Wilms Tumor

Anatomy

Epidemiology

Wilms tumor is an embryonic kidney tumor. It is the most common abdominal tumor in children and represents 6% of all childhood cancers. The incidence is 8.1/million in under 15 year old group. The median age of diagnosis is 41.5 months for boys wiht unilateral tumors and 46.9 months for girls with unilateral tumors. For bilateral tumors the median age is 29 months.

Pathology

Low-risk tumors
- Mesoblastic nephroma
- Cystic partially differentiated nephroblastoma
- Completely necrotic nephroblastoma
Intermediate-risk tumors
- Nephroblastoma, epithelial type
- Nephroblastoma, stromal type
- Nephroblastoma, mixed type
- Nephroblastoma, regressive type
- Nephroblastoma, focal anaplasia
High-risk tumors
- Nephroblastoma,blastemal type
- Nephroblastoma,diffuse anaplasia
- Clear cell sarcoma of the Kidney
- Rhabdoid tumor of the kidney

Halperin states that CCSK and RTK are no longer considered Wilm's variants, but are distinct entities. The sole remaining high risk pathology is anaplastic variant. Anaplasia is defined as the significant enlargement of nuclei in stromal, epithelial or blastemal cell lines at least 3x the diameter of adjacent cells.

Natural History

There are several clinical syndromes associated with Wilms: WAGR (Wilms, aniridia, GU malformation, mental retardation; Denys-Drash (pseudohermaphroditism, mesagial sclerosis, renal failure, Wilms); Beckwith-Wiedmann ot (gigantism, omphalocele, macroglossia, GU abnormalities, ear creases, hypglycemia, hemihypertrophy, Wilms)

Staging

Children's Oncology Group Staging of Wilms Tumor
Stage I	Tumor limited to kidney, completely resected. The renal capsule is intact. The tumor was not ruptured or biopsied prior to removal. The vessels of the renal sinus are not involved. There is no evidence of tumor at or beyond the margins of resection. Note: For a tumor to qualify for certain therapeutic protocols as Stage I, regional lymph nodes must be examined microscopically.

Stage II	The tumor is completely resected and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond kidney, as is evidenced by any one of the following criteria: There is regional extension of the tumor (i.e., penetration of the renal capsule, or extensive invasion of the soft tissue of the renal sinus, as discussed below). Blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor. Note: Rupture or spillage confined to the flank, including biopsy of the tumor, is no longer included in Stage II and is now included in Stage III.
Stage III	Residual nonhematogenous tumor present following surgery, and confined to abdomen. Any one of the following may occur: Lymph nodes within the abdomen or pelvis are involved by tumor. (Lymph node involvement in the thorax or other extra-abdominal sites is a criterion for Stage IV.) The tumor has penetrated through the peritoneal surface. Tumor implants are found on the peritoneal surface. Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination). The tumor is not completely resectable because of local infiltration into vital structures. Tumor spillage occurring either before or during surgery. The tumor was biopsied (whether core needle, open, or fine needle aspiration) before removal. Tumor is removed in greater than one piece (e.g., tumor cells are found in a separately excised adrenal gland; a tumor thrombus within the renal vein is removed separately from the nephrectomy specimen).
Stage IV	Hematogenous metastases (lung, liver, bone, brain, etc.), or lymph node metastases outside the abdominopelvic region are present. (The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present.)
Stage V	Bilateral renal involvement by tumor is present at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of the extent of disease.

Clinical Workup and Evaluation

The majority of children with Wilm's are diagnosed as a result of symptoms: 83% present with abdominal mass, fever in 23% and hematuria in 23%. Abdominal pain results from mass effect, spontaneous intralesional hemorrhage or peritoneal rupture.

Transabdominal ultrasound is the present means of imaging the abdomen in suspected Wilm's disease. Ultrasound helps localized the origin of a pediatric abdominal mass, identifies the contralateral kidney and demonstrates the extent, if any, of tumor penetration into the renal vein or IVC. CT is used to evaluate the volume of tumor involvement in one or bilateral kidneys, hydronephrosis, retroperitoneal lymph nodes, and the invasion of the collecting system. CT is also used to evaluate the margin between the tumor and surrounding structures. Plain films or CT of the chest should be obtained ot assess for pulmonary metastases. Bone scan and skeletal survey are both recommended for CCSK. The concern is if only one method is used, mets may be missed. Cranial CT is useful in rhabdoid tumors and possibly in Wilms with overt pulmonary involvement at diagnosis.

Pre-treatment Workup

Wilms tumors are divided into favorable and unfavorable histologies. Unfavorable is generally anaplastic variants. Clear Cell Sarcoma of the Kidney is now recognized as a non-Wilms tumor, although it, and rhabdoid were carried in the NWTS trials. Favorable is everything else.

Risk Classifications

Wilms tumors are classified into Very Low risk, low risk, Standard risk, Higher risk, High Risk and further segregated by favorable v. unfavorable histology.

General Management and Treatment

The general management in the US is based on the COG protocols which are derived from the NWST trials. The keys to understanding what to do when is understanding the staging, histology and extent of disease. The following table is derived from the risk factors (low, standard, higher, high risk groups).

COG Wilms Risk Groups
Risk Group	Attributes	Treatment
Very Low Risk FH	Stage I < 2 years Tumor < 550g LOH: Any	Nephrectomy & obs. (no RT)
Low Risk FH	Stage I ≥ 2 yr Tumor ≥ 550g no LOH	Nephrectomy → VA → obs (no RT)
Low Risk FH	Stage II any age Tumor any no LOH	Nephrectomy → VA → obs (no RT)
Standard Risk FH	Stage I-II LOH 1p 16q (except very low risk group)	Nephrectomy → VAD → Obs.
	Stage III No LOH	Nephrectomy → RT → VAD
	Stage IV no LOH lung mets rapid response @ week 6 VAD	Nephrectomy → RT→ No whole lung RT
Higher Risk FH	Stage III LOH 1p, 16q	Nephrectomy → RT→ VAD/C/E
Higher Risk FH	Stage IV with LOH Stage IV no LOH Slow Responders/Lung, non-pulm mets	Nephrectomy →RT(primary, lung, mets) →VAD/C/E
High Risk UH	Stage I-IV focal anaplasia Stage I diffuse anaplasia	Nephrectomy → RT→ VAD
High Risk UH	Stage I-III clear cell	Nephrectomy → RT→ alternating VDC/CPE → RT(mets)
Highest Risk	Stage II-IV diffuse anaplasia Stage IV Clear cell Stage I-IV Rhabdoid	Nephrectomy → RT→ alternating VDC/CPE &rar; RT(mets)

Chemotherapy Abreviations:

V — vincristine
A — actinomycin D*
C — cyclophosphamide
D — doxorubicin
E — etoposide
P — carboplatin
I — Irinotecan

*actinomycin is not given with radiation

Bilateral Wilms

Bilateral Wilms poses as special circumstance: Each side should be individually staged. The initial surgical approach is a nephron sparing resection only if > 2/3 of each kidney can be saved. Otherwise, the initial approach is induction chemotherapy → surgery. Flank radiation is indicated for Stage I/II FH only if unresectable disease remains after chemotherapy, there is residual tumor or positive margins. For other stages, RT is given per the above schedule.

Radiation Therapy Treatment Planning And Techniques

The COG RT schedules contains significant nuances for therapy decision making. Here is a general approach:

Key	Recommendation
General	Plan to start Radiation by POD 9 CT planning is required, contour normal structures 3D-conformal but typically APPA fields are the best with 6 MV photons Fractionate at 1.8 Gy/fraction, but reduce to 1.5 Gy for whole abdomen and whole lung A SIB type technique allows the flank 1.8 Gy by blocking abdomen/lung after 1.5 Gy Stage I-III focal anaplasia
Stage I-II FH	No Radiation
Stage III FH	10.8 Gy to flank at 1.8 Gy/day in 6 fractions
Stage I-III — focal anaplasia	Whole abdominal RT indicated if: diffuse spillage pre-op or intraperitoneal tumor rupture peritoneal seeding positive cytology ascites 10 Gy boost to gross residual disease
Stage I-II — diffuse anaplasia
Stage I-III — clear cell
Stage III diffuse anaplasia	19.8 Gy to the whole flank (infants 10.8 Gy) Whole abdomen RT indicated if diffuse tumor spillage pre-op or intraperitoneal tumor rupture peritoneal seeding positive cytology ascites 10 Gy boost to gross residual disease
Stage I-III rhabdoid
Abdominal Recurrence	—12.6 Gy - 18 Gy (if < 12 months) — 21.6 Gy if prior RT dose ≤10.8 Gy — Boost up to 9 Gy gross residual post-op tumor (30.6 Gy)
Lung mets	12 Gy to whole lung in 8 (1.5 Gy) fractions concurrent with primary field
Brain Mets	30.6 Gy to whole brain at 1.8 Gy/fraction in 17 fx OR 21.6 Gy WBRT + 10.8 Gy IMRT/SRT boost
Liver mets	19.8 Gy Whole Liver at 1.8 Gy/fx in 11 fx
Bone Mets	25.2 Gy + 3 cm margin
Unresected Lymph nodes	19.8 Gy to positive nodes

Techniques

Treatment volumes should be determined by pre-operative CT/MRI fusion and includes the involved kidney and the tumor + 1-2 cm margin.
When crossing the midline in any pediatric case, treat all the vertebral body to avoid severe scoliosis
For para-aortic lymph nodes, treat the bilateral chains to 10.8 Gy
For whole abdomen RT, the superior border is the dome of the diaphragm, the inferior border is the bottom of the obturator foramenae, with blocks to protect the femoral heads
Lateral borders for whole abdomen RT is flash.
Whole lung irradiation borders: Flash the supraclavicular fossa bilaterally, extend 1-4 cm beyond the ribs laterally, and extend below the posterior aspect of the diaphragm inferiorly (L1 VB)
Patients treated with Whole Lung RT should receive Bactrim for PCP prophylaxis

Dose limits NWTS-5

Opposite kidney ≤ 14.4 Gy
Liver:
- whole liver ≤ 30.6 Gy
- 1/2 of uninvolved liver ≤ 19.8 gy
Bilateral Lung: 9 Gy (age < 1.5 years) or 12 Gy age > 1.5 years)

Outcomes, Patterns of Failure, Prognostic Indicators

For favorable histology, survival at 4 years is pretty good with 99% for Stage I/II/III (complete resection), dropping to 85% for Stage IV, and 90% for Stage V.

For unfavorable histology, the situation is worse, with Stage I/II over 80%, Stage III 70%, Stage IV (hematogenous mets), 38% and Stage V (bilateral kidneys) 55%.