Cellular Congenital Mesoblastic Nephroma: What are the Options

0022-5347 /88/1422-0479$02"00/G Vol. 142,

THE JOURNAI, Q;' UROLOGY

Copyright© 1989 by

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AMERICAN UROLOGICAL ASSOCIATION, INC.

CELLULAR CONGENITAL MESOBLASTIC NEPHROMA: WHAT ARE THE OPTIONS THOMAS S. GORMLEY, STEVEN J. SKOOG,* ROBERT V. JONES

AND

DAVID MAYBEE

From the Departments of Urology, Pathology and Pediatrics, Walter Reed Army Medical Center, Washington, D. C.

ABSTRACT

Cellular congenital mesoblastic nephroma is a potentially aggressive variant of the usually benign congenital mesoblastic nephroma. Our recent experience with 3 patients with cellular congenital mesoblastic nephroma prompted a critical review of the literature to evaluate risk factors for recurrence and present treatment programs. A total of 38 patients, including our 3 patients, with cellular congenital mesoblastic nephroma were divided into 2 groups: those with recurrent (7) and those with nonrecurrent (31) tumors. A statistical comparison of clinical and pathological data was performed. Of the 7 patients with local recurrence and/or pulmonary metastasis, 3 died. The average time to first recurrence was 5.4 months. Histological differences were not predictive of recurrent disease. Pathologically positive surgical margins (p less than or equal to 0.02) were the only statistically significant variable suggesting recurrent disease. While the presenting age was not predictive of recurrence (p equals 0.27), the relative risk of recurrence doubles in the first 3 months of life and quadruples after 6 months of life. Treatment programs also were evaluated. An infant with cellular congenital mesoblastic nephroma, regardless of age, is cured with surgery alone given clear pathological margins. In 4 of 5 children with :recurrent tumors Wilms tumor treatment agents (vincristine and actinomycin D) failed to control local or distant disease. Of these cases 2 subsequently were treated with sarcomatous chemotherapy (vincristine, cyclophosphamide and doxorubicin) and both are in remission. These agents may prove to be more efficacious in the treatment of local or metastatic disease. (J. Ural., part 2, 142: 479-483, 1989) Cellular congenital mesoblastic nephroma is an aggressive variant of the usually benign congenital mesoblastic nephroma. Congenital mesoblastic nephroma, also known as leiomyomatous 1 or fetal hamartoma, 2 is the most common solid renal tumor in the neonate and infants less than 6 months old. 3 -G Clinical and demographic data are discussed in detail elsewhere. 7 - 13 Eolande and associates first described congenital mesoblastic nephroma as a histologically separate and clinically benign pediatric renal tumor to be differentiated from Wilms tumor. 7 Bolande's review of 48 cases with congenital mesoblastic nephroma revealed that most morbidity and mortality appeared to be due to treatment with irradiation and chemotherapy. 8 Due to Bolande's observations of the ,.,~,aH~'"~,,,v,,, difference V/ilrn_s tumor betw·een congenital mesoblastic nephroma and its apparent benignity, nephrectomy alone was the recommended treatment despite often worrisome histopathology with foci of hypercellularity, elevated mitotic rates and the finger-like infiltrative pattern exhibited the tumor, 2 ' 7 ' 8 Reports of local recurrence of l patient, 14 and recurrence and death of another is prompted Beckwith to re-evaluate congenital mesoblastic nephroma and to assign the designation of a "pathological spectrum" of congenital mesoblastic nephroma, which spanned from the benign typical congenital mesoblastic nephroma through a "gray zone or cellular variant" to the malignant spindle cell sarcoma. 16 Since 1973, 31 additional cases of cellular congenital mesoblastic nephroma have been reported under a variety of synonyms, including malignant mesenchymal nephroma, cellular variant of congenital mesoblastic nephroma, cystic The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. *Requests for reprints: Department of Urology, Walter Reed Army Medical Center, Washington, D. C. 20307-5001. 479

cellular mesoblastic nephroma and atypical mesoblastic nephroma. 9 , 17- 25 Seven infants had tumor recurrence,9· 10, ,., 15, 19, 21, 25 3 of whom died_ 10. 1•, 15 In 1986 Beckwith and Weeks discussed factors that appeared to be important regarding recurrence of the aggressive form of congenital mesoblastic nephroma (that is cellular congenital mesoblastic nephroma). 26 Adequacy of surgical resection and patient age at presentation appeared to be important prognostic factors in infants with recurrent disease. 26 Treatment recommendations proposed by Beckwith for congenital mesoblastic nephroma and cellular congenital mesoblastic nephroma include adjuvant therapy (Wilms tumor favorable histology chemotherapy) for any infant with incomplete resection or intraoperative rupture, He notes that densely cellular, highly of concern in patients more mitotic lesions are than 3 months old. further recommendations are provided except consideration of radiation for clinically apparent second recurrence. Our recent experience with 3 patients, including 2 infants older than 3 months, prompted a critical review of the literature. We found that existing clinical and pathological data for recurrent and nonrecurrent cellular congenital mesoblastic nephroma had not been statistically analyzed to evaluate the risk factors for recurrence. Treatment strategies had not been compared in the literature. Thus, we add 3 case reports to the literature, and provide a new analysis of clinical data and specific treatment recommendations for infants with cellular congenital mesoblastic nephroma. MATERIALS AND METHODS

A total of 38 solitary cases of cellular congenital mesoblastic nephroma was reviewed9 • 10' 14 • 15• 17- 25 • 27 ' 28 and divided into 2 groups: 31 patients had no evidence of recurrence following initial treatment, while 7 had local and/or metastatic recurrences. The clinical presentation was examined, and a statisti-

480

GORMLEY AND ASSOCIATES

cal analysis of the presenting signs and symptoms and demographics was performed to define risk factors for recurrence. The chi-square test was used to compare presenting signs and symptoms and the tumor margin data of the 2 groups. A 2sample t test was used to compare the demographic and age data. A logistic regression analysis using age as the independent variable examined the likelihood of a positive margin, tumor recurrence and infant mortality as the presenting age increased. The relative risks of these factors at selected ages also were calculated. Surgical, chemotherapeutic and radiation therapy regimens were examined to define the clinical experience and discuss treatment options. CASE REPORTS

Case 1. A 5-month-old white/black male infant presented with a large left flank mass and a fever of 103F. Hematocrit was 21.6 per cent (normal mean 33) and white blood count was 18,700 cells per mm. 3 (normal 6,000 to 17,000). The child was born at 36½ weeks of gestation to a gravida I, para 1, woman. An excretory urogram (IVP) showed a normal right kidney and a nonobstructing left intrarenal mass. Ultrasound and computerized axial tomography (CT) confirmed a mixed density, 12 X 10 x 10.5 cm. left intrarenal mass with evidence of hemorrhage and no calcification (fig. 1). An uncomplicated radical nephrectomy with lymph node dissection was performed through a transverse incision. Surgical margins were clear. Convalescence was uneventful. A baseline CT scan was obtained when the patient was discharged from the hospital. He has no evidence of disease after 18 months. Pathological examination revealed cellular congenital mesoblastic nephroma. Figure 2 presents the pathological characteristics commonly seen in cellular congenital mesoblastic nephroma. Figure 2, A shows tumor, normal kidney and capsule from left to right. Figure 2, B demonstrates features similar to a sarcoma with densely packed fusiform cells arranged in featureless sheets on a myxoid background. A high mitotic rate of 5 to 7 per high power field is present. Figure 2, C reveals hemorrhage, tumor necrosis and cystic areas. Case 2. An 8-month-old white boy presented with a 1-week history of irritability, vomiting and hematuria. Physical examination revealed a nontender, mobile left upper quadrant mass. Urinalysis, and hematological and serological tests were normal. Ultrasound and CT scans revealed a solid 4 cm. left renal mass with hemorrhage and no calcification. Left radical nephrectomy with lymph node sampling was performed through a subcostal incision. There were no complications and convalescence was uneventful. Pathological examination revealed cellular congenital mesoblastic nephroma and clear surgical margins. The patient was discharged from the FIG. 2. Case 1. A, low power view shows tumor, normal kidney and capsule from left to right. Reduced from XlOO. B, high power view reveals densely packed fusiform cells arranged in featureless sheets on myxoid background. Up to 5 to 7 mitotic figures per high power field are seen. Reduced from X400. C, hemorrhage (top), necrosis (left and right) and cystic areas (center) are common. Reduced from XlOO.

FIG. 1. Case 1. Contrast abdominal CT scan of abdomen shows 12 10 cm. mixed density, left intrarenal mass with evidence of hemorrhage. X

hospital 5 days postoperatively and at 12-month followup there was no evidence of recurrence. Case 3. A 2-month-old female infant presented with nausea, vomiting and a left abdominal mass. She was the product of an induced labor at 34 weeks of gestation. The patient was at the 5th percentile for height and weight at presentation. Physical examination revealed hypertension with systolic pressures between 170 and 210 and diastolic pressures between 80 and 120. All laboratory values, except for a hematocrit of 27 per cent (normal 31 to 41), were normal. An IVP revealed a large left intrarenal mass distorting functional renal parenchyma. CT showed a large multiloculated cystic mass without evidence of

481

CELLULAR CONGENITAL MESOBLASTIC NEPHROMA TABLE 1.

Presenting signs and symptoms in 38 patients with cellular congenital mesoblastic nephroma

Symptoms

Recurrent Cellular Congenital Mesoblastic Nephroma

Cellular Congenital Mesoblastic Nephroma

Totals

Total No. pts. Mass: Lt. Rt. Hypertension Gastrointestinal upset Hematuria Anemia Fever Hypercalcemia Prematurity Hyperglycemia Polyhydramnios

7 7 3 4 2 1 0 1 1 0 0 0 0

31 31 10 6 7 7 5 3 2 2 2 1 0

38 38 13 10 9 8 5 4 3 2 2 1 0

TABLE 2.

Demographics of cellular congenital mesoblastic nephroma

Factors

Data available in the literature.

calcification or adenopathy. Preoperative diagnosis was multilocular cystic nephroma or a cystic Wilms tumor. Abdominal exploration was performed through a transabdominal incision. Surgery was complicated by intraoperative tumor rupture. Pathological examination revealed a cystic cellular congenital mesoblastic nephroma and clear surgical margins. Because of the intraoperative tumor rupture, adjuvant chemotherapy was recommended. Vincristine and actinomycin D were given for 10 weeks. The patient remains free of disease 9 months postoperatively. RESULTS

Every child presented with a palpable abdominal mass. Hypertension, gastrointestinal upset and hematuria were common signs or symptoms (table 1). Polyhydramnios, commonly associated with congenital mesoblastic nephroma, did not occur. 13 A chi-square test comparing each sign or symptom showed no significant difference between infants with recurrent and nonrecurrent tumors. The ratio of male-to-female patients in the 2 groups was approximately equal. Information on race was incomplete in the literature. A 2-sample t test revealed no significant difference between the tumor weights (p = 0.78) of the recurrent and nonrecurrent groups (table 2). Mean patient age at presentation in the nonrecurrent tumor group was 3.81 months compared to 6.59 in the recurrent tumor group. No child was older than 18 months. Of the 7 infants with recurrent cellular congenital mesoblastic nephroma 6 compared to only 5 of the 23 infants with nonrecurrent cellular congenital mesoblastic nephroma presented after they were 3 months old. However, a 2-sample t test revealed no significant difference between the presenting ages of the 2 groups (p = 0.27, table 2). Using logistic regression analysis with age as the independent variable, the probability of recurrence for each age was derived and the relative risk was determined. Compared to infants presenting with cellular congenital mesoblastic nephroma at birth, infants 3 months old had twice the chance of recurrence and at 6 months of age the chance of recurrence was quadrupled. Thus, age remains a relative risk factor although not statistically predictive of recurrence. Surgical margin status was the only clinicopathological feature in which a significant difference was found between the 2 groups (table 2). A 2 X 2 table (Fisher's exact test) comparing margin status and episodes of recurrence between the 2 groups showed the probability of tumor recurrence given unclear surgical margins to be statistically significant (p = 0.02). A positive surgical margin is a risk factor for recurrence. The treatment regimens and clinical courses of the 31 children with nonrecurrent cellular congenital mesoblastic nephroma were re-viewed (table 3). Of the 31 children 11 (35 per cent) were treated with surgery alone, including 3 who were

Recurrent Cellular Congenital Mesoblastic Nephroma

Total No. pts. 7 Sex: Male 3 Female 4 Unknown Race: White 2 Black 2 Black/White Unknown 3 Tumor wt. (gm.): Mean 420 Range 150-800 Unknown 0 Age: Mean (mos.) 6.59 Range 1 day-18 mos. No. >3 mos. 6 No. <3 mos. 1 Unknown 0 Margin(%): Clear 2 (28.6) Involved: 5 (71.4) Tumor rupture 0 Local extension 4 Rupture and extension 1 Unknown 0

Cellular Congenital Mesoblastic Nephroma

Totals

31

38

12 14 5

15 18 5

2 2 1 26

4 4 1 29

481 47-1,350 16

458 47-1,350

3.81 1 day-10 mos. 5 18 8

4.61 1 day-18 mos.

16

11

19 8

14 (45) 3 (10) 1 1 1 14 (45)

older than 3 months at presentation and presumed to be at increased risk of recurrence. In the remaining children surgery plus chemotherapy and/or radiation therapy were given. No standard chemotherapeutic regimen was used, although vincristine and actinomycin D was given in 75 per cent of the patients. Table 4 outlines the clinical and treatment course of the 7 children with recurrent cellular congenital mesoblastic nephroma. There were 5 local recurrences, 1 with pulmonary metastasis and 1 with local and pulmonary involvement. Three children had second recurrences. The mean time to the initial recurrence was 5.43 months with a range of 2 to 11 months. Mean time to the second recurrence was 9 months with a range of 6 to 14 months. Five children with recurrence were treated initially with surgery alone, 1 with surgery and chemotherapy, and 1 with surgery, chemotherapy and radiation. In treating the first recurrence 6 children were re-explored, 2 of whom received additional radiation, 2 received radiation, and vincristine and actinomycin D, and 2 received the Wilms regimen plus doxorubicin or doxorubicin and cyclophosphamide. The remaining child who had pulmonary metastasis received only actinomycin D and radiation. Of the 7 infants 3 died: 2 had local recurrences that were unresectable and 1 died 2 days postoperatively with residual tumor. The remaining 4 infants are alive with followup from 20 months to 7 years. The patient with pulmonary metastasis had a second recurrence of a pulmonary nodule that was treated successfully with resection alone. The use of vincristine and actinomycin D (Wilms tumor regimen) failed in 3 of 4 patients but the addition of cyclophosphamide and doxorubicin (sarcomatous chemotherapeutic agents) produced remission in one and resolution of pulmonary nodules in another. DISCUSSION

Eolande and associates observed that congenital mesoblastic nephroma was pathologically distinct from Wilms tumor, clinically benign and treatable by nephrectomy alone. 7 This saved many children from the unwarranted risks of adjuvant radiation and chemotherapy. Cellular congenital mesoblastic nephroma is now recognized as a histologically different and potentially more aggressive form of congenital mesoblastic

482

GORMLEY AND ASSOCIATES TABLE 3.

Initial treatment of 31 nonrecurrent cellular congenital mesoblastic nephromas

Surgery Surgery + chemotherapy: Vincristine + actinomycin D, 9* Actinomycin D, 3 Vincristine + actinomycin D + doxorubicin, 1 Vincristine + doxorubicin, 1 Surgery + radiation therapy Surgery + chemotherapy + radiation therapy Unknown

No. Cases

Clinical Course

11 14

No evidence of disease, 6 mos.-27 yrs. No evidence of disease, 11 mos.-8.5 yrs.

2

1 3

No evidence of disease (?) No evidence of disease, 10.5 yrs. No evidence of disease (?)

* Three cases were associated with tumor spill or unclear surgical margins. TABLE 4.

Site

Reference

Treatment of 7 recurrent cellular congenital mesoblastic nephromas Initial Treatment

Joshi and associates 14

Local

Surgery

Walker and Richard15

Local

Surgery

Joshi and associates'°

Local

Gonzalez-Crussi and associates 17 Howell and associates9

Pulmonary

Surgery + vincristine + actinomycin D + 1,700 rad radiation therapy Surgery

Local

Surgery + vincristine + actinomycin D

Steinfeld and associates 25

Local + pulmonary Surgery

Chan and associates21

Local

Surgery

Treatment of First Recurrence

Interim Course

Surgery with 1,700 rad ra- Re-exploration+ cydiation therapy clophosphamide Surgery + radiation therapy X2 days Surgery+ vincristine + actinomycin D + doxorubicin Actinomycin D + 1,700 rad radiation therapy (X2) Surgery + vincristine + actinomycin D + doxorubicin + cyclophosphamide Surgery + vincristine + ac- No change, add doxorubicin + cyclophostinomycin D + radiation therapy phamide with resolution Surgery + vincristine + actinomycin D + 2,000 Gy. radiation therapy

nephroma, similar perhaps to sarcoma. Because 7 of 38 infants with cellular congenital mesoblastic nephroma suffered recurrences with 3 subsequent deaths, more aggressive treatment has again been advocated. 29 Of our 3 infants with cellular congenital mesoblastic nephroma, 2 had clear surgical margins but they were older than 3 months at presentation. Recommended treatment included adjuvant chemotherapy (actinomycin D plus cyclophosphamide) based on age at presentation alone while disregarding surgical margin status. 29 Adjuvant treatment based on age alone was disconcerting because complete surgical excision appeared curative for infants less than 3 months old with cellular congenital mesoblastic nephroma and those of all ages with congenital mesoblastic nephroma. Our literature review and subsequent analysis were ensued to determine clinical risk factors for recurrence, present treatment experiences and, thus, provide specific treatment guidelines. There are no distinguishing radiological features or serological criteria that differentiate cellular congenital mesoblastic nephroma from congenital mesoblastic nephroma or other common solid abdominal masses in infants. 10 • 21 • 30- 32 No presenting signs or symptoms (table 1) proved statistically significant when comparing recurrent and nonrecurrent cellular congenital mesoblastic nephroma. Demographic information was inconclusive and mean tumor weights were almost identical (table 2). Joshi and associates provided an in-depth pathological comparison of cellular congenital mesoblastic nephroma and congenital mesoblastic nephroma. 10 They noted that there were no pathological characteristics that predicted recurrence or mortality. Beckwith and Weeks cautioned about using the pathological appearance as the basis for clinical treatment and they have stressed, as did Joshi and associates, that 25 to 30 per cent of congenital mesoblastic nephroma show focal areas of hemorrhage, necrosis, dense cellularity and high mitotic rates characteristic of cellular congenital mesoblastic nephroma. 26

Treatment of Second Recurrence Locally unresectable

Clinical Course Death, 18 mos. Death, 2 days

Surgery incomplete, cisplatin + cyclophosphamide Surgery only

Death, 28 mos.

No evidence of disease, 7 yrs. No evidence of disease, 22 mos. No evidence of disease, 23 mos. No evidence of disease, 20 mos.

Thus, pathological features alone should not alter treatment beyond surgical excision. Presenting age remains a concerning feature but our data show that, by itself, it is not statistically predictive of recurrence. Beckwith's suggestion that adjuvant treatment for infants with cellular congenital mesoblastic nephroma presenting after age 3 months with clear surgical margins appears conservative but it may be overly aggressive. 29 While a consideration, we believe that age alone does not merit additional therapy given clear surgical margins. A positive surgical margin is the only prognostic factor related to tumor recurrence (p = 0.02). Cellular congenital mesoblastic nephroma and congenital mesoblastic nephroma have finger-like projections that commonly invade the renal parenchyma, renal capsule, perihilar tissue and perirenal fascia, which makes incomplete surgical resection readily conceivable. The greatest area of concern appears to be the medial margin of resection. Of the 7 children with recurrent disease 3 were reported to have medial involvement (1 ureteral and 2 involving the renal vein and/or vena cava). 10• 14• 21 • 26 Frozen sections are necessary to establish clear margins in areas of question. Pathologists should examine carefully and report the status of all tumor margins to enable accurate treatment decisions, including the need for early surgical reassessment and chemotherapy. Of 28 infants with nonrecurrent cellular congenital mesoblastic nephroma 11 with clear surgical margins were treated succe:ssfully with surgery alone (table 3), including 3 older than 3 months at presentation. The potential morbidity of adjuvant therapy was avoided. Thus, infants with clear surgical margins, regardless of presenting age, should be treated with surgery alone and close followup with a CT scan as was done in 2 of 3 of our cases. None of the 7 infants with recurrent cellular congenital mesoblastic nephroma was treated in the same fashion (table 4). Examination of the chemotherapeutic regimens revealed the failure of the standard Wilms tumor agents (vincristine and

CELLULAR CONGENITAL MESOBLASTIC NEPffROlV1A actinomycin D), either alone, with doxorubicin, or with radiation therapy, to control local or metastatic disease in 4 of 5 treatment attempts. The addition of cyclophosphamide and doxorubicin, commonly used in sarcomatous regimens, appeared helpful in 2 patients. The initial use of vincristine, doxorubicin and cyclophosphamide (VAC) may be a better first line regimen when treating recurrent cellular congenital mesoblastic nephroma. The response of cellular congenital mesoblastic nephroma to sarcomatous chemotherapeutic agents suggests significant similarities between cellular congenital mesoblastic nephroma and other pediatric sarcomas. Other evidence supports this relationship. Snyder and associates 18 present an attractive unifying embryological schema based on the 2-step process of tumor induction proposed by Knudson and Strong, 33 which links congenital mesoblastic nephroma through cellular congenital mesoblastic nephroma to the malignant sarcomas. Jayabose and associates reported 14 cases of hypercalcemia associated with sarcomatous pediatric renal tumors. 34 Congenital mesoblastic nephroma ( 4 cases) and nonrecurrent cellular congenital mesoblastic nephroma (2 cases) presented with this uncommon finding. Hypercalcemia has never been seen with Wilms tumor. Finally, Joshi 10 and Haas 35 and their associates have noted pathological similarities in cellular congenital mesoblastic nephroma resembling clear cell sarcoma of the kidney. The role of radiation in the treatment of cellular congenital mesoblastic nephroma is unclear. The serious sequela of radiation in infants must be considered. 7 Whether its addition is helpful cannot be ascertained since no child has been treated with this modality alone. Of the 5 cases in which radiation therapy was used 4 had recurrences. Sarcomatous tumors, in general, are relatively insensitive to radiation. Our third case involved a 2-month-old infant with clear surgical margins but intraoperative tumor rupture. Insufficient information exists on the treatment of cellular congenital mesoblastic nephroma with tumor rupture. Chemotherapy is recommended if this unfortunate event occurs. It is noteworthy that in 4 infants experiencing tumor rupture congenital mesoblastic nephroma did not recur, including 2 who were treated with surgery alone. 9 CONCLUSION

Eolande and associates correctly cautioned about over treatment of infants with congenital mesoblastic nephroma. 7 We believe that the same caution should be used with cellular congenital mesoblastic nephroma. A positive surgical margin is the only statistically significant factor that predicts recurrence. Treatment of cellular congenital mesoblastic nephroma should be based upon the presence of clear surgical margins regardless of presenting age. Complete excision requires no further treatment. A positive surgical margin warrants early re-exploration for gross residual disease and the use of V AC chemotherapy for microscopic residual disease or tumor rupture. Treatment of tumor recurrences requires aggressive surgical resection and use of sarcomatous chemotherapeutic agents. Drs. H. G. Rushton and R. Ferrigni provided the case reports, Dr. S. Sihelnik provided computer assistance, and Mr. T. R. Young and Ms. R. Howard performed the statistical analysis. REFERENCES

1. Bogdan, R., Taylor, D. E. M. and Mostofi, F. K.: Leiomyomatous hamartoma of the kidney. A clinical and pathologic analysis of 20 cases from the Kidney Tumor Registry. Cancer, 31: 462, 1973. 2. Wigger, H. J.: Fetal hamartoma of the kidney. A benign symptomatic congenital tumor, not a form of Wilms' tumor. Amer. J. Clin. Path., 51: 323, 1969. 3. Marsden, H.B. and Lawler, W.: Primary renal tumours in the first year of life. A population based review. Virch. Arch., 399: 1, 1983. 4. Eolande, R. P.: Congenital and infantile neoplasia of the kidney. Lancet, 2: 1497, 1974.

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5. Bolande, R. P.: Neoplasia of early life and its relationship to teratogenesis. Perspect. Ped. Path., 3: 145, 1976. 6. Wigger, H. J.: Fetal mesenchymal hamartoma of kidney, a tumor of secondary mesenchyme. Cancer, 36: 1002, 1975. 7. Eolande, R. P., Brough, A. J. and Izant, R. J., Jr.: Congenital mesoblastic nephroma of infancy. A report of eight cases and the relationship to Wilms' tumor. Pediatrics, 40: 272, 1967. 8. Bolande, R. P.: Congenital mesoblastic nephroma of infancy. Perspect. Ped. Path., l: 227, 1973. 9. Howell, C. G., Othersen, H.B., Kiviat, N. E., Korkool, P., Beckwith, J. B. and D'Angio, G. J.: Therapy and outcome in 51 children with mesoblastic nephroma: a report of the National Wilms' Tumor Study. J. Ped. Surg., 17: 826, 1982. 10. Joshi, V. V., Kasznica, J. and Walters, T. R.: Atypical mesoblastic nephroma: pathologic characterization of a potentially aggressive variant of conventional congenital mesoblastic nephroma. Arch. Path. Lab. Med., HO: 100, 1986. 11. Levin, N. P., Damjanov, I. and Depillis, V. J.: Mesoblastic nephroma in an adult patient: recurrence 21 years after removal of the primary lesion. Cancer, 49: 573, 1982. 12. Block, N. L., Grabstald, H. G. and Melamed, M. R.: Congenital mesoblastic nephroma (leiomyomatous hamartoma): first adult case. J. Urol., 110: 380, 1973. 13. Blank, E., Neerhout, R. C. and Burry, K. A.: Congenital mesoblastic nephroma and polyhydramnios. J.A.M.A., 240: 1504, 1978. 14. Joshi, V. V., Kay, S., Milsten, R., Koontz, W.W. and Mc Williams, N. B.: Congenital mesoblastic nephroma of infancy: report of a case with unusual clinical behavior. Amer. J. Clin. Path., 60: 811, 1973. 15. Walker, D. and Richard, G. A.: Fetal hamartoma of the kidney: recurrence and death of a patient. J. Urol., 110: 352, 1973. 16. Beckwith, J.B.: Mesenchymal renal neoplasms of infancy revisited. J. Ped. Surg., 9: 803, 1974. 17. Gonzalez-Crussi, F., Sotelo-Avila, C. and Kidd, J. M.: Malignant mesenchymal nephroma of infancy: report of a case with pulmonary metastases. Amer. J. Surg. Path., 4: 185, 1980. 18. Snyder, H. M., III, Lack, E. E., Chetty-Baktavizian, A., Bauer, S. B., Colodny, A. H. and Retik, A. B.: Congenital mesoblastic nephroma: relationship to other renal tumors of infancy. J. Urol., 126: 513, 1981. 19. Gonzalez-Crussi, F., Sotelo-Avila, C. and Kidd, J. M.: Mesenchymal renal tumors in infancy: a reappraisal. Hum. Path., 12: 78, 1981. 20. Slasky, B. S., Penkrot, R. J. and Bron, K. M.: Cystic mesoblastic nephroma. Urology, 19: 220, 1982. 21. Chan, H. S. C., Cheng, M. Y., Mancer, K., Payton, D., Weitzman, S. S., Kotecha, P. and Daneman, A.: Congenital mesoblastic nephroma: a clinicoradiologic study of 17 cases representing the pathologic spectrum of the disease. J. Ped., 111: 64, 1987. 22. Kelly, D. R.: Cystic cellular mesoblastic nephroma. Ped. Path., 4: 157, 1985. 23. Schmidt, D., Harms, D. and Lehner-Geisser, M.: Cellular congenital mesoblastic nephroma in a newborn. Path. Res. Pract., 179: 242, 1984. 24. Shen, S. C. and Yunis, E. J.: A study of cellularity and ultrastructure of congenital mesoblastic nephroma. Cancer, 45: 306, 1980. 25. Steinfeld, A. D., Crowley, C. A., O'Shea, P. A. and Tefft, M.: Recurrent and metastatic mesoblastic nephroma in infancy. J. Clin. Oncol., 2: 956, 1984. 26. Beckwith, J. B. and Weeks, D. A.: Congenital mesoblastic nephroma: when should we worry? Arch. Path. Lab. Med., 110: 98, 1986. 27. Fu, Y. and Kay, S.: Congenital mesoblastic nephroma and its recurrence. Arch. Path., 96: 66, 1973. 28. Beckwith, J. B. and Palmer, N. F.: Histopathology and prognosis of Wilms tumors. Results from the first National Wilms Tumor Study. Cancer, 41: 1937, 1978. 29. Beckwith, J.B.: Wilms tumor and other renal tumors of childhood: an update. J. Urol., 136: 320, 1986. 30. Kaplan, G. W. and Brock, W. A.: Abdominal masses. In: Clinical Pediatric Urology. Edited by P. P. Kelalis, L. R. King and A. B. Belman. Philadelphia: W. B. Saunders Co., vol. 1, chapt. 5, pp. 57-75, 1985. 31. Hartman, D. S., Lesar, M. S. L., Madewell, J. E., Lichtenstein, J. E. and Davis, C. J., Jr.: Mesoblastic nephroma: radiologic-pathologic correlation of 20 cases. Amer. J. Roentgen., 136: 69, 1981. 32. Sty, J. R. and Oechler, H.: Tc-99m glucoheptonate renal imaging: congenital mesoblastic nephroma. Letter to the Editor. J. Nucl. Med., 21: 809, 1980. 33. Knudson, A. G., Jr. and Strong, L. C.: Mutation and cancer: a model for Wilms' tumor of the kidney. J. Natl. Cancer Inst., 48: 313, 1972. 34. Jayabose, S., Igbal, K., Newman, L., San Filippo, J. A., Davidian, M. M., Noto, R. and Sagel, I.: Hypercalcemia in childhood renal tumors. Cancer, 61: 788, 1988. 35. Haas, J.E., Bonadio, J. F. and Beckwith, J.B.: Clear cell sarcoma of the kidney with emphasis on ultrastructural studies. Cancer, 54: 2978, 1984.