Case 2 -

Stage IV Favorable Histology Wilms Tumor Robert B. Fraser IWK Health Centre Halifax, Nova Scotia, Canada

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Clinical History A 6-year-old boy presented with a one-week history of intermittent abdominal pain and abdominal swelling. There were no other constitutional symptoms except for a suspicion of weight loss. Physical examination and ultrasound revealed a large firm left-sided abdominal mass arising from the kidney. Past medical history was unremarkable with no significant family history or associated dysmorphic features. Chest x-ray shows distinct pulmonary nodules, chest and abdominal CT confirms the presence of pulmonary nodules (multiple) and a large left-sided renal mass. Possible hilar lymph node involvement was present but there was no evidence of tumor in the renal vein or IVC. Two lesions were also visible in the right kidney. Ultrasound confirms the mass arising from the left kidney. Doppler of the vessels shows no evidence of tumor in the renal vein. He was admitted for a left nephrectomy. Case 2 - Figure 1 Case 2 - Figure 2 Case 2 - Figure 3 Case 2 - Figure 4 Case 2 - Figure 5 Case 2 - Figure 6 Gross Examination A left nephrectomy and adrenalectomy were performed. The kidney/tumor weighed 1254 grams and the tumor measured 13 x 13 x 10 cm. The surface of the specimen demonstrated no tumor extension. The specimen was inked and bisected. On the cut surface the tumor mass was in the lower medial pole with expansion and compression of the residual upper/lateral pole. The tumor demonstrated areas of myxoid change and hemorrhagic necrosis. The renal pelvis and calyx were grossly involved with tumor. The renal artery, vein and ureter resection margins were negative for gross tumor. The adrenal gland was unremarkable. Histologic Findings Sections of the tumor showed a classic triphasic Wilms tumor with extensive myoblastic differentiation with striated skeletal muscle strap-like cells. Many of the myoblastic cells demonstrated enlarged and hyperchromatic nuclei complicating the evaluation for the presence or absence of anaplasia. Multiple hilar lymph nodes showed a predominance of undifferentiated blastemal tumor component. Resection margins for the ureter, renal artery and vein were negative for tumor. Paraortic lymph nodes showed sinus histiocytosis with no metastatic tumor identified. Cytogenetic Results Chromosome analysis of the tumor with G-banding revealed an abnormal male karyotype in which all 10 metaphase cells examined had a hyperdiploid karyotype with a modal chromosome number of 57 due to a gain of chromosomes 7, 8, 12, 17, 21, two additional copies of chromosomes 13 and 20 and two unidentified marker chromosomes. One of the marker chromosomes is acquired and is comprised, in part, of the long arm of chromosome 1 resulting in a gain of 1q. The remainder could not be identified with certainty. Hyperdiploidy is a common cytogenetic abnormality in Wilms tumor with frequent gains of chromosomes 6, 7, 8, 12, 13, 17 and 20. Unbalanced translocations generating a gain of 1q are a common structural abnormality. Diagnosis Stage IV favorable histology Wilms tumor (Table 1) Clinical History Continues This young boy was treated with NWTS chemotherapy protocol DD4A (doxorubicin, actinomycin and vincristine) with local radiotherapy to his lungs and left flank. Thirty months after his initial diagnosis, he presented with a 6-week history of limp and x-rays demonstrated a lytic lesion in the proximal right tibia. Bone scan and MRI showed an extensive lesion of his proximal tibia. He had no distant skeletal disease. CT of the chest, abdomen and the pelvis showed no local recurrence or pulmonary metastasis. A biopsy of the leg lesion was undertaken. Histologic Findings in the Bone Biopsy Sections of trabecular bone showed focal areas of devitalization and remodeling. The marrow was replaced by a fibrous stroma containing nests of cells demonstrating extensive crush artifact. In areas better preserved and with less crush artifact, neoplastic cells demonstrated eccentric pleomorphic and hyperchromatic nuclei with eosinophilic cytoplasm. No cross striations were noted. The cells appeared discohesive with no obvious alveolar architecture. Immunohistochemical staining demonstrated the neoplastic cells to show positive cytoplasmic staining for WT1, desmin, actin, and vimentin with positive nuclear staining for MyoD1 and myogenin, while staining negatively for keratin, CD 1a, and CD 99. Second Diagnosis Biopsy, right proximal tibia: Most consistent with metastatic Wilms tumor. Discussion During the evaluation of the tibial lesion, the original Wilms tumor (WT) and the bony lesion were submitted to COG for central review. The consensus was that the original left nephrectomy specimen demonstrated unequivocal triphasic WT with abundant skeletal muscle differentiation. Histologically, in the areas of myoblastic differentiation, tumor cells demonstrated enlarged hyperchromic nuclei. These features, however, were not accompanied by atypical or multipolar mitotic figures. Also of significance was the fact the tumor within the lymph nodes did not have this histological appearance, but instead was mostly blastemal. The bone tumor also did not histologically have this atypical appearance. The relapsed tumor to the right tibia was determined to be metastatic WT with rhabdomyomatous differentiation. The differential diagnosis at the time included a rhabdomyosarcoma arising from his WT, a second primary notably rhabdomyosarcoma arising from bone or a small cell osteogenic sarcoma. The secondary development of a rhabdomyosarcoma within a WT is extraordinarily rare and since the 1960s fewer than 5 such cases can be documented (personal communication). In all of these cases there was a WT, and within the WT a homogeneous mass developed and behaved differently and outstripped the growth pattern of the WT. For our original WT, there is no evidence of such a separate tumor. Anaplastic sarcomas of the kidney with polyphenotypic features have also been reported. Histologically they are composed of spindle cells containing either multiple foci or diffuse, widespread anaplastic changes with bizarre pleomorphic cells and very atypical mitotic figures. None of these histological features were present in either our nephrectomy or bone biopsy specimens. With respect to the bone lesion, it was difficult to evaluate histologically because of the extensive crushed artifact. It was evident however this metastatic deposit was composed of embryonal neoplastic cells showing muscle differentiation with positive cytoplasmic WT-1 and desmin and nuclear myogenin and Myo-D staining. The pattern of immunohistochemical staining was identical to that of the patient's previous WT. Another possibility was that this boy had developed a second primary rhabdomyosarcoma involving the bone. In the absence of a cancer predisposition syndrome this would be an extremely rare event for a patient to present with two separate primaries. Small cell osteogenic sarcoma could be a ruled out based on the convincing demonstration of skeletal muscle differentiation as well the lack of histologic evidence to support malignant osteoid formation. Regarding this boy's therapy, it was recognized that this was a high-risk relapsed given his previous stage of disease and treatment. Another issue regarded local control measures. It is recognized that WT is a radiosensitive tumor and, therefore, radiation therapy was recommended. The prognosis for recurrent WT is approximately 50% event free survival. Response is typically an important indicator but this would be difficult to measure given that there is really no soft tissue component to examine and that the bony lesion will be difficult to assess in terms of response. Also, rhabdomyomatous differentiated WT tends to shrink in response to chemotherapy. It was recommended additional chemotherapy would include 6 cycles of ICE (ifosfamide, carboplatin and etoposide) plus local radiotherapy without further surgery. WT is also known as nephroblastoma. It constitutes the prototypical example of a neoplastic process that faithfully recapitulates embryogenesis at both morphologic and molecular levels. WT are seen primarily in infants, 50% of the cases occurring before the age of 3 years, 90% before the age of 6 years and 98% of cases occur in individuals under 10 years of age, although presentation in adulthood has been reported. The mean age at diagnosis is 37 and 43 months for males and females respectively. There is no striking sex predilection and tumors occur with equal frequency in both kidneys. There is variation in the incidence among different racial groups indicating a genetic predisposition for this tumor is likely. WT comprise more than 80% of renal tumors of childhood (Table 2). It affects 1 in every 8000 children with approximately 500 cases diagnosed annually in the United States. Presently, because of accurate diagnostic criteria, stage and histology-based therapeutic stratifications, the overall cure rate for WT in 2000 is now over 90%. The classic location for WT is the kidney, however, cases with the typical morphologic features of WT have been reported in extra renal sites, including the retroperitoneum, sacrococcygeal region, testis, uterus, inguinal canal, and mediastinum. Several dysmorphic syndromes are associated with a high risk of developing this neoplasm. Approximately 10% of WT develop in association with one of several well characterize dysmorphic syndromes. Conditions associated with an increased risk of WT are WAGR syndrome (WT, aniridia, genitourinary malformations, mental retardation), Beckwith-Wiedemann syndrome (hemihypertrophy, macroglossia, omphalocele and visceromegaly) and Denys-Drash syndrome (mesangial sclerosis, and pseudohermaphroditis). The WAGR syndrome carries a 30% risk of developing WT. These patients have a consistent deletion of chromosome 11p13 in their somatic cells involving the WT1 gene. WT1 encodes a zink finger transcription factor that plays a major role in renal and gonadal development. Abnormalities involving WT1 are consistently found in the tumors of WAGR patient's as well as in patients with Denys-Drash syndrome. WT has also been encountered in association with other malignancies, such as osteosarcoma, botryoid rhabdomyosarcoma, retinoblastoma, hepatocellular carcinoma and neuroblastoma. The most common sites of metastasis are regional lymph nodes, lung and liver (the 3 L's). Spread to other organs is rare even in advanced cases. In WT, metastases to bone is exceedingly rare. In the first and second National Wilms Tumor Study (NWTS), 13 among 76 patients developed skeletal metastases, and in 7 of these 13, the skeleton was the first site of dissemination of tumor. Clear cell sarcoma constituted the particular histological pattern in these 13 cases. In our case, neither the clear cell nor anaplastic sarcoma pattern was identified in the primary WT or in the metastasis. Anaplasia was also not identified. In an attempt to differentiate the possibility that this patient had developed a rhabdomyosarcoma involving the bone (with or without an origin from the original WT) it was recommended that microarray samples be sent from the original tumor and from the recurrence to further examine the possibility of an underlying rhabdomyosarcoma profile. If the microarray genetic analysis were consistent with WT, further therapy would include the 6 cycles of ICE chemotherapy plus local radiotherapy without further surgery. If the findings were more consistent with rhabdomyosarcoma, additional chemotherapy and surgery may have to be entertained. Table 1: Staging of Pediatric Renal Tumors Stage I Tumor limited to the kidney and completely resected Intact renal capsule No previous tumor or biopsy Renal sinus vessels not involved No evidence of tumor at or beyond the margins of resection Stage II Tumor completely resected No evidence of tumor at or beyond the margins of resection Tumor extends beyond the kidney, as evidenced by one of the following: Penetration of the renal capsule, or Extensive invasion of the soft tissue of the renal sinus, or Blood vessels outside the renal parenchyma, including those of the renal sinus, containing tumor, or The tumor was biopsied (except for fine needle aspiration) during surgery prior to removal of kidney Stage III Residual non-hematogenous tumor confined to the abdomen is present, as evidenced by the following: Involvement of lymph nodes within the abdomen or pelvis, or Penetration through the peritoneal surface, or Tumor implants on the peritoneal surface, or Tumor present at the margin of surgical resection, or Tumor not resectable because of local infiltration into the vital structures, or Tumor spillage of any degree or localization occurring before or during surgery, or Tumor removed in greater than one piece Stage IV Hematogenous metastasis (lung, liver, bone, brain, etc.) Lymph node metastasis outside the abdomino-pelvic region Stage V Bilateral renal involvement at diagnosis Each side should be separately staged according to the above criteria Table 2: Pediatric Renal Tumors Nephroblastic Tumors Nephroblastoma (Wilms tumor) Favorable histology Anaplasia, diffuse or focal Nephrogenic rests or Nephroblastomatosis Cystic Nephroma and Cystic Partially Differentiated Nephroblastoma Mesonephric Tumors (adenoma, adenofibroma, stromal tumor) Mesoblastic Nephroma (cellular, classic, mixed) Clear Cell Sarcoma Rhabdoid Tumor Renal Epithelial Tumors of Childhood Clear cell renal tumors RCC with Xp11.2 (TFE3) translocations Conventional RCC Others Papillary renal cell carcinoma Renal medullary carcinoma Oncocytic renal neoplasms following neuroblast Other Microscopic Features of WT Blastemal patterns in Wilms tumor Diffuse blastemal pattern Organized blastemal pattern Serpentine blastema Nodular blastema Basaloid blastema Epithelial patterns in Wilms tumor Patterns or cells resembling nephrogenesis Tubular Glomeruloid Papillary Transitional Heterologous cell types Mucinous cells Squamous cells Neural cells Neuroendocrine cells Stromal cells in Wilms tumor Neuroglial cells Osteoid Cartilage Smooth muscle Skeletal muscle Adipose cells Fiberglass, myofibroblast Myxoid Undifferentiated References: Chevalier G, Yeger H, Martinerie C, Laurent M, Alami J, Schofield PN, Perbal B. novH: Differential expression in developing kidney and Wilms' tumors. 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Society for Pediatric Pathology Short Course, San Diego, CA, March 24-25, 2007.