Case of the Month: Kidney

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2013, case 23, and is a congenital mesoblastic nephroma.

The clinicopathologic findings in this patient's case support a congenital mesoblastic nephroma, classical type. Congenital mesoblastic nephroma represents approximately 2-4% of all pediatric renal neoplasms. Ninety percent of these tumors occur within the first year of life and nearly all cases have been reported in children less than 30 months of age. Patients affected typically present with a solitary palpable abdominal mass. Some cases are diagnosed prenatally. Prenatal cases may present with associated features of hydrops fetalis, premature delivery and hydramnios. Other findings that may be encountered in the patient may include hypertension, hypercalcemia, vomiting and hyperreninemia. Patients with congenital mesoblastic nephroma almost always have an excellent prognosis when the tumor has been completely excised. Local recurrence and metastatic tumors may occur in up to 10% of cases. Gross pathologic findings of congenital mesoblastic nephroma typically include tumor, which may measure up to or greater than 10.0 cm. Tumors demonstrate a white-tan and firm cut surface but they also demonstrate areas of hemorrhage, necrosis and cyst formation. Histologically, two types of congenital mesoblastic nephroma are recognized, the cellular type and the classical type. Cellular mesoblastic nephromas account for approximately 60% of all congenital mesoblastic nephroma cases. These tumors are morphologically identical to infantile fibrosarcoma and are characterized by a spindle-shaped tumor cells with scanty cytoplasm, vesicular and bland appearing nuclei, and may demonstrate a high mitotic count. Typically, necrosis and hemorrhage are not identified.

Classical congenital mesoblastic nephroma represents approximately 20% of all congenital mesoblastic nephromas and these tumors are morphologically similar to infantile fibromatosis. The tumors are characterized by interlacing fascicles of fibroblasticappearing cells with thin, tapered, bland-appearing nuclei and minimal eosinophilic cytoplasm. The mitotic count is typically low and there is abundant stromal collagen. These tumors oftentimes have a highly irregular interface with the kidney parenchyma and have fascicles of tumor cells interlacing with renal parenchyma. Another 20% of cases include mixed-type congenital mesoblastic nephroma, those tumors containing histologic features of both cellular and classical congenital mesoblastic nephroma.

Immunohistochemical staining may be helpful in evaluating these tumors. The cells of congenital mesoblastic nephroma are positive for markers of myofibroblasts including actin and vimentin. Desmin is rarely positive. WT1 is also rarely positive in these tumors. Congenital mesoblastic nephroma is typically negative for BCL2, CD34 and pancytokeratin. Cellular mesoblastic nephroma is characterized by recurring cytogenetic abnormalities similar to that identified within infantile fibrosarcoma. This includes a translocation involving chromosomes 12 and 15 as well as trisomy 11. The translocation of 12 and 15 identified within congenital mesoblastic nephromas of the cellular subtype include an ETV6-NTRK3 fusion gene.

The main differential diagnosis of congenital mesoblastic nephroma includes other pediatric renal tumors such as clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, stromal predominant Wilms tumors (monophasic stromal type) as well as metanephric stromal tumors. Clear cell sarcoma of the kidney is a diagnostic consideration in this case; however, most cases of clear cell sarcoma of the kidney present between the ages of 2 and 4 years of age and occurrences within the first year of life are relatively uncommon. This tumor, unlike the congenital mesoblastic nephroma, is a malignant tumor with a propensity for metastasis to bone and recurrence many years after initial diagnosis. Histologically this tumor is characterized by a branching delicate capillary network as well as sheets of tumor cells showing moderate amounts of pale or clear-appearing cytoplasm and ovoid, optically clear nuclei. Immunohistochemistry often demonstrates clear cell sarcoma of the kidney cells negative for actin and desmin. The genetics of clear cell sarcoma of the kidney are not well understood; however, recurring translocations involving chromosome 17p have been reported. Unlike congenital mesoblastic nephroma where resection is often curative, patients with clear cell sarcoma of the kidney must receive combination chemotherapy and/or radiation therapy.

Rhabdoid tumor of the kidney is also a clinical consideration. Rhabdoid tumors of the kidney are rare, accounting for approximately 2% of all pediatric renal neoplasms. Almost all patients with rhabdoid tumor of the kidney are younger than 5 years of age. Unlike congenital mesoblastic nephroma, rhabdoid tumors are characterized by an aggressive clinical behavior. The histology of rhabdoid tumors is distinct from that of congenital mesoblastic nephroma. These tumors are characterized by cells with large vesicular nuclei, prominent nucleoli and paranuclear cytoplasmic globular inclusions representing intracytoplasmic accumulations of vimentin intermediate filaments. Rhabdoid tumors demonstrate immunoreactivity for vimentin and show focal positivity for epithelial membrane antigen. These tumors are negative for INI-1 and tumors demonstrate inconsistent staining patterns with pancytokeratin, S-100 and desmin. Rhabdoid tumors of the kidney are associated with biallelic inactivation of the SMARCB1 (INI1, SNF5) gene located on chromosome 22q11; these genes and co-proteins are a component of the chromatin remodeling complex.

Another diagnostic consideration is monophasic or stromal predominant Wilms tumors. Wilms tumors almost always include other components besides a stromal component, a feature which helps discriminate Wilms tumor from congenital mesoblastic nephroma. Like clear cell sarcoma of the kidney and other pediatric renal tumors, Wilms tumors typically occur in an older age group, peaking between the ages of 2 and 4 years of age. Wilms tumors represent the most common renal tumor of childhood, accounting for up to 85-90% of all pediatric renal tumors. Wilms tumors are derived from nephrogenic blastemal cells that recapitulate stages of the normal developing kidney. The tumor is also known as a nephroblastoma. Like congenital mesoblastic nephroma, patients with Wilms tumors may present with a palpable, nontender abdominal mass. The vast majority of patients with Wilms tumors do well clinically following surgical resection via radical nephrectomy, chemotherapy or both. Metastatic disease may occur and most commonly involves the regional lymph nodes, lung and the liver. Patients with high stage and nuclear anaplasia have unfavorable prognostic features. Most Wilms tumors demonstrate histologic features including triphasic patterns including blastemal, epithelial and stromal components. The stromal component commonly shows smooth muscle and fibroblastic differentiation; however, skeletal muscle, adipose tissue, cartilage, bone, ganglion cells and neuroglial tissue may also be identified in some cases. Immunohistochemistry demonstrates a positive stain for vimentin and CD56 and WT1 stains primitive blastemal and epithelial components. Wilms tumors are associated with mutations of the WT1 gene located on chromosome 11p13. WT1 mutations or genetic alterations are more common in syndromic cases including WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations and mental retardation). Point mutations of WT1 gene are associated with Denys-Drash syndrome. WT1 gene alterations are far less commonly identified in sporadic Wilms tumors.

Metanephric stromal tumors also fall within the differential in congenital mesoblastic nephroma. These cases, however, are extremely rare with fewer than 50 cases having been reported in the literature. The mean age at diagnosis is approximately 24 months; however, the tumor may be encountered from the neonatal period up to age 15 years. Patients with metanephric stromal tumor typically present with an abdominal mass. Some patients have hypertension associated with juxtaglomerular cell hyperplasia. Gross pathologic findings include measuring up to 10.0 cm, well circumscribed and the lesion may have cystic areas. Histologic features show alternating hypocellular and hypercellular regions. The tumor cells are spindled or stellate in shape, have tapered hyperchromatic nuclei and some demonstrate an epithelioid stroma. Angiodysplasia of arterioles within the tumor with expansion and disorganization of the smooth muscle tunica media is the most diagnostic feature in this tumor. Heterologous differentiation may also be encountered including chondroid and primitive neuroectodermal-type cells. Immunohistochemistry demonstrates distinctive findings within this tumor. Tumor shows immunoreactivity for CD34, particularly within regions surrounding entrapped tubules. Desmin is typically negative. Keratins will highlight entrapped renal tubules. S100 stain may be identified in primitive neural elements.

1. Which of the following is false regarding congenital mesoblastic nephroma?
   
   1. The classical type has abundant stromal collagen.
   2. The classical type accounts for 20% of all cases.
   3. The classical type has a characteristic translocation involving chromosomes 12 and 15.
   4. The tumor generally has an excellent prognosis.
   5. The tumor occurs almost exclusively within the neonatal period.
2. Which of the following immunohistochemical stains are positive in the tumors cells of congenital mesoblastic nephroma?
   
   1. BCL2
   2. CD34
   3. Pancytokeratin
   4. Vimentin and actin
   5. WT1
3. Clear cell sarcoma of the kidney may be confused with congenital mesoblastic nephroma in some cases. Unlike congenital mesoblastic nephroma, clear cell sarcoma of the kidney:
   
   1. Contains a characteristic loss of INI1 immunohistochemical staining
   2. Is commonly associated with mutations of WT1 gene
   3. Is considered a benign tumor with no need for chemotherapy or radiation therapy
   4. Shows immunoreactivity for actin
   5. Typically occurs in older children and is associated with a propensity for bony metastases

1. Murphy, W.M., Grignon, D.J., Perlman, E.J. Tumors of the Kidney, Bladder and Related Urinary Structures. AFIP Atlas of Tumor Pathology, Series 4, American Registry of Pathology, 2004.
2. Zhou, M., Netto, G.J., Epstein, J.I. Uropathology. Philadelphia, PA: Elsevier; 2012.

2013
Noel Brownlee, MD, PhD
Surgical Pathology Committee
Bon Secours Saint Francis Health System
Greenville, SC 

1. The classical type has a characteristic translocation involving chromosomes 12 and 15 (c). 
2. Vimentin and actin (d). 
3. Typically occurs in older children and is associated with a propensity for bony metastases (e).