Case 195 - Discussion

Uploaded: 2008-03-18, Updated: 2008-04-06

 

Wilm's Tumor (Nephroblastoma)

The Key Features

  • Triphasic patterns (blastemal, stromal, and epithelial cell types), favorable histology;

  • WAGR syndrome (del(11p13), WT1), Beckwith-Wiedemann syndrome (WT2, 11p15), Hemihypertrophy, Denys-Drash syndrome (WT1, 11p13); Familial nephroblastoma (FWT1, 17q12-21; FWT2, 19q13.3-13.4);

  • Unfavorable histology, diffuse nuclear atypia.

CLINICAL FEATURES

  • Malignant embryonal neoplasm derived from nephrogenic blastemal cells;

  • Most common genitourinary cancer in children, ~1/8,000 children, ~400 new cases each year in the US;

  • Slight higher incidence in girls, male to female ratio of 0.6-0.9 to 1.0;

  • Mean age at diagnosis, 36 and 42 months for males and females, respectively. 98% of cases occur in individuals under 10 years of age. Rarely occur in adults;

  • ~10% of nephroblastomas are associated with some well-characterized dysmorphic syndromes: WAGR syndrome (Wilms' tumor, aniridia, genitourinary malformation, mental retardation), 30% risk of developing a nephroblastoma, consistent somatic del(11p13) that encodes WT1; Beckwith-Wiedemann syndrome (WT2, 11p15); Hemihypertrophy; Denys-Drash syndrome (WT1, 11p13); Familial nephroblastoma (FWT1, 17q12-21; FWT2, 19q13.3-13.4);

  • Synchronous multicentric masses in a single kidney and bilateral primary lesions are observed in 7% and 5% of cases;

  • Most common clinical presentation: presence of an abdominal mass. Abdominal pain, hematuria, hypertension, and symptoms related to traumatic rupture are also common;

  • Imaging usually reveals one or more intrarenal sharply demarcated and heterogeneous masses.

GROSS FINDINGS

  • Usually solitary, round, capsulated and sharply demarcated with a lobulated appearance due to prominent septa;

  • Cut surface: uniform, pale, gray or tan and soft. The mature stromal elements are usually firm and whorled;

  • Often cystic changes, hemorrhage and necrosis;

  • Commonly local extension into the renal vein and metastases to regional lymph nodes.

MICROSCOPIC FINDINGS

  • Triphasic patterns, blastemal, stromal, and epithelial cell types at various proportions;

  • Blastemal Component: present in most cases and may be the only element. Arranged in serpentine, nodular, basaloid or diffuse pattern. Blastemal cells: small, closely packed with minimal differentiation and scant cytoplasm; usually rounded or polygonal but may be slightly elongated; small and regular nuclei with evenly distributed, slightly coarse chromatin and small nucleoli; indistinct cell borders and prominent overlapping of nuclei. Mitotic figures are numerous in most specimens;

  • Epithelial Component: present in most nephroblastomas. Several different patterns:

    • Primitive rosette-like structures, tubular or papillary elements that recapitulate various stages of normal nephrogenesis;

    • Glomerular structures may closely resemble those of normal kidneys;

    • Foci of more mature cells with low mitotic rates and increasing cytoplasm, particularly following therapy;

    • Heterologous epithelial differentiation: most commonly mucinous and squamous epithelia, and occasionally ciliated epithelium;

  • Stromal Component: myxoid and spindle cells resembling embryonic mesenchyme in nearly all specimens, and form the matrix for most of the blastemal and epithelial foci. Smooth muscle and fibroblasts may be present with variable degrees of differentiation. Skeletal muscle is the most common heterologous stromal cell type. More primitive myoblastic elements can also be found, including the condensed mesenchyme characteristic of the cambium layer of botryoid embryonal rhabdomyosarcoma;

  • Other stromal differentiation: adipose tissue, cartilage, osteoid, mature ganglion cells, and neuroglial tissue. This heterogeneity may be so prominent as to suggest a teratoma.

  • Nuclear anaplasia:

    • Extreme nuclear atypia and hyperchromasia rather than to a lack of cellular differentiation;

    • Histologic Criteria for Anaplasia: multipolar polyploid mitotic figure, and nuclear enlargement with hyperchromasia;

    • Focal anaplasia: presence of one or a few sharply localized regions of anaplasia within a primary tumor, and the remaining majority of the tumor contain no significant nuclear atypia.

DIFFERENTIAL DIAGNOSES

  • Neuroblastoma:

    • Elevated levels of catecholamine metabolites, and stippled calcification on imaging studies;

    • Grossly, neuroblastomas lack of circumscription and fibrous capsule, much more hemorrhage, and widespread metastases;

    • Histologically, neuroblastomas display invasive growth pattern, prominent nesting of tumor cells, prominent hemorrhage, non-overlapping nuclei with coarse "salt and pepper" chromatin, and classic Homer-Wright rosette;

  • Primitive neuroectodermal tumors (PNETs):

    • Wider age;

    • Grossly poorly circumscribed without fibrous capsule;

    • Microscopically, primitive round cells with variable rosette formation and non-overlapping nuclei;

    • Positive MIC2 antigen (CD99) and FLI1, negative WT1;

    • Presence of  t(11;22) (q24;q12).

IMMUNOHISTOCHEMISTRY AND SPECIAL STAINS

  • WT1 protein, confined to the nucleus, variable and correlate with tumor histology;

  • Bastemal cells regularly express vimentin and maybe neuron-specific enolase, but other differentiation markers are usually absent.

CYTOGENETIC STUDIES

Syndromes Associated with Highest Risk of Nephroblastoma

Other Conditions Associated with Nephroblastoma

  • Wilms-aniridia-genital anomaly-retardation (WAGR) syndrome (WT1, 11p13)

  • Beckwith-Wiedemann syndrome (WT2, 11p15)

  • Hemihypertrophy

  • Denys-Drash syndrome (WT1, 11p13)

  • Familial nephroblastoma (FWT1, 17q12-21; FWT2, 19q13.3-13.4)

  • Frasier's syndrome (WT1, 11p13)

  • Simpson-Golabi-Behmel syndrome (GPC3, Xq26)

  • Renal or genital malformations

  • Cutaneous nevi, angiomas

  • Trisomy 18

  • Klippel-Trenaunay syndrome

  • Neurofibromatosis

  • Bloom's syndrome

  • Perlman's syndrome

  • Sotos' syndrome

  • Cerebral gigantism

TREATMENT AND PROGNOSIS

  • Most tumors in the favorable group are highly responsive to chemotherapy. The prognosis is not affected by tumor size or weight. The overall 4-year survival rate for patients with favorable histology nephroblastomas of all stages approaches 90%. The most significant unfavorable prognostic factors are age at detection, high stage, and unfavorable histology (presence of nuclear anaplasia).

  • Dactinomycin and vincristine are the most effective drugs for most patients with favorable histology tumors and are now in standard use around the world. These drugs are used in conjunction with surgery, without radiotherapy, for all patients with stage I and II lesions with favorable histology. Radiotherapy and more toxic chemotherapeutic agents are reserved for patients with stage III and IV disease

REFERENCES

  • AFIP, tumor of the kidney, bladder and related urinary structures, series 4;