Extrarenal Wilms' Tumor: Staging, Treatment, and Prognosis

REVIEW ARTICLE Extrarenal Wilms' Tumor: Staging, Treatment, and Prognosis By Max J. Coppes, Peter C.G. Wilson, and Sheila Weitzman Extrarenal Wilms' ...
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REVIEW ARTICLE

Extrarenal Wilms' Tumor: Staging, Treatment, and Prognosis By Max J. Coppes, Peter C.G. Wilson, and Sheila Weitzman Extrarenal Wilms' tumors are rare and have mainly been the subject of isolated case reports. This retrospective evaluation of 34 patients suggests a clinical course very similar to that of renal Wilms' tumor. While clinical presentation varies according to the extrarenal localization, investigations to determine the size of the primary tumor (T), regional lymph node involvement (N), and the occurrence of distant metastasis (M) are very similar, ie, chest x-ray, abdominal ultrasound (US), and computed axial tomographic (CAT) scan of the abdomen and chest. Stage grouping according to the pathologic TNM classification showed stage I in 30%, stage II in 10%, stage Ilia in 34%, stage IIIb in 23%, and stage IVa in 3%; four patients could not be

W

LMS' TUMOR or nephroblastoma is one of the most common malignant abdominal tumors of childhood, almost exclusively arising from the kidney. Its incidence is estimated at 350 new cases per year in the United States.' It is most

commonly a unilateral disease, but in 5% to 10% of the patients, both kidneys are affected either

synchronously or asynchronously. 2 Extrarenal cases are rare and have been the subject of isolated case reports.3 41 When the tumor arises in the retroperitoneal area, uncertainty may exist as to whether

they are truly "extrarenal" in origin. If appropriate radiologic, surgical and pathologic criteria are met, however, the diagnosis of extrarenal Wilms' tumor can be justified. The extent of disease at diagnosis, as reflected by the stage of disease, influences the choice of treatment and survival. Extrarenal Wilms' tumor has been considered "unstageable," 42 and as a consequence, treatment

has not been uniform. Moreover, long-term sur-

staged. Evaluation of therapy and survival indicate the need for postoperative chemotherapy (CT) to all patients, while the same data suggest that the drugs used for renal Wilms' tumor are equally effective for extrarenal Wilms' tumor. Radiotherapy (RT) probably should be reserved for those patients with unresectable gross residual disease and for metastatic disease. The radiation dose used in the reviewed cases varied from 2,000 to 5,000 cGy. However, recent experience suggests that high doses are not justified in renal Wilms' tumor. The estimated overall 2-year survival of the 34 patients is 82% (95%confidence interval, 63% to 92%). J Clin Oncol 9:167-174. © 1991 by American Society of Clinical Oncology. PATIENTS AND METHODS

Case Report A 3-month-old white girl was admitted to our institution because of a left inguinal hernia, diagnosed in the first week of life. Physical examination was unremarkable except for the inguinal hernia. At surgery, a 1 x 0.5 cm firm mass was found at the distal end of the inguinal hernia sac. The mass was densely adherent to the surrounding structures. It did not appear to be either an ovary or testicle. After exploration of the left groin, the hernia sac was transected and together with the mass sent for pathologic evaluation. The patient had an uneventful postoperative course. Microscopically, the mass was composed of undifferentiated blastema, arranged in nests and cords. Tubular and glomerular differentiation were noted, as well as small cystic spaces lined by primitive tubular type epithelium. There was no evidence of anaplasia. No areas of normal renal tissue were found. The surgical margin showed tumor cells. The diagnosis of extrarenal Wilms' tumor was made and a diagnostic evaluation was initiated, including intravenous pyelogram (IVP), abdominal ultrasound (US), chest x-ray, and computed axial tomographic (CAT) scan of abdomen and chest. All studies were negative. This patient was

vival data are not available. An overview of extrarenal

Wilms' tumor is

presented with particular emphasis on the use of a

standard staging system in which the tumor is classified based on the size of the primary tumor

(T), regional lymph node involvement (N), and the occurrence of distant metastases (M). The TNM

classification and pathologic stage grouping for nephroblastoma used in this report4 3 are shown in Tables 1 and 2. Clinical presentation, treatment, and long-term follow-up data are also discussed. A new case of extrarenal Wilms' tumor is presented.

From the Division of Hematology/Oncology, Department of Pediatrics,The Hospitalfor Sick Children, Toronto, Canada. Submitted March 28, 1990; acceptedJuly 20, 1990. Dr Coppes is supported by both the Koningin Wilhelmina Fonds, the Netherlands Cancer Foundation, and the Ter Meulen Fonds, the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. Address reprint requests to Sheila Weitzman, MB, ChB, FRCP(C),Division of Hematology/Oncology, The Hospitalfor Sick Children, 555 UniversityAve, Toronto, Ontario, Canada, M5G 1X8. © 1991 by American Society of ClinicalOncology. 0732-183X/91/0901-0005$3.00/0

Journalof Clinical Oncology, Vol 9, No 1 (January), 1991: pp 167-174

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167

168

COPPES, WILSON, AND WEITZMAN

Table 1. Pathologic Classification of Primary T, Regional Lymph N, and Distant M Description

pTNM pTx pTo pT, pT2 pT3

pT3, pT3b pT,3 pT4 pNx pN 0 pN, pN,. pNb pMx pM0 pM1

Primary tumor cannot be assessed No evidence of primary tumor Intrarenal tumor completely encapsulated; excision complete and margins histologically free Tumor invades beyond the capsule or renal parenchyma; excision complete Tumor invades beyond the capsule or renal parenchyma; excision incomplete or preoperative or operative rupture Microscopic residual tumor limited to tumor bed Macroscopic residual tumor or spillage or malignant ascites Surgical exploration only; tumor not resected Bilateral tumors Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Regional lymph node metastasis completely resected Regional lymph node metastasis incompletely resected Presence of distant metastasis cannot be assessed No distant metastasis Distant metastasis

therefore staged according to the pathologic TNM classification, as pTlaNoMo, reflecting microscopic residual tumor limited to the tumor bed. Treatment consisted of actinomycin (AMD) and vincristine (VCR) for 12 months; no radiotherapy (RT) was given. This patient completed therapy in November 1989 and remains free of tumor at the time of this report (8 months). LiteratureReview An extensive review of the literature showed 48 cases of nephroblastoma that were diagnosed as extrarenal Wilms' tumor. However, Akhtar et a129 report on a patient also presented by Madanat et al,"2 and Tebbi et al"0 one also 9 described by Ward and Dehner." For tumors to be accepted as extrarenal in this study, they had to have histologic confirmation of nephroblastoma and appropriate investigations to document extrarenal localization and to exclude a primary renal origin. Fourteen of the 48 studied cases, shown in Table 3, were excluded based on these criteria. Not included were those retroperitoneally localized nephroblastomata that were so closely related to kidney that nephrectomy was performed as part of the initial surgery. These tumors are juxtarenal rather than extrarenal. The case reported by Nicod 39 was not included in this report because we were unable to locate the author and the case report lacked sufficient detail. Two patients not previously reported in literature, patients no. 16 (J.Z. Jona, personal communication, November 1989) and 17, were added, so that 34 cases of extrarenal Wilms' tumor, shown in

Table 4, were included in this study, of which two occurred within a teratoma (patients no. 14 and 20). All institutions that reported an extrarenal Wilms' tumor fulfilling the inclusion criteria were contacted in order to tabulate age at diagnosis, sex, localization, clinical presentation, work-up to exclude renal origin, pTNM classification, treatment, and follow-up data. Thirty-four questionnaires were sent to 31 institutions, three institutions each receiving two questionnaires. Thirty-three questionnaires were returned (97%). Overall survival was estimated by the method of Kaplan and Meier." Confidence intervals were calculated using the formula of Rothman.45 The questionnaire on patient no. 32 was not returned. In three additional cases (patients no. 31, 33, and 34), the questionnaires were returned, but no further information was available. Nevertheless, all available information on these four patients was included in this study. RESULTS Results from the 34 patients are shown in

Tables 4 and 5. Age at diagnosis was available in 34 patients. Median age was 3.6 years (range, 2

months to 56 years). Excluding the four adult patients, overall median age was 3.25 years (range,

2 months to 14 years); for boys, 3 years (range, 2 months to 10 years); and for girls, 4.5 years (range, 9 months to 14 years). There were 19 female and 15 male patients, including two adult females and two adult males. The localization of the tumors in the 34 patients is shown in Table 6. In male

patients the most common site of origin of extrarenal Wilms' tumor was the retroperitoneum

(n = 8), while in female patients it was the inguinal region (n = 6). The clinical presentation could be evaluated in all 34 patients. This was nonspecific, largely de-

pending on the site of the tumor. Nine patients

Table 2. Pathologic Stage Grouping, pTNM Stage

I II IIIA IllB

T, T,

N,

T,2

No, N,, No, Na, N1b N,,b

T 3,

T, T2 T3 .

N,,1b

T3 b

Any N Any N Any N Any N Any N Any N Any N Any N

TR,

IVA

T, T2 T 3o

T3b

IVB

T3, T4

Mo

N1.

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Mo Mo Mo Mo Mo MO MO MO M1

M, M, M, M, Any M

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EXTRARENAL WILMS' TUMOR Table 3. Patients Excluded From This Study No. of Patients

Reference

Wakely et al" 3 Shimao et al ' Johnson et a132 Fruhling et alS3

3 1 1 1

Moyson et al14

1

Naito et al"

1 36

Wu and Garcia 7 Carney"

1 1

Toudoire and Nereux38 3 Nicod" 4 Broecker et al1

2 1 1

Total

Reason for Exclusion

Patients no. 2, 3, and 4 juxtarenal rather than extrarenal Retrourethral mass most likely represents metastasis of bilateral tumor Tumor shared blood supply with left kidney Tumor origin presumably in juxtarenal region of left kidney; documentation incomplete to confirm extrarenal origin Second author, in retrospect, does not consider this case extrarenal; unable to contact first author Received preoperative chemotherapy under presumed diagnosis of right nephroblastoma; extrarenal localization diagnosed postchemotherapy (80%tumor reduction) Wilms' tumor in supernumerary kidney, not extrarenal Wilms' tumor + renal carcinoma in retroperitoneal teratoma; patient had had a teratoma 5 years previous to the reported one Both patients juxtarenal rather than extrarenal Unable to locate authors for details Patient no. 2 juxtarenal rather than extrarenal

14

with a retroperitoneal tumor presented with an abdominal mass and/or abdominal distention, two with abdominal pain, and in two, the tumor was discovered during routine physical examination. Nine patients with inguinal extrarenal Wilms' tumor presented with a mass; in only one of these did progressive enlargement occur. In two of these nine, including our patient, the mass was discovered at birth and diagnosed as an inguinal hernia. Patient no. 9 underwent inguinal exploration because of a nonpalpable undescended right testicle since birth. At surgery, an inguinal mass continguous with a hernia sac was noticed. The 11 remaining patients had more specific complaints, related to localization of the tumor: vaginal bleeding (patients no. 4 and 25), cough and chest pain (patient no. 28), painless scrotal mass (patients no. 5 and 11), enlarging mass in sacrococcygeal area (patients no. 2 and 20), and bilateral calf pain (patient no. 26). In patient no. 3, the mass was discovered incidentally while performing a biopsy of an intraabdominally located right gonad because of true hermaphroditism. In patient no. 16, the mother of the patient discovered a vaginal mass while bathing her child. The diagnostic work-up to exclude renal origin and to determine extent of disease could be evaluated in 30 patients. Many of the investigations were performed after surgery once the diagnosis had been confirmed. The investigations included plain radiographs of the chest in 25, of the abdomen in three, and of the sacrum and pelvis in one; skeletal survey in three; IVP in 25; abdominal

US in 16; CAT scan of the abdomen in 14, of the chest in three; and magnetic resonance imaging (MRI) of the abdomen in two. Lung tomography was carried out in three patients, contrast studies of the gastrointestinal tract in three, bone scan in six, liver spleen scan in two, and a gallium scan in one. Five patients had a renal arteriogram, one patient had a splenic portogram, one a bipedal lymphangiogram, one a liver biopsy, and six had bone marrow aspiration. Of the 30 patients about whom sufficient data are available (Table 4) all could be characterized using the pTNM classification shown in Table 1. In nine patients, there was complete excision of tumor with no metastatic disease (pT 1NoM0); in three, tumor invaded beyond the capsule and complete excision was performed (pT 2N0 M0 ); in 10, microscopic residual tumor was limited to the tumor bed (pT 3aNoM 0); in five, macroscopic residual tumor (pT 3bNM,); in two, there was only

surgical exploration and no tumor resection (pT3cNoMo); and in one, metastatic disease (PT3aN1M1 ). Based on the pTNM classification, pathologic stage grouping as shown in Table 2 showed nine patients with stage I, three with stage II, 10 with stage IIIa, seven with stage IIIb, and one with stage IVa disease. Five of nine stage I patients were treated with surgery only, four had postoperative chemotherapy (CT), none received postoperative radiotherapy (RT). Two of the stage II patients received postoperative CT and local RT, while one was

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170

COPPES, WILSON, AND WEITZMAN Table 4. Clinical Data, Staging, Treatment, and Follow-Up in Extrarenal Wilms' Tumor Therapy

Patient No.

Sex

Age (year)

Localization

pTNM

Pathologic Stage

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

M M M F M F F M M M M M M F F F

1.2 0.8 21 13 3.5 10 5 3 0.9 10 0.5 49 3 6 3.8 1.5

Retroperitoneal Retroperitoneal Ovotestis Endocervix Supratesticular Uterus inguinal Inguinal Inguinal Retroperitoneal Scrotal Retroperitoneal Retroperitoneal Retroperitoneal* Inguinal Vagina

T1 NoMo T1 NoMo TIN oMo T 1NoMo TINo M0 TiNoMo T1 NoMo T1 NoMo T1 NoMo T2NoMo T2 NoMo T2 NoMo ToNoMo T3.N oM0 T3 No0 Mo T3,NoMo

I I I I I I I I I II II II IIIA IIIA IIIA IIIA

S S S S S S S S S S S S S S S S

17 18 19 20

F F M F

3.5 1.2 6 3

Inguinal Inguinal Retroperitoneal Sacrococcygeal*

T3aNoMo T3aNoMo T3aNoMo T3,NoMo

IIIA IIIA IIIA IIIA

21 22 23 24 25 26 27 28 29 30 31 32 33 34

F F F F F F M F M F M M M F

0.7 1.8 4.5 5.5 14 56 2 8 36 6 3 0.2 3 4.5

Round ligament Retroperitoneum Retroperitoneal Retroperitoneal Uterus Ovary Retroperitoneal Chest wall Retroperitoneal Inguinal Retroperitoneal Inguinal Inguinal Inguinal

T3aNoMo T3.NoMo T3bNoMO T3bNOMO T3 bNOMo T3bNOMo T3bNM 0 5 T3cNoMo T3cNoMo T3aNMi ni ni ni ni

IIIA IIIA IIIB IIIB IIIB IIIB IIIB IIIB IIIB IVA ni ni ni ni

RT Local

Follow-Up (months)

AMD,VCR AMD,VCR AMD,VCR AMD, VCR VCR, ADR, CTX AMD, VCR, ADR 5FU AMD AMD, VCR

3,000 cGy 2,000 cGy + -

I LFU 8LFU 12 LFU 114+

Hoaetal 4 Gaikwad et al Heyns etal' Bell etal6

146+ 28+ 36 LFU 126+ 17+ Died 70 LFU Died 1 LFU 48 LFU 82+ 8+

Orlowski et al' Wakely et als Laietal' Harms and Lohr'o

S S S S

AMD, VCR AMD,VCR,ADR AMD, VCR, ADR AMD, VCR

3,975 cGy 5,400 cGy

20+ 72+ 88+ 138+

S S S S S S S S S S S S S

AMD, AMD, AMD, AMD,

2,100 cGy 2,000 cGy 4,400 cGy 4,640 cGy 5,000 cGy 3,000 cGy 4,680 cGy ni ni + -

41+ 40+ 94+ 120+ 141 + 142+ 10 LFU 172+ Died Died 8 nfi 18 nfi Died 24 nfi

S

CT

VCR VCR VCR VCR + AMD, VCR, CTX AMD, VCR, CTX, ADR V, CP, Bleo AMD, VCR, ADR ni ni AMD -

Reference 3

Strand et al" Adam et al" 2 Taylor et al 28 Fukutomi et a1 Meng and Jagadeesani3 Malik et al" Okamura et al1 J.Z. Jona, personal communication Present report 16 Luchtrath et al Todd et al" Tebbi et ali and Ward and Dehner"s 0 Broecker et al4 Broecker et al'4 McCauley et alJ2 23 Aterman et a1 24 Bittencourt et a1 Sahin and Benda" 2 Bhajekar et a1" 20 Madanat et al and Akhtar et al" Koretz et a121 7 Todd et al 7 Edelstein eta12 Akhtar et a12" Thompson et al03 0 Thompson et a13

Abbreviations: S, surgery; CT, chemotherapy; RT,radiotherapy; LFU, lost to follow-up; ni, no information available; nfi, no further information available; ADR, Adriamycin (doxorubicin; Adria Laol,atories, Columbus, OH); AMD, actinomycin; V, vinblostine; VCR, vincristine; CTX, cyclophosphamide; CP, cisplatin; Bleo, bleomycin; 5FU, fluorouracil. *Teratoma.

treated with fluorouracil only. Eight of 10 patients with microscopic residual disease (stage IIIa) received postoperative CT, two of whom also received local RT, one had surgery only, and one only postoperative RT. Four of seven stage IIIb patients had postoperative CT and RT, one only postoperative RT, while patient no. 29 underwent complete resection after initial exploratory surgery and biopsy and was started on CT. He, however, died from a gram-negative pneumonia 1 month postoperatively; at autopsy no tumor was found. Patient no. 28 had CT and local RT following biopsy; no complete resection was attempted. The patient with metastatic disease received postoperative CT and RT. Three of the stage I patients are long-term

survivors (for the purpose of this report, 5 years or more), one of whom had received postoperative CT. Patient no. 5 who was treated with surgery only developed lung metastases at 36 months but was successfully salvaged. The remaining six stage I patients have a follow-up ranging from 1 to 36 months, and four have been lost to follow-up. Two stage II patients died, patient no. 12 with liver metastases and patient no. 10 with a local recurrence. Patient no. 11 was lost to follow-up at 70 months with no evidence of tumor when last seen. Eight stage IIIa patients are known to be alive with a follow-up ranging from 2+ to 138+ months, six of whom had been treated with surgery followed by CT and two with surgery followed by CT plus RT. Patient no. 22 developed lung metastases and

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171

EXTRARENAL WILMS' TUMOR Table 5. Detailed Data on Patients With Recurrent Disease and/or Death Due to Other Causes Patient No.

pTNM

Initial Treatment

Comments

5

TINoMo

Complete resection, no CT, no RT

7

T,NoMo0

S: complete resection; CT: VCR 2 mg/m' weekly AMD 0.015 mg/kg for 5 days every 6 weeks (4 months)

10

T2NoMo

S: complete resection; CT: ADR, CTX, VCR for 1 month; RT: 3,000 cGy to lower abdomen

12

T2 NoM0

S: complete resection; CT: fluorouracil orally

22

T3 ,NoM 0

S: microscopic incomplete removal; CT: AMD, VCR for 75 weeks

28

T3,NoM,

S: only biopsy; CT: VCR, AMD, CTX, ADR for 2 years; RT: 3,000 cGy to initial site

29

T3 ,NoM.

S: initially only biopsy, then complete resection; CT: vinblastine, cisplatin, bleomycin

30

T3,N 1 M,

S: microscopic incomplete surgical removal; CT: AMD, VCR, ADR; RT: 4,680 cGy to abdomen and pelvis

33

Insufficient information available

Table 6. Localization of Extrarenal Wilms' Tumors Female

Retroperitoneum Inguinal Uterus Scrotum

5 6 2

Round ligament Total

8 4 -

-

Vagina Endocervix Chest wall Ovary Sacrococcygeal area Ovotestis

Male

2

1 1 1 1 1 -

1 19

-

1 15

12 months postdiagnosis lung metastasis, successfully treated with S, CT, and RT; patient alive 12 years postdiagnosis Local recurrence 11 months postdiagnosis, second complete resection; brain metastasis 24 months postdiagnosis, surgical resection, relapse 12 months later, then lost to follow-up Local recurrence at 9 months unsuccessfully treated with CT and RT; died 13 months postdiagnosis Patient died 13 months postoperatively with liver metastases; no autopsy Developed pulmonary nodule 6 months after initial diagnosis; ADR added, no RT; second pulmonary relapse 15 months later, confirmed by biopsy; thoracotomy and metastasectomy followed by high-dose CT and autologous bone marrow transplant 75+ months disease-free since transplant 4 years postdiagnosis bone metastasis in calcaneous (biopsy-proven); treated with S, CT (VCR, AMD, CTX), and RT, 3,500 cGy locally; disease-free since then for 10 years Died 19th day postsecond surgery due to gram-negative pneumonia without evidence of tumor at autopsy Developed pulmonary metastases on CT, regressed on bleomycin, vinblastine, cisplatin, CTX, AMD, and local RT; local recurrence 8 months later and further pulmonary metastases; died 19 months after initial diagnosis Probably incomplete resection; postoperative course of XRT and 500 Ig AMD; local recurrence after 6 months, also pulmonary metastases; died due to tumor

is at present 15 + months disease-free after autologous bone marrow transplantation (Table 5). The remaining two stage IIIa patients were lost to follow-up at 1 and 48 months, respectively. Five stage IIIb patients are long-term survivors, one of whom developed bone metastases 6 years postdiagnosis. The latter patient was salvaged and is disease-free for 10 years from the time of relapse. One stage IIIb patient died 1 month postoperatively due to postoperative infection and one was lost to follow-up at 10 months. The patient with metastatic disease died despite extensive therapy. In patients no. 31, 32, 33, and 34, information on staging, treatment, and follow-up were not obtainable. The estimated overall 2-year survival in the 34

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172

COPPES, WILSON, AND WEITZMAN

patients is 82% (95% confidence interval, 63% to 92%). DISCUSSION

Extrarenal Wilms' tumor is a rare but welldocumented entity. Extensive review of the literature showed 46 cases published since 1964. Earlier reports have suggested that up to half of the reported cases arise within teratomas'1,1729; our study does not confirm this observation, as only two of 34 patients (6%) had associated teratomatous elements. While renal tissue is an uncommon component of teratomas,19' 23 when present, malignant change may readily occur. 23 These data suggest that in all cases of extrarenal Wilms' tumor a thorough histologic examination of the whole tumor is indicated to exclude a teratomatous component. It has been postulated that extrarenal Wilms' tumor arises from extrarenal displacement of metanephric or mesonephric remnants. 7',2,23'" Aterman et a123 point out that the frequency with which this happens cannot be assessed, but the uncommon instances of supernumerary kidneys would tend to argue in favor of its occurrence. The close proximity of the urogenital ridge and mesonephron during embryologic development may explain cases of extrarenal Wilms' tumor arising in or close to the spermatic cord, epididymis, uterus, and uterine cervix. Supporting this hypothesis is the finding of nonmetastatic renal remnants associated with an extrarenal Wilms' tumor in the groin in one case7 and in an ovotestis in another.5 However, other possible mechanisms postulated for the etiology of extrarenal Wilms' tumor include dedifferentiation of differentiated cells and persistence of cells with embryologic potential. 7', From a clinical point of view extrarenal Wilms' tumors appear to be in many ways similar to renal nephroblastoma. If the four adult patients are excluded, age and sex do not differ from patients with renal Wilms' tumor.46,47 Median age in boys is

36 months, both in extrarenal and unilateral renal Wilms' tumor; in girls, respectively, it is 54 months and 43 months. The lower median age found in boys in this study is of particular interest as a significantly younger age in boys has been noticed in unilateral nephroblastoma.4 7 The retroperitoneum and inguinal canal are the commonest sites of origin of extrarenal Wilms' tumor, as has been reported previously. 6 Retroperi-

toneal tumors are more common in males (eight of 13 patients), while inguinal tumors are more common in females (six of 10 patients). We are unable to explain this observation, but the small number of cases makes it difficult to determine if this difference is real. The clinical presentation is not specific and depends on the site of origin. Retroperitoneal tumors are usually detected when abdominal distention or a mass becomes apparent, while inguinal tumors are detected at an early stage, but most often watched for a period of time. Although, in general, tumors have to grow to be detected, interestingly, progressive enlargement of the inguinal extrarenal Wilms' tumors was only reported in one case. Tumors developing in other sites had varying clinical symptoms. There were no symptoms or signs that pointed to the correct diagnosis, and it seems unlikely that a diagnosis can be made prior to surgery or biopsy. While, preoperatively, a large variety of investigations were performed, studies performed after surgery were more uniform. Exclusion of renal Wilms' tumor is important, as metastases to strange sites, including chest wall, mediastinum, ovary, vagina, and scrotum have been reported.4 We recognize the importance of histology in prognosis. However, this was not evaluated in all reported cases. Favorable histology was present in 10 patients in whom this aspect had been analyzed. Tumor burden at the time of diagnosis, as reflected by stage, is important both for determining therapy and for prognosis. The two most widely used staging systems for renal nephroblastoma are those formulated by the National Wilms' Tumor Study (NWTS) 49 and the International Society of Pediatric Oncology (SIOP).'5 These two classifications are very similar but both are less than adequate to stage extrarenal Wilms' tumor. We therefore attempted to stage all reported cases according to the TNM classification in order to compare therapy and survival data. While four cases could not be classified due to inadequate information, nine patients were stage I (30%), three stage II (10%), 10 stage IIIa (34%), seven stage IIIb (23%), and one stage IVa (3%). The high incidence of stage IIIa (microscopic residual tumor) is remarkable. It can probably be explained by preoperative misdiagnosis resulting in inadequate "tumor" surgery, but could also reflect a

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EXTRARENAL WILMS' TUMOR

more invasive disease, suggesting a different biologic behavior of extrarenal Wilms' tumors. All patients in whom adequate information was available could be staged, and the TNM classification should be used in future cases. Analysis of therapy and survival according to the pTNM stage indicates that all patients with extrarenal Wilms' tumor should receive postoperative CT. The data suggest that the drugs used for renal Wilms' tumor appear to be equally effective for extrarenal Wilms' tumor. The duration of CT required, however, could not be determined from this study. Based on current knowledge, we would suggest that therapy should be the same as for comparable stage renal Wilms' tumor, for which there is extensive data. The indication for RT is more difficult to assess from this study. Our data, together with our experience in renal Wilms' tumor, lead us to suggest that radiation should be limited to patients with postoperative unresectable gross residual disease and for metastatic disease. If surgery is incomplete only because of an incorrect preoperative diagnosis, a repeat attempt with a view to complete excision is warranted in order to avoid the late complications of RT in these young children. The dose of RT used over the long time period of this retrospective study varied from 2,000 cGy to 5,000 cGy. Review of this data suggests that in this small number of patients, 2,000 cGy achieved as good results as this higher doses. Recent data from the NWTS-3 study suggest that 1,000 cGy to gross residual disease results in a similar survival and local recurrence rate as 2,000 cGy, when concurrent CT was given. 50 It would therefore seem reasonable to limit the radiation dose in patients with extrarenal Wilms' tumor. Based on the SIOP Wilms' tumor studies using preoperative CT,51, 52 an alternative approach to large tumors could be the use of 4 to 6 weeks of

VCR and AMD, after histologic confirmation, followed by the definitive surgery to increase the chance of complete surgical removal. The estimated overall 2-year survival of 82% is good, but has to be interpreted with caution as the number of patients studied is small. The number of patients lost to follow-up, 11 of 34, should also be taken into consideration, especially as seven were lost to follow-up within the first 2 years. While no deaths due to tumor after 2 years were recorded, patient no. 7 has to be assumed to be dead as he had metastases when last seen at 36 months of follow-up. This indicates that late deaths due to tumor, as observed in renal nephroblastoma,2 do occur.

Extrarenal Wilms' tumor is a rare disease. This report suggests that the clinical course parallels that of renal Wilms' tumor and that therefore the experience gained in the management of renal nephroblastoma can be applied to extrarenal cases. The pTNM classification forms a good basis for a rational approach to treatment, and survival appears to be good if appropriate therapy is given. ACKNOWLEDGMENT We would like to recognize the efforts undertaken by many colleagues that made this study possible. We thank Dr Kurt Aterman, Dr Debra Bell, Dr Jo Ann Benda, Dr Achilea Bittencourt, Dr Bruce Broecker, Carol Brubaker, Dr Ayten Cangir, Dr L.P. Dehner, Dr Paul Etzell, Dr Yasushi Fukutomi, Dr K.D. Gaikwad, Dr A.A. Gillis, Dr Ganesh Gopalakrishnan, Dr M. Hamagaki, Dr D. Harms, Dr C.F. Heyns, Dr Joana Ho, Dr J.Z. Jona, Dr Michael Koretz, Dr R.J. Labotka, Dr Hong-Shiee Lai, Dr H. Liichtrath, Dr A.E. MacKinnon, Dr Roy McCauley, Dr Gauri Malik, Dr R. Maurus, Dr Looi Lai Meng, Dr Don Norris, Dr James Orlowski, Dr Ada Rosen, Dr B Shandling, Dr Susan Shurin, Dr William Strand, Dr Teresa J. Vietti, and Dr Paul Wakely, Jr for sharing their patients with us. We also thank the Word Processing Department of The Hospital for Sick Children for their help in preparing this manuscript.

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