British Journalof Urology (1992), 70, 23&235 0 1992 British Journal of Urology

Adult Wilms‘ Tumour: Review of 14 Patients

GRANT WILLIAMS, R. A. COLBECK and N. F. C. GOWING

Nephro-urology Unit, Harley Street Clinic; Department of Urology, Northwick Park Hospital; Department of Histopathology, Royal Marsden Hospital, London

Summary-Wilms’ tumour, or nephroblastoma, is the commonest renal neoplasm found in children, but is rarely found in adults, the world literature recording only approximately 200 cases. Individual case reports continue to be published but only within the last 10 years have definitive treatment regimes been suggested. In order to determine the UK experience of adult Wilms‘ tumour, members of the British Association of Urological Surgeons were circulated with a questionnaire, and from 141 replies, 13 members reported 17 cases. Critical review of the original histology slides excluded 3 of these; the 14 remaining cases are described and their management discussed in the light of current recommended treatment.

Nephroblastoma (Wilms’ tumour) is a malignant embryonic tumour of the kidney, which arises from the metanephric blastema. It is the commonest renal neoplasm in children and accounts for approximately 20% of all malignant tumours in this age group.

The first comprehensive account of the tumour was given by Wilms (1899), although a specimen existed in the Hunterian Museum and was de- scribed by Rance (1814) and Gairdner (1828) as “Fungus Haematodes of the Kidney”.

The incidence of the tumour in adults is estimated at about 1% of all cases and about 200 cases have been described in the world literature to date (Roth et al., 1984). At least 53 synonyms have been used to describe the tumour (Culp and Hartman, 1948). Babaian et al. (1980) reviewed the collected series of Wilms’ tumours in adults which had appeared in the world literature since 1878 and determined that a total of only 167 cases had been reported. Because of this rarity, the exact incidence of the tumour is difficult to ascertain and the most effective form of treatment is unknown.

Patients and Methods Sporadic reports of Wilms’ tumour in adults continue to be published and it was the experience

Accepted for publication 11 September 1991

of 1 of us (GW) in managing 2 patients within 7 years which prompted a survey of the members of BAUS to discover their collective experience, document the patients and determine if any patterns of treatment emerged. A questionnaire was circu- lated to all members asking whether they had ever operated on any individual over the age of 20 with a Wilms’ tumour. Positive responders were asked for details of the patient’s history and management and for slides of the original histology specimens. A total of 17 adults believed to have Wilms’ tumours were reported by members of BAUS. In all of these cases the original histological sections were re- viewed (NFCG). Of the 17 specimens reviewed, 3 did not meet the criteria for diagnosis of adult Wilms’ tumour. One, in a female, was possibly “a bone seeking renal sarcoma of childhood” and the other 2, in females, were other anaplastic malignant neoplasms.

The remaining 14 specimens satisfied the histo- logical criteria and are summarised in Table 1. All the neoplasms featured undifferentiated blastema as seen in childhood cases, composed of darkly staining, spheroidal, ovoid and fusiform cells with hyperchromatic nuclei and relatively scanty cyto- plasm. Tubule formation was seen in 11 tumours and 2 displayed prominent proglomeruli. In no specimen was differentiated mesenchymal tissue present, neither were heterologous. tissues (e.g. ,

230

ADULT WILMS’ TUMOUR 23 1

Table 1 Summary of Principal Histological Features of 14 Patients with Adult Wilms’ Tumour

Patient No. Sex Age Stage Principal histological features

1 F 36 I Mixture of undifferentiated blastema and abundant tubules 2 F 30 I Undifferentiated blastema with numerous tubules and proglomeruli, sections of lung also

examined with metastases 3 F 22 I Mainly undifferentiated blastema, with tubules and proglomeruli 4 M 45 I Mixture of undifferentiated blastema and abundant tubules 5 M 28 IV Undifferentiated, metastatic deposit in section of adrenal 6 M 28 I1 Mainly undifferentiated but with some tubule formation I F 21 111 Mixture of undifferentiated blastema and abundant tubules 8 F 33 I11 Undifferentiated blastema and moderate number of tubules 9 M 21 IV Mainly undifferentiated but with some tubule formation

10 M 23 IV Mainly undifferentiated but with some tubule formation I 1 M 22 NK Undifferentiated 12 M NK NK Mixture of undifferentiated blastema, tubules and proglomeruli 13 F 26 NK Undifferentiated 14 NK 20 NK Predominantly undifferentiated but with tubule formation

NK = Not known

striated muscle, cartilage or bone) found (Figs 1, 2 and 3).

Some of the confusion in reporting arises from the problems of histological interpretation of renal tumours in adults. Kilton et al. (1980) described criteria for the diagnosis of adult Wilms’ tumour. These are (1) a primary renal neoplasm, (2) primitive blastematous spindle or round cell com- ponent, (3) formation of abortive or embryonal

Fig. 2 Adult nephroblastoma featuring many tubules with intraluminal tufts : embryonic glomeruli or proglomeruli. (H and E ~ 3 1 2 ) .

tubular or glomeruloid structures, (4) no area of tumour diagnostic of renal carcinoma, (5) pictorial confirmation of histology and (6) age > 15 years.

Of 192 adult patients with Wilms’ tumour reported up to 1980, 75% had unconvincing or absent photomicrographs or incomplete histologi- cal description (Kilton et al., 1980).

Our 14 confirmed patients are summarised in

progress discussed in the light of current treatment

Fig. 1 Adult nephroblastoma showing tubule formation and intervening, undifferentiated spheroidal and fusiform cells. (H andE ~ 3 1 2 ) .

and their management and subsequent

232 BRITISH JOURNAL OF UROLOGY

Fig. 3 Adult nephroblastoma showing proglomeruli, interven- ing undifferentiated spindle-shaped cells and a solid mass of undifferentiated tumour cells (in lower right comer of the field). (Hand E x 312).

regimes. In all, 10 patients have substantially complete records. Histology slides were available for the remaining 4, but not clinical details.

Results

A total of 10 cases of nephroblastoma are described in Table 1, and a further 4 poorly documented cases are noted. Only the 10 well documented cases are discussed. The youngest patient was aged 15 and the oldest 45 years, 5 were men and 5 were women.

The disease was staged according to the criteria of the National Wilms’ Tumor Study (Breslow et al., 1981).

At the time of initial diagnosis 9 patients underwent removal of the primary renal tumour. One patient, case 5, with an extensive renal tumour, was considered inoperable and treated with vincris- tine, doxorubicin hydrochloride and methotrexate on the erroneous diagnosis of lymphoma. After 5 months the mass had shrunk considerably and he had a second exploration and subsequent right nephrectomy. A further 4 patients received radio- therapy to the primary tumour site, 2 with stage I disease, 1 with stage I1 and 1 with stage 111. Radiotherapy was given to 4 patients who devel- oped metastatic disease-3 patients with pulmo- nary metastases and 1 patient with a local loin

recurrence. These 4 patients subsequently died of their disease.

Only 1 patient was managed without adjuvant radiotherapy or chemotherapy. The most frequently used chemotherapeutic agents for primary disease were vincristine (8 patients), doxorubicin hydro- chloride (6 patients), actinomycin-D (5 patients) and cyclophosphamide (4 patients). Less commonly used were prednisolone (1 patient) and methotrex- ate (1 patient).

In the treatment of secondary deposits, the following agents were used : cisplatin (3), etoposide (2), doxorubicin hydrochloride (3), actinomycin-D (2), cyclophosphamide (l), 5-fluorouracil (1) and prednisolone (1). Of the 4 patients with stage I disease, only 2 received chemotherapy as a primary treatment.

Discussion

This review was undertaken because there appears to be no agreed protocol for the treatment of adult Wilms’ tumour.

Wilms’ tumour arises from the totipotential cells of the metanephrogenic blastema, and although commonest in children, has presented in all age groups, up to the age of 82. The degree of differentiation of the tumour has been found to correlate with survival, and 2 categories of histol- ogy, favourable and unfavourable, have been proposed (Beckwith and Palmer, 1978). The meta- static sites of these differ, the favourable spreading to the lungs and the unfavourable to the bones. In this series, the histology was not assigned to 1 or other group in the majority of cases.

It is difficult to make comparisons in a small series of 10 patients, when there is no multicentre national study with strict treatment criteria. How- ever, a broad picture emerges of the probable fate of patients within each stage, and the effect of treatment on the progress of their disease. ,The treatment of childhood Wilms’ tumour has made dramatic improvements since the 1920s, when only 5% were expected to survive 2 years. Advances in surgical techniques improved the 2-year survival rate to 20%. The addition of renal tumour bed irradiation brought another improvement in sur- vival to 40%. The addition in the 1960s of adjuvant chemotherapy has resulted in the current cure rate of >SO% (D’Angio et al., 1976). However, the results of the treatment of adult Wilms’ tumour have not been as successful. Byrd et al. (1982) described 31 adults who were reported to the National Wilms’ Tumor Study from 1968 to 1979.

ADULT WILMS’ TUMOUR

Table 2 Details of Treatment and Survival of Patients with Adult Wilms’ Tumour

233

~

Case Age Sex Presentation Stage Surgery Radiotherapy Chemotherapy Outcome

F 1 36 L. loin pain I Transabdominal nep hrectom y

4250 cGy renal bed

Vincristine Alive 33 months Doxorubicin Cyclophosphamide Actinomycin-D

2 30 F L. loinpain I L. loin mass

Alive 17 years Transabdominal nephrectomy

L. lower lobe lobectomy at 7 years for metastasis

L. nephrectomy R. partial

nephrectom y

R. nephrectomy

Vincristine Doxorubicin Actinomycin-D

15

45

Haematuria Details unknown Alive 9 years

Died 64 years Painless haematuria

3000 cGy to renal bed

2000 cGy to lung -

Vincristine Actinomycin-D Doxorubicin

5 28 M Loin mass Haematuria

IV R. nephrectomy following chemotherapy

Vincristine Doxorubicin Methotrexate Prednisolone

Vincristine Actinomycin-D

Vincristine Actinomycin-D

Cyclophosphamide Cisplatin

Vincristine

Died 21 months

28

21

M

F

Painless

Haematuria

haematuria I1

I11

L. nephrectomy 4000 cGy to renal bed

Alive 5 years

Died 8 months Transabdominal nep hrectomy

2000 cGy to lung

4100 cGy to renal bed

2400 cGy to lung

5170 cGy to local recurrence

-

8 33 F L. loin pain and UTI

I11 L. lower polar hemi- nep hrectomy

Completion nephrectomy at 2 months

Died 2 years

Doxorubicin

9 21 M Haematuria IV Lnephrectomy Vincristine Died 7 months Doxorubicin abroad Cyclophosphamide

Bleomycin Etoposide Cisplatin Methotrexate 5-Fluorouracil

Vincristine Died at 4 months Doxorubicin Actinomycin-D Cyclophosphamide Etoposide Cisplatin

NK NK

NK Died aged 21

NK NK

NK NK

Open lung biopsy

10 23 M Loin pain Haematuria

IV L. nephrectomy Abdominal and pulmonary irradiation

11

12

13

14

22

NK

26

20

M

M

F F

NK

NK NK

NK

NK

NK

NK

NK

NK

NK

NK NK

NK

NK

NK

NK

NK =Not known

234 BRITISH JOURNAL OF UROLOGY

Their 3-year survival rate was 24% : 48% for stages I and 11, and 11% for stage IV disease. This contrasts with children’s survival rates of 74%, 87% and 53% respectively. In our series, 100% of stage I patients were alive at 2 years, and 80% of stage I and I1 at 3 years. Conversely, the stage IV patients did very poorly, none surviving 3 years, and the longest surviving living only 7 months after diag- nosis.

Adult Wilms’ tumour should be a potentially curable disease. The major problem confronting a surgeon faced with a patient over 16 years of age with a nephroblastoma is the lack of any defined treatment protocol, due principally to the rarity of the disease. In children, long experience and centralised studies have led to well defined treat- ment protocols for the various stages. The funda- mental treatment is trans-abdominal nephrectomy with node biopsy and assessment of the opposite kidney to exclude bilateral disease. During the 1960s actinomycin-D was found to be an effective drug and the second National Wilms’ Tumor Study reported that a combination of vincristine and actinomycin-D was superior to either agent used singly (D’Angio et al., 1976). For late disease, a 3 or 4 drug combination is used, adding doxorubicin hydrochloride and cyclophosphamide (Dunger et al., 1981).

The United Kingdom Children’s Cancer Study Group trial protocol recommended division into favourable and unfavourable histological groups. The favourable groups all underwent surgery, followed by vincristine for 6 months in stage I ; vincristine, actinomycin-D and radiotherapy in stage I1 and vincristine, actinomycin-D, doxorubi- cin hydrochloride and radiotherapy in stage 111 disease. Operable but unfavourable disease of all stages, and stage IV favourable disease receive surgery and 4-agent chemotherapy : actinomycin- D, doxorubicin hydrochloride, vincristine and cyclophosphamide (DAVE), followed by a second- look laparotomy at 20 weeks, and possibly subse- quent radiotherapy.

For inoperable tumours, DAVE was given with radiotherapy to the lung or abdomen, and a second- look laparotomy with continuing chemotherapy if tumour was still present. A number of authors have made recommendations for the treatment of adult disease based either on their own experiences, or reviews of a number of cases. Babaian et al. (1980) described 3 cases and treated them according to the National Wilms’ Tumor Protocol, proposing for stage I disease nephrectomy followed by vincristine and actinomycin-D; stage I1 and I11 receive local

radiotherapy in addition, and stage IV patients receive the same treatment plus irradiation of metastatic deposits. Kilton et al. (1980) took into account their own analysis of 35 patients and the National Wilms’ Tumor Study, and suggested a protocol for all stages consisting of an operation for diagnosis, debulking and definition of the tumour bed for irradiation. All patients received 3500 to 4000 cGy post-operatively with added whole lung irradiation if pulmonary secondaries were present, with adjuvant chemotherapy as for childhood Wilms’ tumour using vincristine and actinomycin- D. They felt that radiotherapy was of demonstrable value, either obtaining a response in metastatic disease or converting inoperable primary disease to operable.

Byrd et al. (1982) reviewed 3 1 adults reported to the National Wilms’ Tumor Study. They concluded that aggressive multimodal therapy be used in all stages of the disease, using surgery, post-operative irradiation and multi-agent chemotherapy, includ- ing at least actinomycin-D, vincristine and doxo- rubicin hydrochloride. Roth et al. (1984) reported 2 patients, 1 with stage I disease treated by excision and actinomycin-D and vincristine who survived disease-free for 3 years and 1 with stage I1 disease, treated with tumour bed irradiation and vincristine, doxorubicin hydrochloride and actinomycin-D. They reinforced the concept of aggressive treatment with combination chemotherapy and irradiation. Advanced disease in 2 patients was reported by Hagiwara et al. (1982) and illustrated the role of surgery in recurrent disease. One patient presented with stage I disease and underwent nephrectomy and tumour bed irradiation only. Two years later she developed a solitary recurrence in the liver and following combination chemotherapy with actino- mycin-D and vincristine, and 6000 cGy irradiation, the metastasis was resected by an extended right hepatic lobectomy. She remained disease-free 4 years later. The other patient had advanced disease including venous extension of tumour thrombus to the right atrium, with pulmonary metastases. The primary tumour was removed together with the thrombus and the metastases were successfully treated with combination chemotherapy. This report underlines the fact that late metastatic disease must be anticipated-in our series a pulmonary metastasis appeared after 7 years-and treated aggressively, by resection if necessary, combined with chemotherapy.

What conclusions about adult Wilms’ tumours may be drawn from this series?

The first is that the tumour is rare, and most

ADULT WILMS’ TUMOUR 235

surgeons will be unlikely to encounter 1 in a lifetime of practice. If they do, it is likely to be in a young adult, in their mid-twenties, who presents with the classical signs of a renal neoplasm. Imaging of any modality is unlikely to provide any diagnostic features. Similarly, angiographic features are not pathognomonic and tumours may be hypovascular, avascular or show neovascularity (Meng and Elkin, 1969). Immediate screening for metastatic disease should include CT scanning of the lungs and abdomen, and an isotope scan.

The discovery of metastatic disease should not prevent exploration and attempted removal of the primary tumour. If the primary tumour is initially inoperable, then following chemotherapy, a second- look laparotomy is worth consideration.

Operation should establish the diagnosis, debulk the tumour and define the tumour bed for subse- quent irradiation. Formerly, post-operative abdom- inal irradiation was used, but is of dubious value. Similarly, whole lung irradiation has not been shown to be valuable.

Chemotherapy should be used for all patients, including vincristine, actinomycin-D and doxorub- icin hydrochloride, on the basis that these drugs are of proven benefit in childhood tumours. Since the prognosis is generally poorer in adults, combination chemotherapy offers the best hope of cure if used in all stages in the adult.

Our experience also suggests that solitary metas- tases are worth treating aggressively by excisional surgery wherever feasible and that local recurrence tends to be associated with a poor prognosis.

Acknowledgements We thank all of the surgeons who replied to the questionnaire and, in particular, the following surgeons, pathologists and radiotherapists for allowing us to include their patients in this study and for providing relevant information: I. Appleyard, R. H. Begent, A. R. Blacklock, Professor J. Blandy, E. C. Edwards, A. Ford, R. Gray, N. A. Green, N. Howard, M. A. Hughes, P. Jarrett, A. McEwan, R. T. Oliver, R. Pointon, D. Richards, J.

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The Authors R. A. Colbeck, BSc, FRCS, Research Registrar, Department of

Grant Williams, MS, MSc, FRCS, Consultant Urologist, Harley

N. F. C. Gowing, MD, FRCPath, Emeritus Professor of

Urology, Northwick Park Hospital.

Street Clinic.

Histopathology, Royal Marsden Hospital.

Reauests for reprints to: Grant Williams, Nephro-urology Unit, -_ Rode, K. Shuttleworth, E. Tinsley, R. Williams and P. Worth. Hailey Street Clinic, London W I N 4BJ.