further intensification of myoablative therapy, effect of radiation on residual and metastatic disease, test the effect of dose-intensified topotecan containing induction therapy.

How is response to therapy assessed?

1. volume (radiologic)
2. urine catecholamine levels
3. MIBG scans

Who are the patients who undergo surgical therapy alone without adjuvant therapy?

Most localized tumors with favorable histology:
stage 1 tumors
stage 2 A/B with no N-MYC amplification and >50% resection
stage 3 midline tumors completely resected with negative nodal disease

When is LN assessment not important in NB?

LN involvement in thoracic neuroblastoma does not affect risk classification, despite potential effect on staging

References: (Ashcraft textbook unless otherwise specified):
1. Ashcraft's Pediatric Surgery. 5th Edition. Chapter 68: Neuroblastoma
2. Okamatsu et al. Clinicopathologic characteristics of ganglioneuroma and ganglioneuroblastoma: A report from the CCG and COG. Pediatr Blood Cancer (2009) 53:563-9

What is the significance of CT-only lung lesions in Wilms' Tumor

The advent of CT imaging of the chest as part of the work up of Wilm's tumor has created substantial controversy. It is natural to assume that lesions of the lung found on CT scan,in the setting of a known primary tumor, represent metastatic disease. False. A study by Ehrlich et al, from the National Wilms' Tumor Study 5 showed that up to a third of lung lesions found on CT only (negative CXR) were not malignant (by pathology). This raises the question of how CT-only lesions should change the management.

Based on COG recommendations, patients who are local stage I or II FH Wilms' tumor should undergo biopsy of CT-only lung lesions to gauge therapy. Patients with Stage III or IV disease, who are enrolled in AREN0533 trial (evaluating response of lung lesions to 3 drug therapy after 6 weeks) are not treated differently in the presence of lung lesions unless these lesions persist after 6 weeks, at which time they would be treated with additional lung radiation, preferably after confirming their malignant nature with biopsy.

Erlich PF. The value of surgery in directing therapy for patients with Wilms’ tumor with pulmonary disease. J Ped Surg (2006) 41, 162-167