WILMS’ TUMOR AFTER TREATMENT

Massimo Brisigotti, MD, Cleto Cozzutto, MD, Gioavanna Fabbretti, MD, and Luigi Caliendo, MD 0 Department of Pathology, Giannina Gaslini Children’s Hospital, Genoa, Italy 16148

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

Riccardo Haupt, MD 0 Department of Hematology/Oncology, Giannina Gaslini Children’s Hospital, Genoa, Italy 16148 Paolo Cornaglia-Ferraris, MD Oncology Research Laboratory, Giannina Gaslini Children’s Hospital, Genoa, Italy 16148 Francesco Callea, PhD

0

Department of Pathology, Giannina Gaslini Children’s

Hospital, Genoa, Italy 16148

Sixty-one Wilms’ tumors ( W T s ) from 59 patients who received preoperative therapy were studied. Twenty-seven W T s from 26 patients who did not receive preoperative treatment were also reviewed as controls. Marked and diffuse morphological changes occurred in treated cases. Necrosis affected mostly undifferentiated and replicatinf elements and was extensive, up to 90% of tumor mass. Minimal residual tumor, permitting recognition as Wilms ’, was always spared. Epithelial and rhabdornyoblastic components were more resistant to treatment; moreover, they appeared to be susceptible to differentiation and maturation. Necrosis and muscle cell diffentiation seemed to have prognostic implications. Cases with extensive necrosis (> 90%) had a better outcome, although the difference was not statistically significant. The rhabdomyoblast/tumor mass ratio, after treatment, appears to carry prognostic meaning. Chemotherapy had no apparent effect on anaplasia. 0

KEY WORDS: Wilms’ tumor, patholou, chemotherapy

INTRODUCTION Most pediatric neoplasms such as rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor (WT) present with varying degrees of differentiation that can be histologically assessed and have prognostic implications. Moreover, the same tumors are known to be susceptible to maturation and differentiation after therapy. The clinical relevance of these morphological changes is subject to debate. We report on the histopathology of a large group of Italian WTs excised with or The authors wish to thank Mrs. G. Merano, Mr. C . Pellegrini, Mr. F. Comanducci, and Mr. S. Pizzorni for technical assistance; Mr. G. Rodolfo for preparing photomicrographs; and Mrs. Roberta Boero, Mrs. Marina Fereccio, and Mrs. Anna Capurro for typing and editorial assistance. Address reprint requests to Massimo Brisigotti, M . D . , Department of Pathology, Giannina G a s h Children’s Hospital, Largo Gerolamo Gaslini 5 , 16148, Genoa, Italy.

Pediatric Palhaloo, 12:397-406, 1992 Copyrkht 0 1992 by Hemisphere Publishing Corporation

397

398

M. BRlSlGOTTl ET AL.

without prior therapy, conducted according to the International Society of Paediatric Oncology (SIOP protocol) (1).

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

MATERIALS AND METHODS One hundred and one renal tumors from 98 patients in the pediatric age group, collected at Giannina Gaslini Children’s Hospital over a period of 16 years (1974- 1990), were evaluated retrospectively. Eighty-eight were diagnosed as WTs. The remaining cases were mesoblastic nephroma (eight) including four cellular variants, clear cell sarcoma (four), and rhabdoid tumor (one). Only nephroblastomas were included in the present study. There were 61 WTs from 59 patients with preoperative treatment (group 1) and 27 WTs from 26 patients without any preoperative treatment (group 2). Data on clinical aspects, preoperative chemotherapy or radiotherapy, and histology were reviewed for each patient. The number of hematoxylin-eosin-stained sections available for review ranged from 1 to 23, with an average of 9. Additional staining included periodic acid-Schiff before and after diastase digestion, Masson trichrome, and phosphotungstic acid-hematoxylin (PTAH). In the histological review of both groups, particular attention was paid to the presence of viable neoplastic elements, cellular anaplasia, xanthogranulomatous inflammation, skeletal muscle fibers, and well-differentiated, nonreplicating epithelial structures. In addition, osteoid, bone, cartilage, calcification, and necrosis were recorded. Tumor necrosis was synonymous with the spectrum of changes that represent chemotherapy effect (i.e, cell dropout with residual intact matrix, granulation tissue, xanthogranulomatous inflammation, fibrosis, and hemosiderin deposits) (2, 3). A score of tumor necrosis based on gross and microscopic evaluation was established arbitrarily: grade 1 corresponded to less than 20 % of the entire mass, grade 2 to less than 90%, and grade 3 to 90% or more. The amount of skeletal muscle fiber was evaluated semiquantitatively together with the amount of viable tumor (rhabdomyoblast/tumor mass ratio).

RESULTS Patients and Therapeutic Approach There were 48 males and 37 females; age at diagnosis ranged from 1 day to 13 years with a median of 4 years. Four patients were under 1 year. Forty-one tumors were located in the right kidney and 47 in the left; three patients had bilateral tumors. According to the therapeutic approach, the patients were divided into two groups.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

WILMS' TUMOR AFTER TREATMENT

399

Group 1. Sixty-one WTs from 59 patients who received preoperative therapy. Fifty-five patients were treated with the SIOP 6 preoperative protocol, which includes treatment for 4 weeks with Vincristine (VCR) 1.5 mg/m2 every week plus two cycles of actinomycin-D (Act-D) 15pg/kg for 3 days on weeks 1 and 3. The remaining four patients had different preoperative treatments: radiotherapy (two), Peptichemio (one), and Act-D plus VCR (one). Staging after surgery according to the SIOP criteria revealed stage I in 34 patients, stage I1 in 7 patients, stage I1 plus positive lymph nodes or stage I11 in 10 patients, stage IV in 6 patients, and stage V in 2 patients (both with localized disease). Further treatment was given according to the SIOP 6 protocol. Group 2. Twenty-seven WTs from 26 patients who underwent surgery and staging according to the criteria of the National Wilms Tumor Study (NWTS) group. Nine patients were defined as stage I, 9 as stage 11, 7 as stage 111, and 1 as stage V. Patients below 1 year of age belonged to this group. Gross Pathology Most WTs presented as a solitary round, well-circumscribed mass in a pole of the kidney. Multicentric tumors were observed. WTs ranged from 1.5 to 30 cm in diameter with an average of 10.3 cm. Weight ranged from 22 to 1500 g. with an average of 510 g. Generally, on section, W T had a uniform appearance and a grayish-white color with areas of hemorrhage and necrosis. Cysts were seen in 34 cases. In two cases polypoid growth into the pelvis was observed. Calcifications were not seen macroscopically. Tumors with extensive necrosis displayed a granular homogeneous yellow appearance with large cysts.

Histology Group 1 (61 WTs from 59 Patients). No biopsy was performed prior to treatment. A definitive diagnosis of W T could be made, despite the therapy, in all patients in this group. Even in cases with extensive necrosis, the diagnosis of W T could still be made because of the presence of foci of blastema, often associated with neoplastic tubules or stroma (minimal residues). The amount of necrosis varied from grade 1 (16 cases, 6 with no necrosis at all) to grade 2 (28 cases) to grade 3 (17 cases). Nephrogenic rests were observed in 15 specimens (25%). Anaplasia was seen in four cases (focal in one and diffuse in three). Anaplasia in an extrarenal site was found in one case. A xanthogranulomatous reaction with active histiocyte and foam cell accumulation resulting in a xanthomatous pattern was seen in 43 cases (Fig. 1). Plasma cells, lymphocytes, and foci of hemorrhage were frequent. Hemosiderin deposits were scattered in the infiltrate. Striated muscle cells were observed in 22 of 61 tumors. In 14 this was a

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

400

M. BRlSlGOTTl ET AL.

FIGURE 1. Sheets of foamy histiocytes with a xanthoma-like appearance.

X

75.

focal finding; in 8 cases more than 30% of the viable tissue tumor was composed of striated muscle cells. Large round cells with eosinophilic granular cytoplasm and cross-striations imparted a rhabdomyoma-like pattern (Fig. 2). Bundles of spindle rhabdomyoblasts resembling those encountered in fetal rhabdomyoma could be seen. Xanthogranulomatous process and skeletal muscle areas could be intermingled. In four cases fascicles of spindle cells with deeply acidophilic cytoplasm and blunt-ended nuclei were recognizable as smooth muscle cells. Two cases showed a striking foreign body giant cell reaction in a context of hemorrhage. Foci of squamous epithelium, composed of solid nests, horny pearls, and keratin-filled cysts, were observed in 7 cases. Well-differentiated tubules and glomeruloid structures were seen in fibrous or xanthogranulomatous areas in 22 tumors, within thrombi occurring in the renal and cava veins (2 cases) and at the level of liver capsule (1 case) (Fig. 3). Epithelial cells had a benign appearance and displayed no atypia or mitosis. Apart from the cysts observed grossly, in 22 cases microcysts corresponding to dilated tubules lined by flat cuboidal epithelium were recognizable. Calcifications around or within foci of necrosis were seen in 27 cases. In

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

WILMS' TUMOR AFTER TREATMENT

FIGURE 2. Mature rhabdomyoblasts with abundant large eosinophilic cytoplasm.

X

401

250.

FIGURE 3. Well-differentiated epithelial structures appearing in the form of glomeruli and tubules. x 150.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

402

M. BRlSlGOTTl ET AL.

four cases psammoma bodies were observed in the lumen of neoplastic tubules. Bone was absent but osteoid was observed in three cases. Foci of immature cartilage were seen in a single tumor. Mature fatty tissue was observed in areas of viable tumor in four cases; in one of these, sheets of lipoblasts set in a myxoid matrix with a prominent vascular pattern resulted in a lipoblastoma-like appearance (Fig. 4). One patient developed metachronous metastases in the thoracic wall and in the lower lobe of the right lung. The original tumor was a triphasic nephroblastoma with a predominant skeletal muscle fiber component. The thoracic metastasis showed glands and solid nests of oncocytoid cells (Fig. 5) and several rhabdomyoblasts in a fibrotic tissue. The oncocytoid cells had a large granular cytoplasm with well-defined margins. The lung nodule showed fascicles of spindle cells, rhabdomyoblasts, clusters of adipocytes, nerve bundles, and many mature ganglion cells. Group 2 (27 WTs from 26 patients). In group 2 necrosis was observed in 12 specimens (grade 1 in 10 and grade 2 in 2 cases). Perilobar nephrogenic rests were seen in four cases. Focal anaplasia was observed in one case. Striated muscle cells were recognized in six cases as small foci of large cells with abundant eosinophilic cytoplasm. Smooth muscle cells were not observed. Inflammatory cells were scant and a xanthogranulomatous reaction was absent in all cases. Foci of well-differentiated tubules and glomeruloid structures were seen in six cases; in one case foci of cartilage were noted. In

FIGURE 4. Lipoblasts in mild stroma.

X

250.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

WILMS' TUMOR AFTER TREATMENT

FIGURE 5 . Oncocytic cells organized in a glandular fashion.

X

403

250.

five tumors rare microcysts were observed. Squamous epithelium, osteoid, and bone were not seen. Calcifications were observed in five tumors around foci of necrosis; psammoma bodies were recognized in a few tubules of one additional case.

FOLLOW-UP The clinical follow-up ranged from 3 months to 16 years and 7 months, median 5.3 years. In group 1, 12 patients relapsed and 7 subsequently died. This group had an 85.8% overall survival (0s)and a 78.0% progression-free survival (PFS). Four patients of group 2 relapsed and one subsequently died; the 0s and PFS were 95 % and 83 76, respectively. Among the five patients with cellular anaplasia, three relapsed and one subsequently died. The latter patient had anaplasia in an extrarenal site and belonged to group 1. To evaluate the prognostic meaning of necrosis (greater or less than 90%) after chemotherapy, we have calculated the 0s and PFS of group 1 patients by stratifying for localized (I or 11) or advanced (I11 and IV) stages. The patients with bilateral disease were defined according to the highest local stage between the two kidneys (both were considered localized). The probability of survival was calculated by Kaplan-Meier product limit analysis; life tables were compared statistically by means of log-rank test. Table 1 shows the results and the lack of statistical significance.

404

M. BRlSlGOTTl ET AL.

TABLE 1. Overall survival ( 0 s ) and Progression-Free Survival (PFS) of Patients Treated with Preoperative Chemotherapy, Stratified for Localized (I and 11) or Advanced (I11 or IV) Stage According to Percentage of Necrosis Stage

Necrosis

Localized (I and 11)

< 90 > 90 < 90 > 90

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

Advanced (111 and IV)

(a)

(N)

0s ( % )

(29) (13) (13)

91.5 (P 90.5 65.9 (P 100

(4)

PFS

-

.96) .24)

(a)

81.1 (P 92.3 46.9 (I' 100

-

-

.35) .12)

DISCUSSION

A number of studies on morphological changes after therapy in W T have appeared in the last few years (4-7). Bannayan et al. observed a greater mesenchymal component in metastases when compared to primary WTs after radiotherapy (8). In that study, rhabdomyoblasts were found in 26 of 55 metastatic deposits, whereas only 4 primary tumors had shown muscle cells. Guarda et al. studied 21 WTs after chemotherapy (4). Major changes were observed in the stroma, while differentiated elements including the rhabdomyoblastic component were unaffected. Similar morphological observations were made by Schmidt in a study of a large series of WTs (5) and, more recently, by Zuppan et al. in a series of 83 patients from the NWTS (7). We have studied 61 WTs treated with the SIOP protocol and have made an inventory of morphological changes. The discussion is mainly focused on the following phenomena: necrosis, anaplasia and differentiation, Necrosis was generally not a prominent finding in untreated cases. Only two of them showed grade 2 necrosis that represented less than 50% of the tumor mass. After chemotherapy, necrosis was a constant and impressive feature, occurring as grade 2 or 3 in the vast majority of cases. With regard to necrosis, Zuppan et al. found that extensive tumor necrosis ( > g o % ) was associated with a favorable outcome (7). Our study material differs from the American one because of the small number of cases in an advanced stage and the less aggressive treatment regimen. This might explain the absence of statistical significance of necrosis in our study, although it clearly appears that patients with advanced-stage disease having 90% or more necrosis after chemotherapy have an excellent outcome, compared with those having a lower percentage of necrosis. Extensive necrosis did not replace the tumor mass completely; indeed, in all our cases there was some tumor residue displaying the histological hallmark of WTs, thus permitting their recognition. A similar experience was shared by other authors (4-6). In the morphological spectrum of necrosis, a most remarkable feature was the histiocytic reaction, ranging from focal collections of foamy cells to large sheets of histiocytes, resulting in a xanthogranuloma- or

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

WILMS’ TUMOR AFTER TREATMENT

405

xanthoma-like appearance (9). Focal or diffuse anaplasia, according to the classical criteria (10, l l ) , was found in 4 out of 61 treated and in 1 of 27 untreated cases. It is noteworthy that in treated cases there were no treatment-induced changes that mimicked anaplasia. It follows that the differentiation between favorable and unfavorable histology (10, 11) is not influenced by treatment. Differentiation applies to striated muscle and epithelial cells. Striated muscle cells were observed in 22 cases (36%) of treated WTs, being the major tumor component in 8. In untreated tumors, six cases (22%) contained rhabdomyoblasts with a focal distribution. Striated muscle cells had no mitotic figures or atypia. The rhabdomyoblast/tumor mass ratio appears to correlate with prognosis; indeed, in our series, all patients whose tumors were composed mostly of rhabdomyoblasts are alive and well. With few exceptions (12), the W T variant rich in rhabdomyoblasts designed as “fetal rhabdomyomatous nephroblastoma” has been associated with a good prognosis (13, 14). Well-differentiated epithelial structures including tubules, glomeruli, microcysts, and squamous epithelium were a very common finding in treated WTs. They could be observed even in areas of fibrosis or xanthogranuIomatous reaction. In untreated WTs, epithelial structures as well as rhabdomyoblasts, when present, had a focal distribution. The increase in number of muscle cells and well-differentiated epithelial structures after treatment requires further comment. Chemotherapy may trigger rhabdomyogenesis and induce epithelial differentiation (15, 16), or it may simply make muscle cells and epithelial structures more prominent by destroying undifferentiated and replicating cells. In theory, these two possibilities are not necessarily mutually exclusive, However, the presence in our series of mature-appearing tubules in extrarenal sites, including vein tumor thrombi, and the evidence of maturation in metastatic sites after therapy seem to support the former possibility. Maturation in metastatic sites has been stressed by other authors (17, 18). Mature elements of both epithelial and mesenchymal origin appear to be more resistant to chemotherapy. A peculiar and apparently undescribed finding was the presence, in the present study, of lipoblastoma-like features consisting of vacuolated lipoblasts set in a myxoid stroma. In summary, the results of our study indicate that chemotherapy-induced changes are concentrated primarily on stroma and blastemal elements. Necrosis affects undifferentiated components and may be extensive; minimal residues of the tumor, however, are always spared, allowing the recognition of WT. Epithelial and rhabdomyoblast components appear to be not only resistant to treatment but also susceptible to differentiation and maturation. Both necrosis and muscle cell differentiation appear to have prognostic implications. Cases with extensive necrosis ( >90 %) show a trend to a better outcome, although the difference is not statistically significant. Cases with a high rhabdomyoblast/

406

M. BRlSlGOTTl ET AL.

tumor mass ratio after treatment appear to have an excellent prognosis. Chemotherapy alters neither the morphological features nor the incidence of anaplasia in WTs.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 01/21/15 For personal use only.

REFERENCES 1. Lemerle J, Voute PA, Tournade MF, et al. Effectiveness of preoperative chemotherapy in Wilms’ tumor: Results of an International Society of Paediatric Oncology (SIOP) clinical trial. J Clin Oncol 1983:1:604-9. 2. Raymond AK, Chawla AP, Carrasco H , et al. Osteosarcoma chemotherapy effect: A prognostic factor, Semin Diagn Pathol 1987;4:212-36. 3. Picci P, Bacci G, Campanacci M , et al. Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy. Regional mapping of viable and nonviable tumor. Cancer 1985;56: 1515-21. 4. Guarda LA, Ayala AG, Jaffe N, Sutow WW, Bracken RB. Chemotherapy-induced histologic changes in Wilms’ tumors. Pediatr Pathol 1984;2:197-206. 5. Schmidt D. Nephroblastomas (Wilms’ tumor) and special variations of nephroblastomas. Veroff Pathol 1989;133: 1-1 74. 6. Alvarez-Silvan AM, Gavilan Carrasco F, Pineda Cuevas G, et al. Preservation of anaplastic features in Wilms’ tumor after preoperative chemotherapy. Med Pediatr Oncol 1989;17:131-3. 7. Zuppan CW, Beckwith JB, Weeks DA, Luckey DW, Pringle KC. The effect of preoperative therapy on the histologic features of Wilms’ tumor. Cancer 1991; 68:385-94. 8. Bannayan GA, Huvos AG, D’Angio GJ. Effect of irradiation on the maturation of Wilms’ tumor. Cancer 1971;27:812-8. 9. Cozzutto C , Carbone A. The xanthogranulomatous process (xanthogranulomatous inflammation). Pathol Res Pract 1988;183:395-402. 10. Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms’ tumor. Results from the First National Wilms’ Tumor Study. Cancer 1978;41:1937-48. 11. Beckwith JB. Wilms’ tumor and other renal tumors of childhood. In: Finegold M , ed. Pathology of neoplasia in children and adults. Philadelphia: W. B. Saunders, 1986;313-32. 12. Beckwith JB. Renal neoplasms of childhood. Sternberg SS, ed. Diagnostic Surgical Pathology. New York: Raven Press, 1989;1331-53. 13. Wigger HJ. Fetal rhabdomyomatous nephroblastoma. A variant of Wilms’ tumor. Hum Pathol 1976;7:613-23. 14. Mahoney JP, Saffos R O . Fetal rhabdomyomatous nephroblastoma with a renal pelvic mass simulating sarcoma botryoides. Am J Surg Pathol 1981 ;5:297-306. 15. Hughson M D , Hennigar G R , Othersen HB J . Cytodifferentiated renal tumors occurring with Wilms’ tumors of the opposite kidneys. Report of two cases. Am J Clin Pathol 1976;66:376-89. 16. Joshi VV, Melczer M M , Amirtham D , Kaur P, Walters T R . Sequential bilateral nephroblastic tumors of different cell types in an infant. Possible effect of chemotherapy versus de nova origin. Cancer 1983;51:2209- 13. 17. Alvarez Silvan AM, Gonzalez del Castillo J , Martinez Caro A, et al. Maturation of Wilms’ tumor pulmonary metastases to benign fibromas after therapy. Med Pediatr Oncol 1984;12:2 18-20. 18. Omar R , Davidian M M , Marcus J R , Rose J. Significance of the “maturation” of metastases from Wilms’ tumor after therapy. J Surg Oncol 1986;33:239-42. Received May 28, 1991 Revisions accepted October 28, 1991

Wilms' tumor after treatment.

Sixty-one Wilms' tumors (WTs) from 59 patients who received preoperative therapy were studied. Twenty-seven WTs from 26 patients who did not receive p...
2MB Sizes 0 Downloads 0 Views