Histologically, the cellular variant of CMN is very similar to another rare tumor of infancy, infantile fibrosarcoma (IFS), a malignant tumor of fibroblasts. In fact, it is likely that cellular CMN represents a visceral form of IFS[
7] (and the classic histiotype, the renal analogue of infantile fibromatosis of soft tissue)[
8]. In addition, both tumors share a similar biologic phenotype, with a generally benign clinical course and exquisite sensitivity to chemotherapy. In fact, because both are so highly responsive to chemotherapy, initially unresectable tumors are often pre-treated with neoadjuvant chemotherapy prior to resection.[
9] Although most IFS are treated at presentation, spontaneous regression has been reported. Madden et al described a case of a two week old with an IFS in the upper extremity which would have required amputation at the elbow for complete resection. The tumor was observed and by age 7 months the tumor was no longer palpable. By four years of age, the child was without evidence of disease.[
10] Ours is the first report to describe partial regression of an untreated cellular variant of CMN, further highlighting the similarity between these two tumor types.
In addition to the histologic and biologic similarities, these tumor types share cytogenetic abnormalities, both being associated with polysomies for chromosomes 8, 11, 17 and 20,[
11,
12] as well as translocation t(12;15)(p13;q25).[
7,
13] This translocation fuses the
ETV6 (also known as
TEL) gene on the short arm of chromosome 12 to
NTRK3 (also known as
TRKC) on the long arm of chromosome 15. This results in an ETV6-NTRK3 gene fusion product which contains the helix-loop-helix protein dimerization domain of
ETV6 (amino-terminal end) fused to the kinase domain of
NTRK3 (carboxyl-terminal end). [
13]
ETV6 is a transcription factor originally characterized as an oncogene in several types of leukemias and myeloproliferative syndromes.[
14,
15]
ETV6 translocations can include a number of partners, often tyrosine kinases, such as
NTRK3. [
14,
15] NTRK3 is a member of the neurotrophic tyrosine kinase receptor (NTRK) family of receptor protein tyrosine kinases (PTK) and binds neurotrophin 3 with high affinity, leading to receptor dimerization and autophosphorylation of PTK tyrosine residues.[
16] These residues then serve as anchors for downstream signal transduction molecules. The oncogenic mechanism of ETV6-NTRK3 involves ETV6 HLH-mediated dimerization, resulting in constitutive, ligand-independent, NTRK3 tyrosine kinase activity.[
17] Thus, dysregulated NTRK3 tyrosine kinase activation, mediated by the
ETV6 promoter, is likely important in CMN and IFS oncogenesis, perhaps as the initial transforming event.[
7]
As the standard treatment for both tumors is immediate surgical resection, there have been few opportunities to study their natural history. We have presented the case of a child who did not have immediate surgical resection and whose tumor was untreated for 8 months. During that time, the tumor demonstrated significant regression allowing for subsequent complete surgical resection. The contributions of the intercurrent infections and surgical manipulation to the evolution of this tumor are uncertain. Tumor biopsy can lead to hemorrhage, increased intratumoral pressure and subsequent ischemic necrosis, and vaso-occlusive changes were seen in the resected specimen. Nevertheless, the shared translocation with IFS, a tumor with well-documented potential for spontaneous regression, suggests that this genetic abnormality may have contributed to the favorable clinical course. The generally benign clinical course and marked chemosensitivty of CMN and IFS is somewhat paradoxical given that the ETV6-NTRK3 chimeric protein has potent transforming activity in NIH3T3 fibroblasts, which then become highly tumorigenic.[
18] It has been hypothesized that expression of this oncoprotein somehow renders cells more sensitive to pro-apoptotic stimuli.[
9] It is interesting that NTRK3 is also associated with a more favorable prognosis in children with neuroblastoma, another tumor noted for spontaneous regression.[
19]
This case provided a unique set of circumstances that allowed for the observation of the natural history of a case of cellular CMN. Nevertheless, because of rare cases of progression and metastatic spread, observation is probably not the most appropriate course for an infant with a newly diagnosed CMN. However, this case does support the conservative approach to the treatment of these lesions espoused by Beckwith[
20] and others given the significant potential toxicities associated with giving chemotherapy to very young patients.[
9]
The publisher's final edited version of this article is available at 
