Pediatr Blood Cancer 2008;50:1123–1124

HIGHLIGHTby Giulio J. D’Angio, MD

Renal Tumors in Children: Challenges for DevelopingCountries and Opportunities for Collaboration

(Commentary on van den Heuvel-Eibrink et al., page 1130 and Abuidris et al., page 1135)

T he article by Dr. Abuidris et al. in this issue of Pediatric

Blood & Cancer is eye-opening [1]. The frank review of their

experience with 37 Wilms’ tumor (WT) patients in Sudan reflects

many of the problems inherent in managing children with cancer in

developing nations. Those Societies share socio-economic-reli-

gious-political and cultural impediments to optimal care albeit

each nation has its particular problems. In Sudan, the interplay of

those factors leads to late diagnosis. This is attested to by the

greater average age of the reported Sudanese children with WT,

and the low frequency—22%—of early stage tumors versus 78%

for more advanced disease. These distributions are almost the

inverse of those reported by the National Wilms Tumor Study and

International Society of Pediatric Oncology (SIOP) trials [2,3]. In

fact, the clinical condition of 2 of the 37 Sudanese children was so

poor they died before therapy could be initiated. Financial

pressures in others were too great for treatment to be continued.

In still others, the parents did not bring the child back to the clinic

to continue treatment because the tumor had responded so well to

pre-operative chemotherapy. Continuing care is especially difficult

in Sudan because many families follow a nomadic existence.

To better the chances for effective therapy and hence, survival,

the authors plan to adopt the pre-operative chemotherapy plan

developed by SIOP investigators. This is to be applauded. It will give

the physicians an opportunity to improve the pre-operative

condition of the afflicted children. Tumor shrinkage will also make

easier the daunting, challenging task that confronts the surgeon:

removal of a very large tumor from a very small, depleted child.

Here, the strategy proposed by Professor K.J. Plo of the Ivory

Coast might also play an important role. He has advocated keeping

the child in hospital for the pre- and post-operative periods so that as

many courses of needed therapy can be administered before family

pressures for discharge supervene. He and I have suggested in panel

discussions that, where available, as it is in Sudan, radiation therapy

(RT) of the flank be given during this period of hospitalization. It

would be delivered not only to those with known residual disease1 or

positive lymph nodes but also to children with early stage tumors in

whom only sketchy information is available regarding the status of

the flank. This would include those with SIOP Stage II, node

negative disease. This is because some of these children harbor

occult residual cancer after preoperative chemotherapy, as the

experience in SIOP 6 showed (v.i.) [4]. That flank irradiation has

merit is demonstrated not only by the SIOP 6 experience but also by

data from the pre-chemotherapy era. The 25% 2-year survival rate

for Wilms tumor patients in those days rose to the 50% range for

children who received prompt surgery and routine post-operative

RT [5]. Moreover, a post-operative dose of �20 Gy, given as 180

cGy/day� 11 or 200 cGg daily �10 appears in the current

chemotherapy era to obviate flank recurrences among children at

risk for such a relapse [6]. That dose is not associated with major

growth disturbances [7]. The height deficit (shortening) measured

after the adolescent growth spurt due to 20 Gy delivered to the flank

of a 2- or 4-year-old has been estimated to be 4.8 and 3.5 cm,

respectively.

The risk of an RT-associated second malignant neoplasm (SMN)

rises as the post-therapy years accumulate and with each 10 Gy

increment. Even so, the incidence was low among relevant long-

term survivors reported by Breslow et al. [8] Fewer than 1% of the

2,264 patients given 25 Gy developed an SMN. There were 19 such

including 4 leukemias in their tabulations. These and other

possible secondary effects due to RT; for example, gonadal and

cardiac problems, need to be seen in perspective. They pale in

significance when compared to the devastating consequences that

recurrent abdominal disease would have in such a difficult medical

setting.

In nations like Sudan, where both RTand hospitalization are free

of charge, such a management plan would not add much to the

financial load of the family, although the associated psycho-social

burdens are indubitable.

Dr. Abuidris and colleagues are to be thanked for their candid

detailing of the great difficulties that confront those anxious to

advance the care of children with cancer in much of the developing

world. It will take more than providing the responsible physicians

with simplified versions of complex, multimodal treatment

regimens. It will take economic progress, coupled with Societal

and political will and commitment, plus countrywide efforts at

education of community health care professionals and the populace

as a whole.

The paper by van den Heuvel-Eibrink et al. [9], also in this issue,

contains definitive information regarding babies with renal neo-

plasms. More than that, it displays a remarkable cooperative effort

by those responsible for conducting clinical trials in Europe, the

United Kingdom and the United States. Would that religious and

� 2008 Wiley-Liss, Inc.DOI 10.1002/pbc.21566

1Note that, for various reasons, therapy for 23 of the 37 Sudanese

children did not advance to the point of nephrectomy.

——————Radiation Oncology, Hospital of the University of Pennsylvania, 3400

Spruce Street, Donner 2, Philadelphia, Pennsylvania 19104

*Correspondence to: Giulio J. D’Angio, Radiation Oncology, Hospital

of the University of Pennsylvania, 3400 Spruce Street, Donner 2,

Philadelphia, PA 19104. E-mail: dangio@xrt.upenn.edu

Received 7 February 2008; Accepted 7 February 2008

political figures around the world could work together in similar

harmony!

The authors pooled data from more than 10,000 children

enrolled in successive clinical studies and trials. Their purpose was

to determine the types and stages of renal tumors found among the

750 patients diagnosed during the first 7 months of life they

collected. The authors confirm that the proportions of neoplasms

other than Wilms tumor (WT) are greater than those found among

1–4 year olds, when WTs are far and away the most common. Given

this known histologic diversity and consequent pre-operative

diagnostic ambiguity, immediate surgery was employed in most

of their reported cases. The various chemotherapy regimens

employed are given, and the eventual outcomes tabulated. The

number of congenital mesoblastic nephromas (CMNs) differed

from one national cooperative study to the next. This is because

there was little incentive for investigators to enroll such patients

since no therapeutic questions were being asked. Nonetheless, the

data reveal a sharply decreasing frequency of CMNs by month of

age. For example, they made up about 50% of tumors diagnosed

during the first month of life versus <10% by the fourth. A helpful

differentiating point between these growths and WTs is the presence

of hypercalcemia in some CMN children [10]. Unfortunately, this

finding may also be present in children with the less common but

very aggressive malignant rhabdoid tumor of the kidney (MRTK).

(The latter constituted but 8% of all the classifiable neoplastic

types.) There were 5 CMNs and 8 MRTks among the 15 children

with hypercalcemia collected by Coppes [10]. One of the other two

was a verified WT and the other a ‘‘sarcomatous’’ WT. All 15 were

6 months of age or younger. Thus, the presence of hypercalcemia

could be of help in differential diagnosis in this age group, and at

least points away from WT per se.

The overall 5-year survival varied by tumor type, being >90%

for CMNs and WTs. It was surprisingly low—about 50%—for the

58 children with clear cell sarcoma of the kidney, most of whom had

early stage disease. The authors call attention to the clear cell

sarcoma in infants reviewed by Hung [11]. The latter cautions that

this neoplasm in early life may exhibit an aggressive course.

There is, however, little doubt about the highly malignant nature

of RTK. Most of the 15 RTK patients in the van den Heuvel-

Eibrink et al. [9] report had metastatic disease at diagnosis. Both the

event-free and overall survivals at 5 years were under 20%,

reflecting the fact there are no effective therapies for RTK identified

to date.

One intriguing finding among the RTKs is the fact that 3 of the15

were bilateral cases. This raises questions regarding the as yet

unidentified cell of origin of this cancer. Bilaterality at first glance

suggests that cells of the renal primordium might be responsible.

Dr. J.B. Beckwith points out that RTK may develop in any tissue of

the body, and carries the 22q11.2 deletion as a marker wherever

found, including the brain [12]. In the past, he has concluded that the

RTK lesions in the opposite kidney represent metastases, since

widespread secondary deposits are a feature of the disease. Such a

conclusion would be strengthened in bilateral cases if RTK deposits

were to be found in other organs as well as those in both kidneys. If

only contralateral RTK is present, then simultaneous, independent

growths in both kidneys is a valid hypothesis.

Staging of patients followed the SIOP standards. Those assign

extent of disease found usually after pre-operative chemotherapy.

SIOP Stage II differs from the NWTS system. In SIOP Stage II,

Wilms tumor that extends through the capsule but is totally excised

is then divided between specimens with and without identifiable

lymph node involvement. That prior chemotherapy can obscure the

degree of involvement was shown in the sixth SIOP trial [4]. In

SIOP-6, Stage II node negative patients who had received pre-

operative chemotherapy were divided between those who did and

did not receive post-operative RT. There was a higher relapse rate in

the flank in the unirradiated sample. This indicates there had been

residual but undetected extrarenal involvement present. Thus, the

number of Stage II and III patients tabulated by van den Heuvel-

Eibrink and co-workers may contain some minor errors, minimized

by the fact that most of the children had early surgery.

This very useful report has a wealth of information that could

have been obtained in no other way. The hard work that went into

data-gathering to insure accuracy and coherence of the multiple

categories can only be imagined. It is the only way to proceed,

however, when outstanding issues concerning rare tumors such as

the RTK, including the design of more effective treatment schemes,

need to be addressed.

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Pediatr Blood Cancer DOI 10.1002/pbc

1124 D’Angio