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Understanding the risk of Wilms Tumor in hemihypertrophy: Are we halfway there?

DII small banner By Warren R. Heymann, MD
Nov. 16, 2017

Diffuse capillary malformation with overgrowth. A 2-month-old girl with ill-defined erythematous patches of the bilateral upper extremities, posterior trunk, and left lower extremity. There is also overgrowth of the left lower extremity.
Credit: JAAD

Wilms tumor (WT, nephroblastoma) is the most common pediatric renal cancer, characteristically found in children younger than 5 years old. When should dermatologists be concerned?

WTs are thought to develop from persistent metanephric tissue or nephrogenic rests. Abdominal pain is the most common presenting symptom followed by hypertension and hematuria. (1)
Hemihypertrophy, also known as hemihyperplasia, is genetically heterogeneous, including genomic abnormalities seen in Beckwith-Wiedemann syndrome (macrocephaly, macroglossia, gigantism, a centrofacial capillary malformation, and tumor development), as well as mosaic chromosome or genomic abnormalities, and somatic point mutations. Somatic mutations affecting the P13K-AKT-mTOR pathway result in segmental overgrowth and other physical findings. (2)

Due to significant differences in the clinical presentations among patients, the umbrella term of “PIK3CA-Related Overgrowth Spectrum (PROS)” has been proposed to encompass all patients with somatic PIK3CA mutations and overgrowth. Somatic mutations in PIK3CA are associated with many asymmetric overgrowth disorders, including macrodactyly, facial infiltrating lipomatosis, Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, fibroadipose hyperplasia, Klippel–Trenaunay syndrome, and various megalencephaly syndromes including megalencephaly capillary malformation syndrome and hemimegalencephaly. (3)
Although the association of WTs with overgrowth syndromes is well-known, the actual risk of tumor development, and recommendations for screening are debatable. Abraham based his screening recommendations after citing a study of 168 children with isolated hemihyperplasia, where 10 tumors developed in nine children (one child developed two tumors). Of these, six were WTs, two were adrenal cell carcinoma, and there was one each of hepatoblastoma and leomyosarcoma of the small bowel. Follow up protocols varied in different centers. Two children, an infant and a 5-year-old, developed WTs at nine months and five months respectively, after their previous abdominal ultrasound scans. This led the investigators to conclude that six months may be too long of a screening interval, especially in early childhood. He concluded that from the available evidence, the risk of tumor development in isolated hemihyperplasia is about 1 in 20 (approximately 5%). His recommendation was that these children have abdominal ultrasound scans at three monthly intervals until the age of 6 years. There was insufficient evidence to screen children above 6 years of age. (4)
According to Gripp et al, the risk of tumorigenesis, including WT, in patients with isolated hemihyperplasia ranges from 3.3 to 6%. Very few patients with hemihyperplasia due to somatic PIK3CA mutation have been reported, but have included CLOVES syndrome and the MCAP (megalencephaly-capillary malformation) syndrome. Three patients with PROS and WT had somatic mutations affecting PIK3CA codon 1047, which is associated with oncogenicity in isolated cancers. For isolated hemihyperplasia, their screening recommendations are the same as for Beckwith-Wiiedemann syndrome — abdominal ultrasounds every 3 months until age 4 years; every 6 months until age 7; then annually thereafter. (2)

Peterman et al evaluated the frequency of Wilms tumor in patients with 2 similar conditions: diffuse capillary malformation with overgrowth (DCMO) and macrocephaly-capillary malformation (M-CM). Through their Vascular Anomalies Center database, they retrospectively studied 89 patients: 67 with DCMO, 17 with M-CM, and 5 with an indeterminate diagnosis. No case of Wilms tumor was found in these groups. Patients with DCMO did not appear to be at increased risk for Wilms tumor. Although there were no cases their cohort, they noted that there are 2 reports of M-CM associated with Wilms tumor in the literature. The authors concluded that screening is probably unnecessary in DCMO unless there is associated hemihypertrophy. (5)

In my opinion, the most important word in their conclusion is “probably.” We are currently in a “hemi” state of knowledge. As we move from the impossible morass of syndromal clinical acronyms, many of which have overlapping features, to precise molecular signatures, we will know exactly who is at risk and who should be screened for WTs.

1. Leslie SW, Bhimji SS. Cancer, Wilms (Nephroblastoma). StatPearls [Internet]. Treasure Island (FL). StatPearls Publishing 2017 Jul 1.
2. Gripp KW, et al. Nephroblastomatosis or Wilms tumor in f fourth patient with somatic PIK3CA Am J Med Genet A 2016; 170: 2559-69.
3. Yeung KS, et al. Somatic PIK3CA mutations in seven patients with PIK3CA-related overgrowth spectrum. Am J Med Genet A 2017; 173: 978-84.
4. Abraham P. What is the risk of cancer in a child with hemihypertrophy? Arch Dis Child 2005; 90: 1312-3.
5. Peterman CM, et al. Wilms tumor screening in diffuse capillary malformation with overgrowth and macrocephaly-capillary malformation: A retrospective study. J Am Acad Dermatol 2017; 77: 874-8.

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