After reading the summary, try answering the three related multiple-choice questions below.
A 4-year-old boy presented with abdominal pain following a fall on the playground, and was found to have a large retroperitoneal mass arising from the left kidney. Left nephrectomy and lymph node sampling were performed. The 535 g kidney showed a 10.0 cm soft pale tan mass in the upper pole associated with subcapsular hemorrhage. All lymph nodes were negative for tumor.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2010, case 13, and is a Wilms tumor, favorable histology.
Criteria for Diagnosis and Comments:
Sections of the renal tumor show a neoplasm composed predominantly of primitive small cells (blastema), admixed with intervening bands of loose fibroconnective tissue (stroma) and occasional primitive tubular structures (epithelium), forming the classic triphasic pattern of nephroblastoma (Wilms tumor). There is no evidence of anaplasia in this tumor, and it is therefore classified as “favorable histology”. No nephrogenic rests were identified in the remainder of the kidney.
Described by Max Wilms in 1899, Wilms tumor (nephroblastoma) is the most common primary malignant tumor of the kidney in children. While it rarely occurs in adults, the peak incidence is in young children (average age, 3-4 years). Approximately 500 cases are diagnosed annually in the United States. Wilms tumor most often presents as a painless abdominal mass palpated by a caregiver or pediatrician. Less commonly, abdominal pain following trauma is produced by hemorrhage of the mass and stretch of the renal capsule. Unlike renal cell carcinoma, hematuria and systemic hypertension are unusual modes of presentation for Wilms tumor.
Typically, Wilms tumors has a classic triphasic morphology, although in some cases only one or two of these components are present, for example in the “blastema-predominant” variant composed only of the primitive round cell component, or in the “epithelial-predominant” variant mimicking metanephric adenoma. The epithelial component is typically formed by hyperchromatic primitive-appearing tubules and less commonly, small glomeruloid structures. Mesenchymal differentiation within Wilms tumors is prominent in some cases, particularly smooth muscle or skeletal muscle elements. Fat, cartilage, osteoid, squamous or glandular epithelium, and glial elements are also reported.
Histologic classification of Wilms tumor is generally divided into two types: Unfavorable histology (tumors with focal or diffuse anaplasia) and Favorable histology (tumors with no anaplasia). Anaplasia is defined as presence of markedly enlarged hyperchromatic nuclei (3x greater in size than other tumor nuclei) and presence of atypical multipolar mitoses, both of which are changes typically seen at screening magnification. Diffuse anaplasia is defined as presence of anaplastic cells in multiple different fields of the primary tumor or in a metastatic site, whereas focal anaplasia refers to presence of anaplastic cells in one or only a few discretely localized foci. This distinction between focal and diffuse anaplasia warrants documentation or “mapping” of the site of sampling of tissue blocks in order to determine proximity of anaplastic fields submitted in separate blocks.
Variants of Wilms tumor include the rhabdomyoblastic , blastemal-predominant, epithelial-predominant, teratoid, cystic variant, and cystic, partially differentiated nephroblastoma (CPDN). CPDN is characterized by microscopic foci of Wilms tumor within fibrous septations in a grossly cystic tumor. Gross identification of solid nodules within a cystic neoplasm warrants a diagnosis of cystic Wilms tumor rather than CPDN.
The staging system for Wilms tumor and other renal tumors of childhood (except renal cell carcinoma) is described as follows (adapted from Perlman 2005);
|Stage I||Tumor confined to the kidney and completely resected.|
|Stage II||Tumor extends beyond the kidney (penetration of the renal capsule, extrarenal vascular invasion, extensive renal sinus invasion), but completely resected.|
|Stage III||Residual abdominal disease after surgery (positive surgical margins, positive abdominopelvic lymph nodes, tumor rupture/spillage, peritoneal implants, unresectability due to invasion of vital structures, tumor biopsy prior to resection).|
|Stage IV||Tumor with distant metastasis (hematogenous or lymph nodes outside the abdomen and pelvis).|
|Stage V||Bilateral tumors; Each side is separately staged.|
Challenges in accurate staging include assessment of the renal sinus, evaluation of true vascular invasion versus artifactual “carry-over” spread of tumor within vessels, and assessment of invasion beyond the renal capsule. True vascular invasion is characterized by tumor filling and/or distending the vessel lumen. Small aggregates of tumor admixed with blood within vascular lumens should be interpreted with caution and is generally insufficient to upstage the tumor. Extensive soft tissue invasion within the renal sinus is thought to reflect either direct extension beyond the kidney or vascular invasion with overgrowth and replacement of the vessel wall.
Because Wilms tumors typically produce a thickened fibrous pseudocapsule, assessment of renal capsular invasion can prove difficult when the tumor pseudocapsule and renal capsule have merged and fused. Assessment of the renal capsule is facilitated by sections submitted at the peripheral interface of the tumor and adjacent non-neoplastic kidney, allowing assessment of whether the tumor transgresses the plane of the renal capsule. Sampling of tissue sections for microscopic examination should favor both the renal sinus (including intrarenal extensions) as well as the periphery of the tumor. The peripheral sections enhance detection of nephrogenic rests and also allow evaluation of the renal capsule and soft tissue margins. Invasion into the pelvic-calyceal system or ureter does not affect tumor staging.
Approximately 90% of Wilms tumors are sporadic, while a minority are associated with syndromes and/or mutations in the tumor suppressor genes WT1 (chromosome 11p13) or WT2 (chromosome 11p15). Syndromes associated with Wilms tumor include WAGR (Wilms tumor-Aniridia-Growth Retardation), Denys-Drash syndrome (Wilms tumor, mesangial sclerosis, gonadal dysgenesis), Beckwith-Wiedemann syndrome (Wilms tumor predilection, organomegaly, hemihypertrophy of extremities, omphalocele, and other anomalies), Simpson-Golabi-Behmel syndrome (Wilms tumor predilection, facial overgrowth, congenital anomalies), and isolated hemihypertrophy.
Nephrogenic rests are benign pre-neoplastic lesions associated with Wilms tumor in some cases. Detection of nephrogenic rests typically prompts screening and follow-up of the contralateral kidney due to the risk of multifocality and/or metachronous tumor formation. Hyperplastic nephrogenic rests are typically wedge-shaped and interdigitate microscopically with adjacent renal tubules, whereas incipient Wilms tumor nodules are typically spherical and have a capsule separating the tumor from the surrounding kidney. The difficulty in distinguishing a hyperplastic “adenomatous” nephrogenic rest from a small epithelial-predominant Wilms tumor is well-recognized. Accurate distinction requires examination of the edge of the lesion, and cannot be accurately distinguished by needle biopsy.
Therapy for Wilms tumor is dependent on age, stage, and genetic prognostic markers. In the current Children’s Oncology Group treatment protocols widely used in North America, infants (less than 2 years of age) with relatively small stage I Wilms tumors (kidney weight less than 550 grams) may be treated with surgery alone. Most other tumors are treated with primary nephrectomy followed by adjuvant combination chemotherapy (vincristine/actinomycin for Stage I and II; plus doxorubicin for Stage III and IV). Favorable histology Wilms tumors (FHWT) with loss of heterozygosity for chromosomes 1p and 16q (5% of FHWT) receive more aggressive therapy at all stages, including the addition of doxorubicin for Stage I and Stage II tumors, as well as cyclophosphamide and etoposide for Stage III and IV tumors. Radiation therapy is also used for Stage III and Stage IV tumors. Bilateral Wilms tumor, syndromic patients with unilateral Wilms tumor, and patients with diffuse hyperplastic perilobar nephroblastomatosis receive pre-operative chemotherapy (vincristine, actinomycin, doxorubicin) followed by nephron-sparing surgery. Anaplastic (unfavorable histology) Wilms tumors are treated more aggressively and are stratified on treatment protocols depending on presence of focal versus diffuse anaplasia. The overall survival for patients with Wilms tumor is now approximately 90%.
The differential diagnosis of Wilms tumor includes other primary renal tumors of childhood, including malignant rhabdoid tumor, congenital mesoblastic nephroma (classic and cellular variants), clear cell sarcoma of the kidney, and renal cell carcinoma. Other diagnostic considerations include other small cell tumors of the kidney (synovial sarcoma, primitive neuroectodermal tumor of the kidney, desmoplastic small round cell tumor, neuroblastoma, lymphoma) and a variety of benign tumors (cystic nephroma, infantile ossifying tumor of the kidney, oncocytoma, and others). Wilms tumor is distinguished from other malignant renal tumors of childhood by both cytologic and architectural features. Congenital mesoblastic nephroma is a spindle cell lesion of variable cellularity, morphologically resembling fibroma or fibrosarcoma, and has an irregular interface with the adjacent non-neoplastic kidney, in contrast to the well-circumscribed tumor pseudocapsule of Wilms tumor. Rhabdoid tumor is composed of sheets of monotonous discohesive cells with eosinophilic cytoplasm, round eccentric nuclei, and prominent nucleoli. Loss of nuclear INI1 expression by immunohistochemistry is an important diagnostic feature of malignant rhabdoid tumors and distinguishes it from Wilms tumor. Clear cell sarcoma of the kidney is characterized by hypercellular sheets of ovoid to spindled cells and may mimic Wilms tumor, particularly on frozen section. Clear cell sarcoma is distinguished by a “chickenwire” vascular architecture and cells with clearing of the nuclear chromatin. Renal cell carcinoma occurs rarely in children and is easily distinguished from Wilms tumor by the clear cell or papillary morphology and the lack of blastemal and stromal elements.