42: Kidney and Adrenal Malignacies

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Jonathan P. Walker, MD ， 1  Nicholas G. Cost, MD ， 2  & Amanda F. Saltzman, MD 3
  1. Department of Urology, Division of Pediatric Urology, Atrium Health Levine Children’s Hospital, Charlotte, NC, USA
  2. Department of Surgery, Division of Urology, Children's Hospital Colorado, Aurora, CO, USA
  3. Urology, Pediatric Urology, University of Kentucky, Lexington, KY, USA

Tumors of the Adrenal Gland: Pheochromocytoma and Paraganglioma

Introduction

Pheochromocytoma (PCC) is a catecholamine secreting tumor. There are limited data available concerning management of this rare tumor in children and adolescents. Management is usually extrapolated from a combination of the adult guidelines and case reports/series. In the pediatric population, surgery is the mainstay of treatment, but there are recent advances in new treatments and management of metastatic disease.1,2

Embryology

PCC arises from the adrenal medulla, specifically the chromaffin cells.3 If PCC arises outside the adrenal gland, it is called a paraganglioma (PG).

Epidemiology

Overall, PCC has an annual incidence of 3 in 1 million individuals. Of all PCC diagnoses, 20% occur in children.3 Although patients can be diagnosed at any age, in children, the mean age is 11–13 years.4,5 Patients classically present with symptoms attributable to catecholamine excess: hypertension, headache, palpations, tremor, excessive sweating and facial pallor.6 These symptoms can be episodic, but in children, they are more likely to be sustained.6 Up to 2% of children with hypertension may have catecholamine secreting tumors compared to this being a rare cause (<1%) in adults.6

Pathogenesis

Discussion of PCC centers around genetic predisposition. Despite the classic “rule of 10s” for PCC, about 40% of pediatric PCCs have a hereditary disposition. Table 1 describes the known genetic syndromes associated with PCC.3,7 The genetic link is so strong that up to 70–80% of pediatric patients with PCC or PG have an associated germline mutation. These germline mutations may or may not be a genetic syndrome or hereditary in nature.4,8,9 In one study of 49 patients age <20y with PCC or PG, almost 80% had a germline mutation involving Succinate Dehydrogenase (SDH), von Hippel Lindau (VHL), or Neurofibromatosis Type 1 (NF1).8 When tested for RET (rearranged during transfection), VHL, and SDH mutations, 70% of patients <10y, 51% of patients 10–20y and 16% of patients >20y had an identifiable germline mutation.9 Considering this strong association, all children, adolescents and young adults with PCC or PG should undergo genetic testing.10 Similarly, for patients with either a family history or known genetic disposition (ex. Multiple Endocrine Neoplasia type 2 (MEN2) and VHL) should undergo regular screening, usually biochemical testing annually beginning at age 5y.11

MEN2 is an autosomal dominant disorder caused by an activating mutation in the RET oncogene. There is a >50% risk of developing PCC.3,5 About 20% of patients with MEN2B develop PCC, and all were associated with the classic M918T RET mutation.12 The majority are diagnosed with screening and few experience clinical symptoms, illustrating the importance of screening for early diagnosis.

Approximately 10–20% of patients with VHL will develop PCC or PG.3 Children with VHL may present with PCC as the event that triggers a VHL diagnosis. These presentations may be atypical, including weight loss,13 metastatic disease without symptoms after screening started,14 and bilateral PCC.15

Although less common, patients with NF1 have an increased risk of developing PCC.16 Usually this is diagnosed at an older age and rarely in children.11 As such, for patients with NF1 biochemical screening should begin at age 10y.16

Germline mutations of SDH complex genes and their association with PCC is a more recent discovery. It seems that a SDHA or B mutation is associated with a higher prevalence of aggressive and metastatic disease.8 As such, asymptomatic carriers are often identified through genetic testing of family members with related diseases.17 PCC associated with SDH mutations are generally biochemically silent, which necessitates serial imaging. In general, abdominal MRI every 18 months and MRI of the neck, thorax, abdomen and pelvis every 3 years is recommended.17

Recently, there have been cases suggesting some type of a relationship between PCC/PG and cyanotic congenital heart disease.18 The theory is that there may be a link between hypoxia-induced cellular pathways and tumorigensis.19

Table 1 Characteristics and screening recommendations of syndromes associated with PCC (Peard, Cost, Saltzman Curr Opin Urol 2019)

Disease Genetic mutation Stigmata of Disease Rate of PCC or PG Surveillance
VHL VHL tumor suppressor (Colvin) Central nervous system and retinal hemangiomas, renal cell carcinoma, PCC, pancreatic neuroendocrine tumors, cysts (Dias Pereira) 10% (PDQ) Plasma or urine metanephrines annually starting at age 5y (Jain)
MEN2A RET oncogene activation (Bholah) Medullary thyroid carcinoma, PCC, primary hyperparathyroidism (Dias Pereira) 68% (Dias Pereira) Plasma or urine metanephrines annually starting at age 5y (Jain)
MEN2B RET oncogene activation (Makri) Medullary thyroid carcinoma, PCC, multiple neuromas, marfanoid habitus (Bholah) 50% (Makri) Plasma or urine metanephrines annually starting at age 5y (Jain)
NF-1 NF1 gene mutation (Gruber) Café au lait lesions, axillary/inguinal freckling, neurofibromas, Lisch nodules, osseous lesions, PCC, GIST, melanoma, breast, lung, colorectal carcinomas (Dias pereira) 8% (Dias Pereira) Plasma or urine metanephrines every 3 years starting at age 10y (Gruber)
SDH SDH respiratory complex tumor suppressor (Jha) PCC, PG, renal cell carcinoma, GIST (settas) Not yet defined (Chen) SDHB: MRI abdomen q18mos, MRI neck, thorax, pelvis q3y (Tufton) /// SDHA, SDHC, SDHD: require less frequent screening (Tufton)
Carney Triad N/A PG, gastrointestinal stromal tumors, pulmonary chondromas (PDQ) 50% (PDQ) No defined screening

Evaluation and Diagnosis

While the majority of PCCs are benign, the systemic effects of catecholamine excess can have significant morbidity and mortality.7 Classically described is the “rule of 10s” (Table 2). To distinguish benign from malignant PCC, metastases must be identified.

Table 2 “Rule of 10s”

10%
Extra adrenal
Bilateral or multiple
Genetic predisposition (actually 25%)
Pediatric
Malignant/metastasize (up to 36%)
Associated with MEN syndromes
Present with stroke
Calcified
Present without hypertension
Recur
Found incidentally
Discussed 10× more common than actually seen

Suggested methods of diagnosis are extrapolated from adult studies, but there is an ongoing debate about preference considering the goal of minimizing radiation exposure in children.

Once an adrenal mass is discovered, laboratory testing to evaluate for catecholamine excess is necessary. Plasma-free metanephrines or 24-hour urine metanephrines are superior to measurement of plasma catecholamines (i.e., norepinephrine, epinephrine) or urine vanillylmandelic acid, since the latter substances are only episodically released, while the metanephrines are constantly present as degradation products.20

Several common medications may cause a false positive result, including selective serotonin reuptake inhibitors, tricyclic amines, monoamine oxidase inhibitors, and sympathomimetics including amphetamines, decongestants, caffeine or nicotine.11 Prior to lab testing, these medications should be stopped. Additionally, patients should be fasting and supine for at least 30 minutes prior to lab draw.6,21 Blood draws in the seated position can cause a 5–7 fold increase in the rate of false positive results.22

Pediatric-specific reference ranges are nebulous and false-positives are high. In general, a false positive should be considered if levels are <3-4 times normal and testing should be repeated.

Patients with laboratory confirmed catecholamine excess need cross sectional imaging. This should be either CT or MRI of the abdomen, with >90% sensitivity for adrenal PCC detection.5 On T2 MRI, PCC is very bright, called the lightbulb sign. For patients with a high suspicion for PCC but inconclusive biochemical testing, and to assess for metastasis, multifocal disease, or regional extension, functional imaging is indicated. This includes 123I- or 131I-metaiodobenzylguanidine (MIBG) scintigraphy and positron emission tomography (PET).5 Both PET and 123I-MIBG are sensitive tests for tumor localization but PET is preferred for identifying metastatic disease.23 Head-to-head comparisons of various types of cross-sectional imaging with or without radiopharmaceuticals have shown the superiority of Ga-DOTA(0)-Tyr(3)-octreotate (Ga-DOTATATE) PET scans for localizing metastatic PCC and other paragangliomas.

Treatment Options and Their Outcomes

Surgical resection is the gold standard treatment for PCC.5 The key to surgical management is the appropriate pre- and perioperative management to preventing sequelae from hypertensive crisis.

With tumor manipulation by the surgeon, catecholamines may be released in large quantities and cause hypertensive crisis with cardiac arrhythmias, myocardial ischemia, pulmonary edema, and stroke.11 Various preoperative regimens have been described, but again management of pediatric patients is largely extrapolated from the adult literature.24 In PCC, there is a high level of catecholamines. These cause vasoconstriction of the peripheral vasculature. As such, the patient is hypovolemic. To counteract this, the alpha receptors are blocked, which dilates the peripheral vasculature. To counteract this drop in blood pressure due to hypovolemia, high salt intake and hydration help to increase intravascular volume.5 Options for alpha blockade include phenoxybenzamine, doxazosin, prazosin, or terazosin.6 Alternative regimens include a tyrosine hydroxylase inhibitors or calcium channel blockers.25 Following alpha blockade, when hypovolemia is present and the vascular resistance is decreased, tachycardia develops. This may require beta blockade. Patients may be admitted preoperatively for this medical optimization and fluid management if there are concerns about doing this on an outpatient basis.26 Of critical importance to intraoperative safety is pre-surgical optimization, involving endocrinology and/or nephrology and anesthesiology. Postoperatively, patients will need to be monitored for blood pressure control and rebound hypoglycemia, potentially requiring an intensive care unit.

When feasible, minimally invasive surgical techniques are preferable for tumor resection.27 However, open resection may be considered for large, locally invasive tumors due to risk of tumor spillage. The approach may be transperitoneal or retroperitoneal depending on surgeon experience.27,28 There is very little literature available evaluating safety of the laparoscopic approach in pediatric patients with PCC, but the few reports appear to yield favorable results and low intraoperative complications.28

Cortical sparing surgery (partial adrenalectomy) is recommended for patients with known bilateral disease or patients at high risk of disease recurrence. These would include patients with known hereditary syndromes. To preserve function, about 15% of the adrenal needs to remain.29 However, these patients are at a 10% risk of local recurrence, so need to be followed postoperatively.30

Malignant PCC is defined by distant spread.31 This is significantly higher in children, up to 50% of cases.32,33 Typical sites of metastases are regional lymph nodes, bone, lung and liver. As expected, survival is significantly lower in malignant PCC (31% vs. 100% in benign disease).32 Despite the high rate of metastases, surgical resection of lesions remains the mainstay of treatment mainly because there are no highly successful alternative therapies. There are therapies to control malignant disease if surgical resection is not possible, but pediatric data are limited. In this scenario, despite extrapolation from the adult literature elsewhere, the inherent differences between tumors in adults and children as well as the impact of toxic therapies in the pediatric population must be considered.

High dose 131I-MIBG administration can be therapeutic in patients with a positive MIBG and malignant disease.34 The radioactive compound is taken up by the active norepinephrine transporter of PCC cells, targeting radiation directly to the cancer cells. In general, tumor volume remains stable with about half of patients having a partial hormone response without progression of disease. However, studies are limited to it is unclear if this is reflective of natural disease progression or a true response to therapy.34 131I-MIBG therapy carries a risk of secondary malignancy in children, well documented after neuroblastoma treatment, so this risk must be considered.35

Radiotherapy can be used, mainly for palliation. External beam radiation therapy has been used alone or with 131I-MIBG therapy. The goal here is usually maintaining disease stability and less for regression or cure.2

Multiple chemotherapy regimens have been reported. Generally, these include gemcitabine, docetaxel, vincristine, cyclophosphamide, doxorubicin, and dacarbazine. There are several studies now evaluating guadecitabine, a DNA methyl transferase inhibitor, sunitinib, a tyrosine kinase inhibitor, but there are limited data supporting its use.

Suggested Follow Up

In addition to genetic counseling and germline testing, follow up is recommended at 6 weeks, 6 months and 1 year postoperatively, followed by annual biochemical screening and intermingled abdominal imaging. Follow up involves an inquiry into catecholamine excess symptoms, blood pressure monitoring, and biochemical testing. This follow up is for a lifetime, particularly for recurrent or metastatic disease.6

Conclusions

Pediatric PCC is rare and most recommendations are extrapolated from adult PCC/PG data. Children with PCC/PG have a high likelihood of an underlying germline mutation, unlike adults, so genetic counseling should be offered. Diagnosis centers on biochemical testing and cross-sectional imaging, followed by surgical resection. Pre-operative optimization and complete surgical resection are essential.

Key Points

  • Measure plasma metanephrines and get cross-sectional imaging, ± MIBG or Dotatate PET
  • Alpha blockade, hydration and NaCl replacement, then beta blockade if necessary pre-operatively
  • Resection of lesions is the mainstay of treatment, ideally with minimally invasive methods
  • All pediatric patients with PCC should be referred for genetic counseling/testing

Wilms’ Tumor

Introduction

The vast majority of renal masses found in children are Wilms’ tumor (WT), but several other rare and important diagnoses can be found. These are summarized in Table 3.

Table 3 Incidence of pediatric renal tumors36

Histology Frequency (%)
Favorable Histology Wilms tumor (WT) 75
Anaplastic WT 5
Congenital mesoblastic nephroma (CMN) 2
Clear cell sarcoma of the kidney (CCSK) 3
Renal Cell Carcinoma (RCC) 4
Rhabdoid tumor of the kidney (RTK) 4
Cystic Nephroma 2
Other 5

There exist competing diagnosis and treatment strategies among two international cooperative working groups. The Children’s Oncology Group (COG), responsible for treatment guidelines, tumor registries and clinical trials for renal masses in North America, advocate upfront renal mass excision with the interpretation of primary unaltered pathology and staging guiding further treatment. The Société Internationale d’Oncologie Pédiatrique (SIOP), the European equivalent to COG, alternatively advocates for combination vincristine and actinomycin (VA) neoadjuvant chemotherapy for all patients ≥6 months old with a solid renal mass followed by surgery and then histologic evaluation to guide subsequent therapy.37 Regardless of approach, survival appears to be similar, but there are nuances and advantages and disadvantages with both approaches. This chapter will focus on the COG guidelines since the authors practice in North America. It is essential to establish early multidisciplinary care with medical oncologists familiar with local ongoing protocols.

In general, it is important to keep a wide differential diagnosis for children with renal masses, as surgical decisions can alter staging, treatment decisions and outcomes. Most renal tumors in children are managed with upfront surgery, usually radical nephrectomy and lymph node (LN) sampling. Then once pathology is determined, more nuanced decisions for adjuvant treatment are made. An important exception is for bilateral renal tumors, patients with a solitary kidney, history of a known WT predisposition syndrome, advanced/locally invasive disease, or inferior vena cava (IVC) tumor thrombus. These cases are assumed to be WT and are managed by upfront chemotherapy followed by attempts at partial nephrectomy to preserve as much renal tissue as possible.

Embryology

WT develops from dysregulated growth of primitive renal tissue and shows a triphasic pattern of stromal, blastemal and epithelial components. Histology is then further described as favorable or unfavorable (anaplastic), and this guides treatment and prognosis.

Epidemiology

There are about 500 cases with WT in the USA annually.36 Patients with WT are usually 3–5 years old and most cases are diagnosed before age <10y. African-American children seem to be at higher risk of developing WT, and patients of Asian decent have the lowest risk of WT.

Pathogenesis

While there are several well described syndromes associated with an increased chance of developing WT, this is seen in the minority of patients with WT. The WT1 gene is critically involved with the development of WT. This is found on the short arm of chromosome 11 (11p13). WT1 is a tumor suppressor gene that codes for a transcription factor that is linked to embryologic genitourinary development. Homozygous mutations of WT1, or nearby coding regions, very often results in the patient developing WT.

Multiple genetic syndromes may predispose children to WT, as listed in Table 1.37 Patients with predisposition syndromes and bilateral tumors typically present at earlier ages than those without. Screening protocols are often used for these patients to attempt to diagnose tumors at an earlier stage, but whether these impact overall outcomes is unclear. In general, screening protocols involve an abdominal ultrasound every 3–6 months until age 7–10 years.37

Table 4 WT Predisposition Syndromes37

Syndrome Genetics Associated Features Risk of WT (%)
WAGR 11p13, WT1, PAX13 WT, Aniridia, Genital abnormalities, Mental delay 98
Denys Drash WT1 WT, Genital abnormalities, Renal failure/nephropathy (mesangial sclerosis) 74
Beckwith-Weideman 11p15.5, WT2 Pre-and post-natal overgrowth, Hemihypertrophy (growth asymmetry), Macroglossia, Anterior abdominal wall defects (omphalocele), Ear creases/pits 7
Frasier syndrome WT1 WT, Nephropathy (FSGS), Genital abnormalities, Gonadoblastoma/GCNIS 6

Evaluation and Diagnosis

Patients with any renal mass typical present with a palpable abdominal mass. Hematuria, hypertension, abdominal pain may also be present. It is important to ask about hematuria specifically, as if this is present, the surgeon may consider cystoscopy and retrograde pyelography at the beginning of the case to rule out ureteral tumor extension, which is seen in 2-5% of patients.37 This may have implications of the level at which the ureter is amputated to avoid intraoperative tumor spillage.

Laboratory studies should include complete blood count, comprehensive metabolic panel and urinalysis. Coagulation studies are critical as an acquired von Willebrand disease is seen in 4–8% of patients with WT.37

The initial imaging modality of choice for a patient with any suspected intra-abdominal mass should be an abdominal ultrasound which then guides further cross-sectional imaging.37 When a solid renal mass is found, a single CT scan of the chest, abdomen and pelvis with iv contrast should be done for staging. For patients with bilateral renal masses, or for patients with another contraindication for CT scan, an abdominal and pelvic MRI with IV contrast is appropriate. Importantly for these patients, CT of the chest is still necessary to complete staging.37 On preoperative imaging, it is important to look for signs of preoperative rupture, enlarged LNs, tumor thrombus in the renal vein or IVC, and for any renal masses in the contralateral kidney. It is critical to note findings in the contralateral kidney as this changes the approach entirely, to chemotherapy first followed by surgery. Venous tumor thrombus presence will affect surgical planning, and if this extends into the IVC and especially near the level of the hepatic veins, consideration for chemotherapy prior to surgery is encouraged to avoid cardiac bypass. While imaging findings suspicious for preoperative rupture have low sensitivity (CT 76% and MRI 53%) and are not used for final staging, they can provide guidance as to what the surgeon may encounter in the operating room.38 Assessment of the involvement of other organs is also important, but keep in mind that WT rarely invades surrounding structures, but rather displaces them.

Treatment Options and Their Outcomes

Pre-operative clinical staging and decisions have significant impact on treatment strategies, as outlined in Table 5.

The standard of care according to COG surgical protocols for the initial treatment of unilateral, non-syndromic WT is open radical nephrectomy with regional LN sampling. Notably, pre-operative renal mass biopsy is considered spillage of tumor, and results in clinical upstaging to stage III. Biopsy is rarely used in COG protocols due to the intensification of chemotherapy and radiation with upstaging, both of which have significant side effects. Neoadjuvant chemotherapy may be considered in locally advanced, unresectable tumors, and always with bilateral tumors. Those with venous tumor thrombus into the IVC at or above the hepatic venous confluence or those with overwhelming liver or lung metastases that compromise normal function, based on surgeon and/or anesthesia judgement, may also benefit from neoadjuvant chemotherapy.

In countries were the SIOP UMBRELLA protocol is being followed, dual agent Vincristine and Actinomycin-D neoadjuvant chemotherapy for patients older than 6 months of age with localized tumors is the standard of care. The goal of neoadjuvant chemotherapy is to down-stage the tumor as well as aid in the ease of surgical resection. Patients with metastatic disease receive additional Doxorubicin neoadjuvant chemotherapy. Nephrectomy is planned between weeks 5 and 8 depending on tumor stage, and adjuvant chemotherapy is based on the final tumor stage and histology.

Radical nephrectomy, with sparing of the adrenal gland if feasible, should be performed via an open transperitoneal abdominal approach. It is important to palpate the surface of the liver and peritoneal surfaces, biopsying any nodules that are felt. Inspect the peritoneal fluid and if bloody, consider declaring pre-operative rupture vs. sending to pathology for cytology to identify any malignant cells. Carefully document any surrounding structures invasion and palpate the renal vein and IVC to identify any venous tumor thrombus. Routine exploration of the contralateral kidney is unnecessary with modern use of preoperative cross-sectional imaging. Although LN sampling is mandated as part of COG surgical protocols, under sampling or omission of LN sampling is the most common protocol violation. In general, at least 6-10 LNs need to be examined in order to achieve an acceptable false negative rate.39 Additionally, LN positivity is one of the most common criteria for Stage III disease and has been shown to be an independent predictor of survival when compared to other Stage III variables.40

Special Treatment Scenarios

In general, nephron-sparring surgery (NSS, partial nephrectomy) is reserved for patients with solitary kidneys, bilateral (stage V) or syndromic tumors and is often preceded by neoadjuvant chemotherapy in an attempt to improve feasibility of NSS. Importantly, biopsy before chemotherapy when WT is the overwhelming likely diagnosis (i.e., age 1–7y), is NOT advocated, as this will result in adjuvant therapy intensification as well. If there is not at least a partial response in tumor size (partial response is ≥30% total tumor size reduction) after 6 weeks of neoadjuvant therapy, consider open renal biopsy to identify either anaplasia or other histology that would change management. LN sampling on both sides is also important in NSS for the treatment of bilateral tumors.

Another important group of patients eligible for treatment modification includes children classified as having very low-risk WT (VLRWT). To meet the criteria for VLRWT, the patient must be <2y at the time of diagnosis and have a Stage I favorable histology WT that weighs <550g. These patients have been shown to have equivalent event free and overall survival (90% and 100% at 4 years) with nephrectomy alone, thus avoiding some of the potential long-term side effects of chemoradiation therapy. Future COG studies will likely expand on the criteria for surgery alone, but these protocols have not been fully developed yet.

Staging is finalized using several factors, described both by the pathologist and the surgeon at the time of surgery. Surgeon findings are emphasized over imaging findings due to poor sensitivity of cross-sectional imaging to estimate things like spillage, lymphadenopathy, surrounding tissue invasion, etc. As with pre-operative renal mass biopsy, intraabdominal tumor implants or pre-operative rupture/intra-operative spill confers clinical stage III disease, all of which are independently associated with poor survival.37

The most important factor affecting prognosis and treatment is anaplasia, or unfavorable histology.37 Additionally, loss of heterozygosity (LOH) for both chromosomes 1p and 16q is associated with increased risk of relapse and cancer-specific mortality37 and leads to adjuvant chemotherapy intensification. Gain of chromosome 1q has also been shown to be predictive of worse event-free and overall survival and is a more common alteration than the combined LOH abnormalities at 1p and 16q (1q Gain 28% vs combined LOH 11%). Currently, no treatment or staging alterations are based on gain of 1q, but this gene target may be incorporated into future treatment algorithms and study protocols.

Table 5 Therapy and clinical outcomes by Wilms’ tumor stage.37 VA = vincristine + actinomycin, VAD = vincristine + actinomycin + doxorubicin, XRT = external beam radiation, FH = favorable histology, UH = unfavorable histology, ° - Chemotherapeutic agent only, not regimen. Treatment is generally intensified for Combined LOH and not reflected in this table, * = with UH, use doxorubicin and XRT earlier with lower stages and 5 drug chemotherapy if diffuse UH, ** = preoperative chemo only indicated with unresectable primary tumor/abdominal disease, *** - exact use of abdominal and chest XRT is dictated by a number of clinical factors and is unique to each patient’s clinical scenario

Stage Incidence (%) Criteria Therapy (FH)*˚ 4-year survival (%UH–%FH)
I 40–45% Confined to kidney, negative margin, no nodal involvement Radical nephrectomy with LN sampling** + VA 83–99%
II 20% Spread beyond kidney, negative margins, no nodal involvement Radical nephrectomy with LN sampling** + VA 81–98%
III 20–25% Peritoneal implants, positive margin, preoperative biopsy, preoperative chemotherapy, Intraoperative tumor rupture, nodal involvement Radical nephrectomy with LN sampling** + VAD + abdominal XRT 72–94%
IV 10% Metastatic disease Radical nephrectomy with LN sampling** + multi-agent + abdominal and chest*** XRT 38–86%
V 5% Bilateral tumors VAD + nephron-sparing surgery with LN sampling 55–87%

Complications

Outcomes for WT have improved dramatically from the 1900s, owing mainly to improvement in anesthesia techniques and optimization of chemoradiation protocols. Because of the excellent outcomes, COG study now focuses on decreasing long term morbidity from treatment. The important complications seen by patients treated with WT are CKD, secondary malignancies from both chemotherapy and radiation, cardiac toxicity from doxorubicin and infertility due to chemoradiation exposure.37

Suggested Follow Up

Various follow-up recommendations exist for surveillance imaging after treatment for WT, with most protocols highlighting the need for more intense surveillance during the first 2 years after treatment. Surveillance imaging options include abdominal ultrasound and chest X-ray screening every 3–6 months for the first 3–4 years followed by yearly imaging after that. Alternatively, cross-sectional imaging with CT or MRI may also be used in surveillance protocols, particularly in high-risk patients or those with indeterminant findings on US or X-ray.

Outside of the standard post-operative clinic visits to assess for immediate and long-term surgical complications or disease recurrence, COG has also published long-term follow-up guidelines that cover treatment and organ specific follow-up recommendations aimed at identifying patients at a high risk for long-term complications ranging from non-target organ dysfunction to mental health and infertility issues.

Key Points

  • Evaluation for a suspected intra-abdominal mass should always begin with ultrasound
  • Open surgery is the standard of care for removal of a pediatric renal tumor
  • Avoid biopsy unless absolutely necessary and subsequent results will likely alter management
  • Always remember to perform LN sampling at the time of surgery

Suggested Readings

  • Saltzman AF, Cost NG. Lesson 19: Childhood Kidney Tumors. AUA Update Series 2018: 37.
  • Saltzman A, Carrasco A, Weinman J, Meyers M, Cost N. Initial imaging for pediatric renal masses: An opportunity for improvement. J Urol 2018; 199 (5): 1330–1336. DOI: 10.1016/j.juro.2017.11.076.
  • Saltzman A, Smith D, Gao D, Ghosh D, Amini A, Aldrink J, et al.. How many lymph nodes are enough? Assessing the adequacy of lymph node yield for staging in favorable histology Wilms’ tumor. J Pediatr Surg 2019; 54 (11): 2331–2335. DOI: 10.1016/j.jpedsurg.2019.06.010.
  • Cost NG, Routh JC. Wilms Tumor. AUA University Core Curriculum; 2022, DOI: 10.1097/01.cot.0000314419.91544.ae.
  • Qureshi SS, Bhagat M, Kazi M, Kembhavi SA, Yadav S, Parambil BC, et al.. Standardizing lymph nodal sampling for Wilms tumor: a feasibility study with outcomes. J Pediatr Surg 2020; 55 (12): 2668–2675.

Pediatric Non-Wilms’ Renal Tumors

Introduction

Renal cell carcinoma (RCC) in the pediatric, adolescent and young adult population is an important histologic subtype of renal malignancy with several unique differences in management when compared to the more common WT pathology. RCC is similar in appearance to WT on standard CT or MRI and should be taken into consideration during the evaluation of a suspected renal malignancy, especially in adolescent children and young adults. Unlike their adult counterparts, pediatric RCC tends to follow a more aggressive clinical course in large part due to differences in the molecular biology of these tumors.

Embryology

Multiple genetic mutations have been associated with predisposition syndromes for sub-types of RCC (Table 6).

Table 6 Genetic syndromes associated with RCC.

Genetic Predisposition Syndrome Gene Presentation
Von Hippel Lindau VHL (3p) Clear cell RCC, Retinal and CNS hemangioblastomasm pheochromocytomas, pancreatic cysts/tumors, epididymal cystadenomas
Tuberous Sclerosis TSC1 or TSC2 AMLs, clear cell RCC, seizures, mental retardation, facial angiofibromas, hamartomas
Hereditary Papillary RCC MET Low grade type 1 papillary RCC
Birt-Hogg-Dubé FLCN Chromophobe RCC, fibrofolliculomas, lung cysts and blebs
Hereditary Leiomyomatosis and RCC FH High grade type 2 papillary RCC, uterine fibroids at young age, cutaneous leiomyomas
Succinate Dehydrogenase RCC SDH Different RCCs, paragangliomas, pheochromocytomas
Sickle hemoglobinopathy Hemoglobin-Beta (11p) Renal Medullary Carcinoma

Epidemiology

RCC is the second most common renal tumor in children, accounting for about 4% of cases. The median age at presentation is 12.9 years, and after age 12y, it is the most common pathology found.37,41 No significant gender or racial predilection has been described.

Pathogenesis

Unlike adult tumors where clear cell RCC is the most common RCC subtype (75–88%), the most common histology in children and young adults is translocation RCC (tRCC, 50%). These tumors have activating mutations of TFE3 on Xp11.2. This causes continuous tyrosine kinase activity and downstream mTOR pathway activation which results in cellular proliferation. This is a common pathway for RCC development. Despite these tumors often being smaller than their WT counterparts, they are aggressive and associated with locally advanced or metastatic disease in 63% of children.37

This type of tumor is unique in that patients who have received chemotherapeutic drugs during treatment of other malignancies are at higher risk of later developing TFE+RCC. There are several case reports detailing the development of translocation RCC after treatment for neuroblastoma, among others.

Evaluation and Diagnosis

While most adult tumors are identified incidentally, pediatric RCCs commonly present with symptom, namely a palpable mass or gross hematuria. Laboratory work up is the same as for WT (complete blood count, comprehensive metabolic panel and urinalysis). Like for WT, abdominal US should be the first imaging modality, followed by complete staging with CT chest and either CT or MRI with intravenous contrast of the abdomen and pelvis. Staging and grading systems are the same as those used for adult RCC (Table 7).

While NSS and minimally invasive approaches for adult RCC are considered standard of care, their role in pediatric RCC is less clear. The reason for this is likely multifactorial. This disease is rare, and the pathology is not known preoperatively. WT COG surgical protocols emphasize open, radical nephrectomy for the initial treatment of a suspected renal malignancy, which limits the widespread use of laparoscopy and NSS in general for pediatric RCC, despite the familiarity with urologists with this technique.

Table 7 American Joint Committee on Cancer (AJCC) TNM Staging for Renal Cell Carcinoma (7th Edition)

Stage Definitiion
T1a Tumor confined to kidney, <4 cm
T1b Tumor confined to kidney, ≥4 cm but <7 cm
T2a Tumor confined to kidney, ≥7 cm but <10 cm
T2b Tumor confined to kidney, ≥10 cm
T3a Tumor extends grossly into renal vein or its segmental branches, or tumor invades perirenal and/or renal sinus fat but not beyond Gerota’s fascia
T3b Spread to infra-diaphragmatic IVC
T3c Spread to supra-diaphragmatic IVC or IVC wall invasion
T4 Involvement of ipsilateral adrenal gland or invades beyond Gerota’s fascia
Nodal Stage  
N0 No nodal involvement
N1 Metastatic involvement of regional LN
Metastasis Stage  
M0 No distant metastases
M1 Distant metastases
Stage Groupings  
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 or N1 with M0
Stage IV T4 or M1

Treatment Options and Outcomes

As mentioned previously, surgery is the mainstay of treatment. It is critical that a multi-disciplinary discussion be had between the surgeon and the oncologist to ensure that any possible surgical decisions made (nephron sparing surgery (NSS) vs. radical nephrectomy (RN), laparoscopy vs. open) or necessitated by the pathology that results from surgery (i.e., positive margin) are considered preoperatively. The downstream consequences of decisions should always be considered up front, as this may change the subsequent treatment, eligibility for research studies, or outcomes.

Surgical treatment revolves around radical nephrectomy versus NSS, and consideration for laparoscopy should be careful and conservative. LN sampling is again imperative for translocation RCC in children, and unlike adult RCC where LNs are rarely involved if not clinically suspicious preoperatively, pre-operative staging imaging has low sensitivity (57%) for identifying the high rate (48%) of LN involvement for cT1 tumors. Extending beyond just children, LN sampling should be strongly encouraged, for both diagnostic and therapeutic reasons, in patients <40 years of age with a suspicious renal mass.37 More recent COG data from AREN0321 suggest that complete surgical resection of disease, including all metastatic sites, and therefore presumably any involved LNs, confers a significant survival advantage, highlighting the importance of careful surgical planning and adherence to current protocols.

5-year overall survival is 71–100% for patients with pT1–3 disease, 55% for patients with LN metastases and just 8% for patients with distant disease. Overall survival trends are lower in children stage-for-stage when compared to adult patients with RCC, a direct correlate to the increased prevalence of tRCC in the younger patient cohort. Traditional adjuvant therapy for adults, such as tyrosine kinase and mammalian target of Rapamycin inhibitors, may be used with advanced disease or adverse pathology, but data are limited in children. The only reported cases of survival in widely metastatic translocation RCC involve complete surgical resection (primary tumor, regional lymph nodes, and metastatic lesions). AREN 1721, a current COG study, is currently examining the benefit of immunotherapy and tyrosine kinase inhibitors in advanced translocation-RCC, which hopefully will add another treatment option for patients with more widespread disease.

Complications

Complications of treatment for RCC are similar to those for WT, namely CKD and surgical complications such as bowel obstruction, bleeding, adjacent organ injury, urine leak, etc. Since chemotherapy and radiation are rarely used for this type of tumor, there are not associated side effects from these treatments.

Conclusions

Pediatric RCC, although not as common as WT, is a very important entity that every pediatric surgeon and urologist should be aware of when treating pediatric, adolescent, and young adult patients with renal tumors. Since these tumors are often indistinguishable from other histologic variants of renal malignancies, RCC should be kept in the differential diagnosis, especially when treating children older than 12 years of age. Because surgery is the mainstay of treatment, careful adherence to surgical protocols with the careful use of NSS approaches only after thorough multi-disciplinary discussions is vital.

Key Points

  • Begin work up with abdominal US, single arterial phase CT chest, abdomen, pelvis with IV contrast; MRI of the abdomen and pelvis with IV contrast is an acceptable alternative to abdominopelvic imaging
  • Initial treatment is surgical
  • Multi-disciplinary discussion of radical nephrectomy vs. NSS and open vs. laparoscopy is important with the treating oncology team
  • Always sample regional LNs, regardless of preoperative imaging appearance as this has low sensitivity
  • Small masses often have involved LNs, regardless of preoperative imaging appearance

Suggested Readings

  1. Saltzman AF, Cost NG. Lesson 19: Childhood Kidney Tumors. AUA Update Series 2018: 37.
  2. Seibel NL, Sun J, Anderson B JR, NE P, EJ R, M.L.. Outcome of clear cell sarcoma of the kidney (CCSK) treated on the National Wilms Tumor Study-5 (NWTS. J Clin Oncol 2006; 24 (90180): 9000–9000. DOI: 10.1200/jco.2006.24.18_suppl.9000.
  3. Geller JI, Ehrlich PF, Cost NG, Khanna G, Mullen EA, Gratias EJ. Characterization of adolescent and pediatric renal cell carcinoma: A report from the Children’s Oncology Group study AREN03B2: Adolescent Renal Cell Carcinoma. Cancer 2015; 121: 2457–2464. DOI: 10.1002/cncr.29368.
  4. Rialon KL, Gulack BC, Englum BR, Routh JC, Rice HE. Factors impacting survival in children with renal cell carcinoma. J Pediatr Surg 2015; 50: 1014–1018. DOI: 10.1016/j.jpedsurg.2015.03.027.

Supplementary Table Other Rare Pediatric Renal Tumors

Tumor Characteristics
Clear Cell Sarcoma of the Kidney (CCSK) Age of onset: 1-4yo
  M:F= 2:1
  Associated with skeletal and brain metastasis
  No known familial predisposition syndromes or cases of bilateral CCSK.
  Radical nephrectomy with LN sampling
  Adjuvant radiation and chemotherapy (vincristine, doxorubicin, cyclophosphamide and etoposide; Seibel 2006)
  80-90% 5yr survival
Rhabdoid Tumor of the Kidney (RTK) 80% <2yo
  Germline mutations in INI-1 on chromosome 22
  Associated with brain metastasis → MRI brain during workup; CNS involvement almost always fatal
  Radical nephrectomy with LN sampling
  Chemotherapy and radioresistant (Denes 2013)
  Worst survival of all pediatric renal tumors - 20% 5-year OS
Congenital Mesoblastic Nephroma (CMN) most common renal tumor in infants <6 months of age
  may be seen prenatal ultrasound with polyhydramnios and preterm birth
  CT chest, abdomen and pelvis for staging
  Radical nephrectomy with LN sampling is diagnostic and therapeutic
  Excellent prognosis, especially with surgery within the first 6 months of life
  Metastasis and recurrence rarely occur, follow with US for 2y
Renal medullary carcinoma (RMC) Often in those with sickle cell trait or disease; strong African-American predominance (Denes 2013).
  Complete cross-sectional staging imaging is necessary
  >90% will have advanced/metastatic disease on presentation
  Radical nephrectomy is the primary treatment modality
  Unresponsive to chemoradiation.
  OS 4-16 months
Angiomyolipoma (AML) 3 histologic components: blood vessels, muscle and adipose
  Often present with spontaneous retroperitoneal hemorrhage
  Associated with Tuberous Sclerosis Complex
  Annual monitoring with ultrasonography or MRI for size and stability
  NSS if excision needed at all
  mTOR inhibitor therapy (everolimus) has been shown to reduce the size and slow progression
  Increased risk of RCC and should be considered in fat-poor lesions
Cystic Tumor Variants: Multilocular Cystic Nephroma (MCN), Cystic Partially differentiated Nephroblastoma (CPDN), Cystic WT MCN and CPDN
  <2 years of age
  MCN associated with DICER-1 mutation (pleuropulmonary blastoma, ovarian stromal tumors)
  MCN have benign septae; CPDN have poorly differentiated tissue/blastemal cells in septae
  Radical nephrectomy is curative
  If NSS, use frozen section analysis to confirm negative margin
  Stage II CPDN require vincristine and actinomycin chemotherapy
  Cystic WT
  More common 3-5yo
  More solid strictures between the cysts with stromal, mesenchymal or epithelial components
  Radical nephrectomy with LN sampling
  Adjuvant therapy based on stage-dependent WT guidelines

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