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PDF File #1: DETAILED BACKGROUND & PATHOPHYSIOLOGY OF CONGENITAL MESOBLASTIC NEPHROMA (CMN). Background: Congenital mesoblastic nephroma (CMN) is the most common renal tumor in the neonate. In rare cases it presents in children and adults. The authors of one study estimated conservatively that about 23% of all primary renal tumors in infants younger than I year are CMNs, although other studies estimate approximately that 60-70% of such tumors are CMNs. A renal neoplasm in an infant younger than 3 months is, with infrequent exceptions, a CMN.

The most common presentation is an asymptomatic abdominal mass discovered in the newborn nursery or later by parents. However, many unusual clinical presentations have been noted. One third to one half of cases are noted in the first week of life. Boys and girls are affected equally. Prognosis is excellent in patients with classical CMN (ie, typical CMN) who undergo surgical resection without requiring chemotherapy and radiation. Recurrence and metastasis are rare except in the more aggressive cellular variant of CMN (ie, atypical CMN).

Pathophysiology: The pathophysiology and histogenesis of classical CMN (ie, typical CMN) remain incompletely defined. Recently discovered molecular genetic evidence supports the theory that the histogenesis of cellular CMN (ie, atypical CMN) in the kidney is akin to congenital infantile fibrosarcoma (CIF), a low-grade tumor that does not occur in the kidney. Both cellular CMN and CIF bear a t(12;15)(p13;q25) translocation, a rearrangement that produces a chimeric fusion gene made up of the ETV6 gene (ie, ETS variant gene 6, also called the TEL gene) and the NTRK3 gene (ie, neurotrophic tyrosine kinase receptor type 3 gene, also called the TRK-C gene).

These findings suggest abnormally activating receptor tyrosine kinase signaling pathways contribute to transformation of normal cells to cancer cells in both cellular CMN and CIF. Furthermore, the ETV6 gene also forms fusion genes with various partner genes encoding for proteins with tyrosine kinase activity, including the PDGFR-beta, JAK2, ABL2 and ABL1 genes, and so is implicated broadly in other hematologic and malignant tumorigenesis. The ETV6-NTRK3 fusion gene event probably represents the “first hit” of Knudson’s “two-hit” hypothesis in cellular CMN, antedating the acquisition of the chromosomes 8, 11, 17, and 20 polysomies also found in cellular CMN, which probably represents “second hits” in this disease. See Causes for details of the molecular genetic advances that have elucidated some aspects of the pathophysiology and histogenesis of cellular CMN.

Therefore, Cellular CMN bears no relationship to the pathophysiology and histogenesis of Wilms tumor, clear cell sarcoma, malignant rhabdoid tumor and renal cell carcinoma in histogenesis.

The pathophysiology and histogenesis of classical CMN and its variants

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(mixed CMN, cystic CMN, adult CMN) remain to be defined.

PDF File #2: DETAILED DESCRIPTION OF RECURRENCE, METASTASIS & DEATH FROM RECURRENCE OR METASTASIS AND DEATH FROM COMPLICATIONS OF CMN.

• Recurrence: The risk of recurrence of classical CMN is estimated to be less than 1%. The relative risk of recurrence doubles after 3 months of age and quadruples after 6 months of age. The relative risk of recurrence is higher in atypical CMN than classical CMN, and in tumors that had ruptured.

o In 1973, Fu and Kay reported a recurrent case with unstated histologic classification.

o In 1980, Reddemann et al, in a review of the literature, reported 7 recurrences (9.5%) among 74 cases of CMN of unstated histologic types.

o In 1982, Levin et al reported a recurrence of classic CMN in an adult 21 years after resection of the primary tumor.

o In 1982, Howell et al reported no recurrence in 51 patients with CMN of unstated histologic types enrolled in NWTS.

o In 1986, Hrabovsky et al reported no recurrence in 27 NWTS patients with CMN of unstated histologic classification.

o In 1992, Gaillard et al reported 1 recurrence (5.9%) in 17 cases of cellular CMN, 5 of which had ruptured.

o In 1998, Truong et al in a literature review, reported 1 recurrent case (4.5%) of classic CMN, 24 years after nephrectomy, among 22 patients with adult CMN (20 classic, 2 cellular).

• Metastasis: The risk of metastasis in classical CMN is estimated to be much less than 1%. The relative risk of recurrence is higher in atypical CMN than classical CMN.

o In 1980, Gonzalez-Crussi et al reported a “malignant mesenchymal nephroma” that caused pulmonary metastasis.

o In 1984, Steinfeld et al reported a case of recurrent and metastatic CMN and 5 other cases from the literature with unstated histologic classification.

o In 1989, Gormley et al reported 7 patients with recurrent and/or metastatic disease in 38 cases of cellular CMN but did not segregate them further.

o In 1993, Heidelberger et al reported a case of classic CMN that metastasized to the brain from a single cellular nodule within the tumor, and referred to 3 other cases in the literature that had metastasized to the lung.

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o In 1993, Vujanic et al reported a case of CMN of unstated histologic classification that metastatized to the lungs and then the heart.

o In 1995, Schlesinger et al reported 2 cases of CMN of unstated histologic classification that metastatized to the brain.

o In 1997, Fallouh et al reported an atypical cellular CMN with marrow, liver and thoracic soft tissue metastasis at diagnosis that responded to surgery and chemotherapy.

• Death from recurrence or metastasis: The risk of death from recurrence or metastasis in classical CMN is estimated to be much less than 1%. The relative risk of such deaths is higher in atypical CMN than classical CMN. The histologic type was not reported in many cases of CMN that had died from recurrence or metastasis.

o In 1973, Joshi et al reported a patient with CMN of unstated histologic classification who died from massive recurrence.

o In 1974, Walker and Richard reported a patient with CMN of unstated histologic classification who died from massive recurrence.

o In 1989, Gormley et al in a review of the literature, reported 7 of 38 patients cellular CMN that had local recurrence and/or pulmonary metastasis (18.4%), 3 (7.9%) of whom died.

• Death from complications: The risk of death from complications is also estimated to be much less than 1%. The perinatal complications included hydrops fetalis, acute hydramnios, premature labor, respiratory compromise, hemorrhagic shock and disseminated intravascular coagulation. The postnatal complications included chemotherapy-related sepsis.

o In 1982, Howell et al reported that I of 51 patients (2%) with CMN in NWTS died (2%) from chemotherapy-related sepsis.

o Gray in 1989, Gray, Angulo et al in 1991, and Liu et al reported cases of CMN associated with hydrops fetalis and stillbirth.

o In 1989, Boulot et al reported a patient who died of CMN, whose birth was complicated by acute hydramnios, premature labor and respiratory compromise.

o In 1991, Zach et al reported a neonate who died of CMN, complicated by hemorrhagic shock and disseminated intravascular coagulation.

PDF File #3: DESCRIPTION OF THE GENDER INCIDENCE OF CMN IN DIFFERENT STUDIES.

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• Sex: Distribution by sex varies in different studies. It is probably no different outside the United States than within the United States. There appears to be a slight male-to-female predominance for cellular CMN, but an equal sex incidence for classical CMN. There appears to be a female predominance for CMN that occurs in adults. The numbers in the reported series are small.

o In 1982: Howell et al reported that of 51 patients with CMN enrolled in NWTS, 33 were males and 18 were females, a 1.8:1 male-to-female ratio.

o In 1987, Chan et al reported a 1:1.25 male-to-female ratio in 9 patients with classic (ie, typical) CMN, and a 1.7:1 male-to-female ratio in 8 patients with cellular (ie, atypical) CMN.

o In 1998, Truong et al, in a literature review, reported 22 adults 2 males and 20 females with CMN (0.1:1 male-to-female ratio), of which 20 cases were classic and 2 cases were cellular.

PDF File #4: DETAILED DESCRIPTION OF THE CLINICAL PRESENTATION OF CMN.

• The most common age of presentation of CMN: is the neonatal period, although rare cases may of present in later childhood and adulthood. In neonates the diagnosis is usually made in first week of life, less so after the first week to 3 months, less commonly at 3-6 months; rarely at 6-12 months, even more rarely after 1 year, and extremely rarely in childhood and adulthood. Renal tumors occurring in infants younger than 1 year of age, particularly the first 3 months of life, should be considered to be CMN until proven otherwise. In infants younger than year of age, different authors estimate that 23-70% of all primary renal tumors are CMN.

• The most common presentation of CMN: is an asymptomatic abdominal mass detected in the newborn nursery or later by parents. In 1982, Howell et al reported that 48 of the 51 patients with CMN enrolled in NWTS were term babies born after uncomplicated pregnancies who presented with an abdominal mass. One third to one half of the patients presented in the first week of life. The numbers of boys and girls were approximately equal for classical CMN.

• Moderately common presentations of CMN consisted of:

o Hematuria

o Proteinemia

o Vomiting

o Dehydration

o Transient azotemia

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o Electrolyte abnormalities and polyuria induced by hypercalcemia

o Jaundice

o Perinatal anemia due to hemorrhage from the tumor

o Dystocia from the large abdominal mass

o Premature labor and delivery

• Rare presentations of CMN: CMN is a great mimicker of many diseases in the neonatal period that included:

o Hypertension from reninism:

§ Bauer et al reported CMN presenting with primary reninism (1979).

§ Cook detected renin in CMN immunohistochemically (1988). § Malone et al renin by immunostaining in renal cortex

entrapped within CMN, and in perivascular spaces outside CMN in hypertensive patients (1989).

§ Taylor et al detected by renin messenger RNA by in situ hybridization in glomeruli and tubules entrapped within CMN, and in actin-positive tumor vessels and larger vascular spaces (1989).

§ Tsuchida et al reported very high plasma renin in a cellular CMN and tissue renin localized mainly in the juxtaglomerular apparatus adjacent to entrapped glomeruli but not in tumor cells (1993).

§ Miller and Kolon reported that hypertension and reninism was due either to the CMN or secondarily from compression and ischemia of the renal vascular pedicle (2000).

o Polyhydramnios:

§ Blank et al reported 3 cases of CMN associated with polyhydramnios and premature delivery (1978).

§ Geirsson et al reported prenatal ultrasound diagnosis of CMN associated with polyhydramnios (1985).

§ Burtner and Willard reported prenatal diagnosed of CMN associated with polyhydramnios (1988).

§ Ohmichi et al reported hydramnios from excessive urine production in a 28-week-gestation fetus with a rapidly growing CMN who lost 18% of the birth weight from polyuria at birth at 34-week-gestation (1989).

§ Boulot et al reported acute hydramnios causing premature labor and death from respiratory compromise of a 33-week-gestation fetus with CMN (1989).

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§ Kuo et al reported a prenatally detected CMN associated with polyhydramnios (1989).

§ Kurosu et al reported polyhydramnios associated with CMN (1992).

§ Fung et al reported CMN with hypercalcemia-induced polyuria causing polyhydramnios (1995).

§ Haddad et al reported premature (35 weeks) delivery after ultrasound diagnosis of CMN with polyhydramnios at 33-week-gestation (1996).

§ Shibahara et al reported prenatal ultrasound diagnosis of CMN with polyhydramnios after transfer of a cryopreserved embryo (1999).

§ Irsutti et al reported that the prenatal ultrasound and MRI diagnosis of CMN in 20 cases aided the management of polyhydramnios and prematurity (2000).

o Hypercalcemia:

§ Shanbhogue et al reported CMN presenting with hypercalcemia (1986).

§ Ferraro et al reported a cellular CMN associated with hypercalcemia (1986).

§ Vido et al reported a CMN with increased tumor and urinary prostaglandin E causing hypercalcemia (1986).

§ Chan et al described a hypercalcemic case of CMN (1987).

§ Woolfield et al reported hypercalcemia as a life-threatening complication of CMN (1988).

§ Angulo et al reported cellular CMN associated with nephrocalcinotic hypercalcemia (1991).

§ Fung et al reported polyuria and polyhydramnios due to hypercalcemia in association with CMN (1995).

o Acquired von Willebrand disease rarer than in Wilms tumor:

§ Noronha et al reported acquired von Willebrand disease in a patient with Wilms tumor (1979).

§ Han et al reported asymptomatic von Willebrand disease reversed after Wilms tumor surgery (1987).

§ Bracey et al reported increased tumor and serum hyaluronic acid in Wilms tumor causing serum hyperviscosity and platelet dysfunction and diminished levels of von Willebrand factor antigen and ristocetin cofactor, and reduced factor VIII coagulant activity (1987).

§ Coppes et al reported acquired von Willebrand disease,

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which sometimes responded to vasopressin, in 4 of 50 (8%) patients with Wilms tumor (1992).

§ Lim et al reported epistaxis and acquired von Willebrand disease that improved after chemotherapy for Wilms tumor (1994).

§ Mogilner et al reported acquired von Willebrand disease in a patient with CMN (1995).

§ Barr et al reported Wilms tumor associated with acquired von Willebrand disease that apparently responded to chemotherapy (1996).

§ Jonge Poerink-Stockschlader et al reviewed the coagulation factor findings of 10 patients described in the literature with acquired von Willebrand disease associated with Wilms tumor (1996).

§ Michiels et al depicted the atypical acquired von Willebrand disease in Wilms tumor (2001).

o Congestive heart failure from hypertension.

o Hydrops fetalis:

§ Angulo et al reported a stillborn with hydrops fetalis and CMN (1991).

§ Liu et al reported lethal hydrops fetalis in an infant with CMN (1996).

o Disseminated intravascular coagulopathy:

§ Zach et al reported a newborn with cellular CMN who died of hemorrhagic shock and disseminated intravascular coagulation (1991).

§ Sailer et al reported hemorrhage into a CMN diagnosed prenatally at 32-week-gestation causing anemia and disseminated intravascular coagulation (1993).

o CMN associated with other abnormalities:

§ Nodular renal blastema (Wockel et al, 1979) § Crossed renal ectopia (ie, horse-shoe kidney) (Williams,

1982)

§ Solitary kidney (Nicholson and Gupta, 1990)

§ Renal artery and abdominal aorta aneurysm and angiomyolipomatosis diagnostic of tuberous sclerosis associated with CMN (Occhionorelli et al, 1991)

§ Hypertrophic pyloric stenosis and nephrocalcinotic hypercalcemia associated with CMN (Angulo et al, 1991)

§ Focal and segmental sclerosis of the kidney (Correia et al,

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1995) § Large perilobar sclerosing nephrogenic rest (Vujanic et al,

1995)

§ Cellular CMN with nephroblastomatosis of the kidney (Sane et al, 1996)

§ Nephrogenic rests (Charles, 1996) § Beckwith-Wiedemann syndrome patient with classic CMN

(Sutherland et al, 1997)

§ Neuroblastoma in contiguity with a renal CMN representing “collision tumors” (Vegunta et al, 2000)

o Huge CMN causing fetal asphyxia or respiratory compromise:

§ Matsumura et al reported a huge CMN that caused fetal asphyxia and ruptured requiring emergency surgery (1993).

o Ruptured CMN:

§ Arensman and Belman successfully treated a ruptured CMN with adjuvant chemotherapy and radiation (1980).

§ Gaillard et al reported 35 CMN in a series of 78 patients younger than 6 months with renal tumors: 14 had classic CMN (mean age of presentation 24 d), 17 had cellular CMN (mean age 70 d), and 4 had mixed CMN (mean age 11 d); 9 classic, 5 cellular and 3 mixed CMN had extended into the perirenal fat (stage II), and 5 cellular CMN had ruptured (stage III). The proliferative activity was lower in classic and mixed CMN than in cellular CMN, and very high in a recurrent cellular CMN (1992).

o Hemorrhage from CMN, hemoperitoneum and hypotensive shock:

§ Goldberg et al reported a CMN that ruptured, causing hemoperitoneum and shock (1994).

o Metastatic CMN at diagnosis to lung, brain, bone marrow, liver and bone:

§ Fallouh et al reported an atypical cellular CMN with marrow, liver and thoracic soft-tissue metastasis at diagnosis that responded to surgery and chemotherapy (1997).

o Late CMN diagnosis in adults:

§ An adult female with CMN (Block et al, 1973) § 19-year-old woman with classic CMN that recurred 21 years

after resection, with invasion of the liver (Levin et al, 1982)

§ Adult with CMN (Iraqi et al, 1984)

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§ 35-year-old man with CMN presenting with flank pain and multiple renal calculi (Terai et al, 1985)

§ 69-year-old man with CMN (Bruet et al, 1989)

§ 24-year-old woman with a giant 2500-gram classic CMN (Ogawa et al, 1989

§ 18-year-old girl with CMN (Smida et al, 1989)

§ 41-year-old woman with CMN (Trillo et al, 1990)

§ A 20-year-old woman with CMN (Van Velden et al, 1990) § Young woman found to have a CMN and

angiomyolipomatosis of tuberous sclerosis at operation for a ruptured renal arterial aneurysm, who had a subsequent abdominal aorta aneurysm and stenosis (Occhionorelli et al, 1991)

§ 40-year-old patient with CMN (Desligneres et al, 1992)

§ 27-year-old woman with an atypical partially cystic CMN (Chandeck et al, 1992)

§ 45-year-old, 64-year-old, and 66-year-old patients with CMN presenting with hematuria and flank mass and pain (Durham et al, 1993)

§ 60-year-old woman with CMN presenting with hematuria and pain (Gonzalez Moran et al, 1993)

§ An eighteen-year-old man with CMN (Mahalati et al, 1994)

§ Adult cases of CMN in the literature (Bouvier et al, 1996) § 54-year-old Ethiopian woman with classic CMN presenting

with flank pain and mass (Gemechu and Bezabeh, 1997)

§ Adult with CMN imaged by spiral computerized tomography (Freeby et al, 1997)

§ 20-year-old Japanese man with classic CMN presenting with hematuria (Yamashita et al, 1998)

§ 17-year-old woman with CMN (Matias Garcia et al, 1998)

§ 22 adult cases of CMN, 17 found through literature review (Truong et al, 1998)

§ 50-year-old woman with an incidentally diagnosed classic CMN (Shiraishi et al, 1999)

§ 50-year-old woman with cellular CMN (Kumar and Jain, 2000)

§ 52-year-old Japanese man with CMN presenting with hematuria and back pain; includes review of 38 cases of adult CMN in the literature (Nakano et al, 2000)

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§ 54-year-old woman with an asymptomatic CMN (Daniel et al, 2000)

§ 44-year-old man with two polypoid renal pelvic CMNs (Yanai et al, 2000)

PDF File #5: DETAILED DESCRIPTION OF THE MOLECULAR GENETIC DATA ELUCIDATING THE PATHOPHYSIOLOGY AND HISTOGENESIS OF CMN.

• Cause: Although the pathophysiology and histogenesis of classical CMN and its variants (mixed CMN, cystic CMN, adult CMN) remain to be defined, recent molecular genetic data have helped to elucidate the origin of cellular CMN.

o Cellular CMN bears no relationship to the pathophysiology and histogenesis of Wilms tumor, clear cell sarcoma, malignant rhabdoid tumor and renal cell carcinoma.

o Recent molecular genetic data suggest that cellular (atypical) renal CMN and the cellular component of mixed renal CMN are histogenetically related to a nonrenal low-grade tumor called congenital infantile fibrosarcoma (CIF).

o Apparently both cellular CMN and CIF have t(12;15)(p13;q25) complex translocations that produce a chimeric fusion ETV6-NTRK3 gene, which is absent in classic CMN and other renal tumors.

o The ETS variant gene 6, which used to be called the TEL gene, is located on chromosome 12p13.

o The NTRK3 (also called the TRK-C gene) neurotrophic tyrosine kinase receptor type 3 gene, is located on chromosome 15q25.3.

o The ETV6-NTRK3 fusion transcript encodes the helix-loop-helix protein dimerization domain of the ETV6 protein, which fuses to the protein tyrosine kinase domain of NTRK3.

o This molecular genetic evidence suggests that the chimeric ETV6-NTRK3 protein dysregulates the NTRK3 signal transduction pathways via ligand-independent dimerization and protein tyrosine kinase activation.

§ Therefore, the chimeric ETV6-NTRK3 protein contributes to the cellular transformation of normal cells to cancer cells by abnormally activating receptor tyrosine kinase signaling pathways.

§ Furthermore, ETV6- NTRK3 is a transforming protein that requires an intact dimerization domain and a functional protein tyrosine kinase domain for these transformation

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activities to occur. o The ETV6 gene is also capable of forming fusion genes with

various partner genes that encode for proteins with tyrosine kinase activity, including the PDGFR-beta, JAK2, ABL2 and ABL1 genes, that are broadly implicated in the tumorigenesis of hematologic and other malignancies.

o The event involving the ETV6-NTRK3 gene probably represents the “first hit” of Knudson’s “two-hit” hypothesis that occurs in cellular CMN, antedating the acquisition of chromosomes 8, 11, 17, and 20 polysomies, the “second hits” also found in cellular CMN.

• Key publications on the molecular genetic etiology of cellular CMN:

o Lowery M, Issa B, Pysher T, Brothman A. Cytogenetic findings in a case of congenital mesoblastic nephroma. Cancer Genet Cytogenet 1995; 84 (2): 113-115.

o Sawyer JR, Miller JP, Roloson GJ. A novel reciprocal translocation (14;15)(q11;q24) in a congenital mesoblastic nephroma. Cancer Genet Cytogenet 1996; 88 (1): 39-42.

o Dal Cin P, Lipcsei G, Hermand G, Boniver J, Van den Berghe H. Congenital mesoblastic nephroma and trisomy 11. Cancer Genet Cytogenet 1998; 103 (1): 68-70.

o Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE, Sorensen PH. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res 1998; 58 (22): 5046-5048.

o Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 1998; 18 (2): 184-187.

o Rubin BP, Chen CJ, Morgan TW, Xiao S, Grier HE, Kozakewich HP, Perez-Atayde AR, Fletcher JA. Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am J Pathol 1998; 153 (5): 1451-1458.

o Eguchi M, Eguchi-Ishimae M, Tojo A, Morishita K, Suzuki K, Sato Y, Kudoh S, Tanaka K, Setoyama M, Nagamura F, Asano S, Kamada N. Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25). Blood 1999; 93 (4): 1355-1363.

o Argani P, Fritsch M, Kadkol SS, Schuster A, Beckwith JB, Perlman EJ. Detection of the ETV6-NTRK3 chimeric RNA of infantile fibrosarcoma/cellular congenital mesoblastic nephroma in paraffin- embedded tissue: application to challenging pediatric renal stromal

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tumors. Mod Pathol 2000; 13 (1): 29-36.

o Bourgeois JM, Knezevich SR, Mathers JA, Sorensen PH. Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors. Am J Surg Pathol 2000; 24 (7): 937-946.

o Punnett HH, Tomczak EZ, Pawel BR, de Chadarevian JP, Sorensen PH. ETV6-NTRK3 gene fusion in metastasizing congenital fibrosarcoma. Med Pediatr Oncol 2000; 35 (2): 137-139.

o Okamoto S, Ishida T, Ohnishi H, MacHinami R, Hashimoto H. Synovial sarcomas of three children in the first decade: clinicopathological and molecular findings. Pathol Int 2000; 50 (10): 818-823.

o Wai DH, Knezevich SR, Lucas T, Jansen B, Kay RJ, Sorensen PH. The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells. Oncogene 2000; 19 (7): 906-915.

o Pujana MA, Nadal M, Gratacos M, Peral B, Csiszar K, Gonzalez-Sarmiento R, Sumoy L, Estivill X. Additional complexity on human chromosome 15q: identification of a set of newly recognized duplicons (LCR15) on 15q11-q13, 15q24, and 15q26. Genome Res 2001; 11 (1): 98-111.

o Van Limbergen H, Beverloo HB, van Drunen E, Janssens A, Hahlen K, Poppe B, Van Roy N, Marynen P, De Paepe A, Slater R, Speleman F. Molecular cytogenetic and clinical findings in ETV6/ABL1-positive leukemia. Genes Chromosomes Cancer 2001; 30 (3): 274-282.

o (o) Sheng WQ, Hisaoka M, Okamoto S, Tanaka A, Meis-Kindblom JM, Kindblom LG, Ishida T, Nojima T, Hashimoto H. Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues. Am J Clin Pathol 2001; 115 (3): 348-355.

PDF File #6: DETAILED DESCRIPTION OF THE ABDOMINAL ULTRASONOGRAPHY FINDINGS OF CMN.

• Abdominal ultrasonography with real-time and Doppler studies is an important modality for confirmation of the diagnosis of CMN: o Most typical (classic) CMN are smaller than atypical (cellular)

CMN and have a homogeneous appearance.

o In classic CMN, the tumor simulated the “ring sign” consisting of a concentric echogenic and echo-poor ring pattern, a radiologic sign that distinguishes classic CMN from Wilms tumor or atypical CMN.

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o In classic CMN, cystic spaces are uncommon, and when present are usually small and few in number.

o In most atypical CMN, but only rarely in classic CMN, an inhomogeneous pattern is seen comprising of complex mixed echogenic and echo-poor areas.

o Ultrasonography may detect hemorrhage and necrosis into CMN tumors with hemoperitoneum.

o Intrauterine ultrasonography may help diagnose typical CMN prenatally in cases of polyhydramnios or hydrops fetalis.

PDF File #7: DETAILED DESCRIPTION OF THE ABDOMINAL ULTRASONOGRAPHY FINDINGS OF CMN.

• Abdominal CT is another important modality for confirmation of the diagnosis of CMN: o CMNs appear as intrarenal tumors that distort the pelvicalyceal

system. The “claw sign” sometimes differentiates an intrarenal tumor from an extrarenal tumor such as neuroblastoma.

o Typical CMN tumors are usually small have a homogeneous pattern of attenuation.

o Atypical CMN tumors tend to be larger and have an inhomogeneous pattern of attenuation.

o However, the patterns of the variants of CMN are not specific and may not distinguish CMN variants from Wilms tumor.

o CT scan may detect hemorrhage and necrosis into CMN tumors with hemoperitoneum.

o CT scan may help diagnose CMN prenatally in cases of polyhydramnios or hydrops fetalis although it is rarely performed because of the radiation-risk to the fetus.

PDF File #8: DETAILED DESCRIPTION OF THE ABDOMINAL MAGNETIC RESONANCE FINDINGS OF CMN.

• Abdominal magnetic resonance imaging (MRI) is useful because there is no radiation-risk to the fetus:

o MRI delineates the anatomy and location of the primary CMN.

o It may help delineate the very rare tumor extension into the renal vein, inferior vena cava and right atrium.

o It is used for confirming ultrasonographic detection of hemorrhage and necrosis into CMN tumors with hemoperitoneum.

o It is used for confirming intrauterine ultrasonographic diagnosis of

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CMN prenatally in cases of polyhydramnios or hydrops fetalis.

PDF File #9: DETAILED DESCRIPTION OF THE GROSS PATHOLOGIC FINDINGS OF CMN.

• The kidney is usually marked enlarged and partly or totally replaced by a grayish-white or slightly yellow to tan colored mass:

o The weights of the kidneys range from 40 to 700 gram, averaging 130 gram. Average weights at presentation are 73+31 grams for classic CMN and 570+198 grams for cellular CMN (Chan et al, 1987); in another study, the average weights at presentation are 94 grams for classic CMN, 150 grams for mixed classic/cellular CMN, and 620 grams for cellular CMN (Pettinato et al, 1989).

o The dimensions of the kidneys range from 6 to 8 cm in diameter. Average dimensions at presentation are 5.7+1.1 cm in diameter for classic CMN and 8.2.7+2.3 cm for cellular CMN (Chan et al, 1987); in another study, the average diameters at presentation are 5.1 cm for classic CMN, 10.5 cm for mixed classic/cellular CMN, and 9.1 cm for cellular CMN (Pettinato et al, 1989).

o A capsule or sharp plane of demarcation is usually not apparent around the CMN, and generally there is a lack of definition between the CMN and the grossly uninvolved kidney.

o The cut surface of classic CMN is firm, with a whorled, trabeculated watered silk-like appearance resembling uterine leiomyoma.

o Variations include the presence of cysts or a homogeneous mucoid appearance with or without hemorrhagic areas.

o Cysts, hemorrhage and necrosis are generally confined to cellular CMN and to the cellular areas of mixed CMN.

o Extension of the CMN beyond the renal capsule is usually not apparent macroscopically.

o Adult CMN may be much larger, ranging from 2 to 24 cm in size; they are well circumscribed, partially encapsulated, and display solid whitish to yellow-tan, firm and homogeneous cut surfaces. Some tumors are mixed solid and cystic, and some are almost purely cystic, involving the renal cortex. Most tumors extend to the renal sinus and pelvicalyxeal region and even into the ureter. Some tumors appear entirely intrapelvic.

PDF File #10: DETAILED DESCRIPTION OF THE MICROSCOPIC FINDINGS OF CMN.

• The appearance of CMN is that of a monotonous population of

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compact spindle cells, likened to smooth muscle cells and fibroblasts, with an interlacing pattern:

o The fascicles of cells have a whorled appearance.

o The stroma is collagenized to varying degrees.

o Degrees of differentiation range from immature fetal-type mesenchyme to fully developed myofibroblasts.

o No capsule surrounds the tumor.

o The interface between the tumor and the adjacent normal kidney is irregular as a result of fingerlike projections of spindle cells infiltrating between tubules and glomeruli.

o Kidney tissue adjacent to the CMN tumor contains vacuolated and dysplastic tubules (reminiscent of those in the Denys-Drash syndrome), cysts and subcapsular tumorlets (reminiscent of nephroblastomatosis foci).

o The number of nephron elements is reduced toward the center of the tumor.

o Tubules and glomeruli in the periphery of CMN tumors, some showing hyperplastic and metaplastic changes, are believed to represent entrapment, while rare central epithelial components with a more complex and variegated appearance may be a component of the tumors.

o Occasional dysplastic tubules with hyperchromatic nuclei may occur without affecting the prognosis.

o Rhabdomyoblastic and extramedullary hematopoietic elements have been described occasionally.

o Heterologous elements within CMN include mature hyaline cartilage, nests of immature cartilage, differentiated skeletal muscle with multinucleated giant cells, and islands of cornified squamous epithelium. Some CMN tumors have no heterologous elements.

o Focal degeneration and necrosis are infrequent.

o Small islands of spindle cells in the renal hilus are common without implying an aggressive biology.

o About 15-20% of cases have microscopic extrarenal extension into adjacent kidney mainly at the renal hilus, perirenal soft tissue, and renal pelvis, observed if multiple sections are examined.

o The microscopic appearance allows the tumors to be classified broadly into classic (ie, typical), cellular (ie, atypical) and mixed CMN (ie, mixture of classic and cellular components), with considerable overlapping of the pathologic subtypes.

o Some tumors, particularly the more cellular types, present a

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storiform fibrohistiocytic appearance.

o Cysts, hemorrhage and necrosis are confined to cellular CMN and to the cellular areas of mixed CMN.

o Mitotic figures may be quite abundant but most investigators agree that this has no prognostic significance. Mitotic activity in classic CMN ranged from 0-1 per10 high-power fields; in cellular CMN, 25-30 per 10 high-power fields.

o The pathologic classification has implications for local recurrence and distant metastasis; cellular CMN (and the cellular elements within mixed CMN) have a greater propensity for local recurrence and distant metastasis than classic CMN, particularly in infants older than 3 months of age.

o Minor microscopic extension into extrarenal tisses has no prognostic significance but gross invasion of adjacent organs, markedly increased mitosis, and markedly increased cellularity do predispose the CMN tumors to local recurrence and distant metastasis.

o Recurrent tumors and the metastasis exhibit a higher degree of cellularity with less apparent differentiation.

o CMN tumor extension into renal vein, inferior vena cava and right atrium is extremely rare.

o Most adult CMNs extend into the renal sinus but do not show destructive invasion of the pelvic wall. Extension of the tumor beyond the renal capsule is rare. Each tumor is composed of both epithelial and stromal components. The epithelial component, which displays no difference to the classic and cellular variants, is composed of isolated or clustered tubules and cysts lined by a benign epithelium with a wide range of differentiation. The stromal component is composed of fibroblasts, myofibroblasts and smooth muscle cells in various combinations. Most adult CMN tumors are still the classic variant rather than the cellular variant, although they tend to be more cystic. Stromal cellularity is low for the classic variant but high for the cellular variant. Hemorrhage, necrosis, and a high mitotic index are noted in the stroma of the cellular, but not in the classic, variant.

o One unusual case of adult CMN consisted of two polypoid renal pelvic tumors that had glandular and stromal components. Some glands in the tumor had ciliated epithelium and were quite similar to the epididymal tubules. Other glands in the tumors resembled the collecting duct or the mesonephric remnant seen in female genitalia. Some psammoma bodies were seen in the glands in the tumor. Immunohistochemistry and electron microscopy revealed smooth muscle differentiation of the stromal cells of the tumor.

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PDF File #11: DETAILED DESCRIPTION OF THE ULTRASTRUCTURAL FINDINGS OF CMN.

• The spindle stromal cells of CMN showed predominantly fibroblastic or myofibroblastic differentiation. o Typically, the cells contain cigar-shaped tapered nuclei, abundant

cisternae of rough endoplasmic reticulum that is often dilated by a granular procollagenous substance.

o Collagen fibrils of the usual type are commonly seen in the interstitum, and the cells may be joined by zonulae adherens or zonulae occludens.

o Subplasmalemmal arrays of microfilaments with interspersed dense bodies, typical of smooth muscles, are present in varying degrees. These cells may have a basal lamina.

o Intracytoplasmic microtubules have been noted.

o Short filopodia, like microvilli, and occasional cilia may be present.

o The fibromatous areas of classic CMN consist predominantly of mature mesenchymal cells.

o Cells with lesser differentiation, analogous to primitive mesenchymal spindle cells, may be present in varing amounts in classic CMN but appear to predominate in cellular CMN and in local recurrences.

o Cellular CMN and cellular areas of mixed CMN are composed mainly of primitive mesenchymal cells, usually containing varying numbers of differentiating fibroblasts and myofibroblasts. These tumors bear a closer resemblance at the ultrastructural level of organization to nonrenal congenital infantile fibrosarcoma (CIF) than to conventional nonrenal fibrosarcoma. CIF also bears the same t(12;15)(p13;q25) translocation and apparently shares a similar molecular genetic histogenesis as cellular CMN.

o Adult CMN tumors show smooth-muscle differentiation and undifferentiated mesenchyme. Immature tubules with numerous intracytoplasmic intermediate filaments are also seen. Both the fibromyomatous stroma and the tubules appeared to be an integral part of adult CMN tumors.

PDF File #12: DETAILED DESCRIPTION OF THE IMMUNOHISTOCHEMICAL FINDINGS OF CMN.

• CMN tumors are composed of mesenchymal cells with varying degrees of fibroblastic and/or myofibroblastic differentiation, confirmed by vimentin, desmin and actin-positivity:

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o Rarely, some spindle cells are cytokeratin-positive.

o One study shows intracellular and pericellular fibronectin and absence of laminin (Kumar et al, 1985), and another study shows positivity for neural cell adhesion molecule-associated polysialic acid (Nadasdy et al, 1993), both of which are indicative of a primitive mesenchyme origin.

o Entrapped distal tubular and collecting duct epithelium is confirmed by nephronic segment-specific lectin staining.

o Renin staining is seen in blood vessels supplying intratumoral epithelial cells, corresponding to high plasma renin levels.

o Immunoreactive renin was present in 10 of 12 infants that were either hypertensive, non-hypertensive, or whose blood pressures were unknown (Cook et al, 1988). Intense staining was present in the blood vessels within the areas of the trapped cortex. In 7 cases, renin was identified within the tumors in the walls of vessels, not adjacent to cortical structures.

o Renin messenger RNA could be localized by in situ hybridization in cortical glomeruli and tubules entrapped within CMN, and in actin-positive tumor vessels and larger vascular spaces (Taylor et al, 1989).

o Immunoreactive renin staining was most intense in the areas of cortex entrapped within the CMN tumors, and in perivascular spaces not associated with entrapped cortex (Malone et al, 1989).

o Immunoreactive renin staining was localized predominantly in the juxtaglomerular apparatus adjacent to glomeruli entrapped within a cellular CMN tumor, but not in the in the tumor cells (Tsuchida et al, 1993).

o Renin production was identified in CMN or secondarily from the renal vascular compression or ischemia (Miller and Kolon, 2000).

o CMN may contain prostaglandin E that mediated hypercalcemia in some patients. Large quantities of prostaglandin E extracted from CMN by radioimmunoassay, correlates to hypercalcemia, raised urinary prostaglandins, and a prostaglandin-induced arteriovenous gradient demonstrated during surgery that normalized after nephrectomy (Tsuchida et al, 1986). Plasma parathyroid hormone was normal.

o CMN may contain marked insulinlike growth factor II (IGF-2) expression. Nine CMN tumors (classic, mixed and cellular) all contains abundant the insulinlike growth factor II (IGF-2) transcript, but not the Wilms tumor (WT1) transcript, by in situ hybridization (Sharifah et al, 1986). IGF-2 transcripts are diffusely distributed over the tumor cells. This suggests that CMN is derived from primitive mesenchymal nephrogenic cells and has a potential to

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differentiate into a stromal cell lineage.

o High-level expression of IGF-2 is demonstrated in both CMN and Wilms tumor (Tomlinson et al, 1992).

o Knudson (1993) has suggested that activation of the IGF-2 gene might be a final common pathway for mutation both for the Wilms tumor gene, WT1, and for the Beckwith-Wiedemann gene, BWS.

o Becroft et al (1995) has reported that good prognosis in a case of cellular CMN is associated with hyperdiploidy and relaxation of the imprinting of the maternal IGF-2 gene. The tumor shows mosaic hyperdiploidy with 54 chromosomes in the hyperdiploid line. Genomic imprinting normally prevents transcription of the maternal IGF-2 gene. Relaxation of IGF2 imprinting leading to abnormal transcription of the maternal gene is found in the majority of Wilms tumors and other malignant neoplasms. The biallelic transcription of IGF2 in this case of CMN is consistent with abnormal transcription of the maternal allele. Relaxation of imprinting of the maternal IGF2 gene or abnormal expression of the gene through other mechanisms might have a role in the genesis of CMN or its cellular subtype.

o One unusual classic CMN from a 3-month-old infant shows strong positivity for proliferating cellular nuclear antigen (PCNA) and negativity for p53 that do not correlate with an aggressive biology.

o Nadasdy et al (1993) has reported an immunohistochemical and lectin study on the differentiation of classic, cellular and mixed infantile CMN along epithelial lines, using the lectins Tetragonolobus purpureas, Phaseolus vulgaris erythroagglutinin and Arachis hypogaea, and antibodies to epithelial membrane antigen, cytokeratin and Tamm-Horsfall protein. Differentiation along mesenchymal lines is studied using antibodies against vimentin, desmin and muscle-specific actin. Differentiation along putative renal oncodevelopmental lines is studied using an antibody to the embryonic polysialic acid long form on the neural cell adhesion molecule. Increased proliferation is studied using an antibody to proliferating cell nuclear antigen. Cellular CMN shows increased proliferative rate, and contains tubular structures with immature, dysplastic epithelium and occasional embedded epithelial cell clusters that show epithelial and mesenchymal differentiation.

o Witte et al (1989) has identified DNA synthesis-stimulating acidic fibroblast growth factorlike activity in a CMN. Acidic fibroblast growth factor-like molecules are present in immature human kidney, although in lower amounts than in CMN. This suggests that the acidic fibroblast growth factorlike activity expressed in developing kidney persists in some renal tumors.

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o Adult CMN tumors show immunohistochemical reactions similar to the developing nephron. The spindle cells display cytoplasmic immunoreactivity for vimentin, desmin, panmuscle actin (HHF- 35), and alpha-smooth-muscle actin, but are nonreactive for keratin (AE1/AE3), epithelial membrane antigen, and S-100 protein. This confirms the presence of fibroblasts, myofibroblasts, smooth muscle cells and prominent vessels in the tumor stroma. Most cysts and tubules within the tumors have the distinctive immunohistochemical profile of collecting ducts, different other portions of normal nephrons. Collecting duct differentiation expressed by most tubules and cysts of adult CMN implies that the ureteric bud, which is the exclusive embryologic origin of collecting ducts, is an important element in histogenesis.

o Another adult CMN study has reported a complex pattern of antigenic expression that is not restricted to collecting ducts, but includes the glycoprotein CD24 and the neural cell adhesion molecule NCAM.

o A third adult CMN study has shown high positivity for keratin in the epithelial lining of the tubular and cystic structures, and for desmin and vimentin in the fusocellular stroma of the tumor.

PDF File #13: DETAILED DESCRIPTION OF THE KARYOTYPIC FINDINGS OF CMN.

• The fibromatous portions of classic CMN show a normal chromosomal pattern.

• Cellular CMN typically shows a genotype with extra copies of chromosome 11, and nonrandom chromosome 8, 17 and 20 gains. The pleomorphic portions of cellular CMN are characterized by aneuploidy due to chromosomal gains (chromosome 11, 8, 17, 20):

o Chromosomal losses have also been reported in CMN.

o Karyotypic studies of cellular CMN showing the t(12;15)(p13;q25) rearrangements associated with the ETV6-NTRK3 fusion gene have been reported in detail in Causes.

o The ETS variant gene 6, which used to be called the TEL gene, is located on chromosome 12p13.

o The NTRK3 neurotrophic tyrosine kinase receptor type 3 gene, also called TRK-C gene, is located on chromosome 15q25.3.

o The complex t(12;15)(p13;q25) rearrangements (translocations, deletions) in cellular CMN antedate the acquisition of chromosomes 8, 11, 17, and 20 polysomies (Rubin et al, 1998).

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PDF File #14: DETAILED DESCRIPTION OF THE MOLECULAR GENETIC FINDINGS OF CMN.

• Classic CMN shows a normal chromosomal pattern by fluorescence in situ hybridization (FISH).

• Cellular CMN may contain extra copies of chromosome 11, and nonrandom chromosome 8 and 17 gains demonstrated by FISH:

o Loss of heterozygosity at chromosomes bands 11p13 and 11p15 on Southern blot analysis, characteristic of Wilms tumor, is absent in CMN (Tomlinson et al, 1992). Also, unlike Wilms tumor, CMN expresses neither the MYCN oncogene nor the putative Wilms tumor suppressor gene, WT1, on northern blot hybridization analysis (Tomlinson et al, 1992).

o However, one rare case of CMN has been documented with an 11p15 rearrangement suggesting a possible genetic link between CMN and Wilms tumor.

o Molecular genetic and histogenesis studies of the ETV6-NTRK3 fusion gene mRNA transcript characteristic of cellular CMN have been reported under Causes. These studies are performed by FISH and reverse transcriptase polymerase chain reaction.

o The ETS variant gene 6, which used to be called the TEL gene, is located on chromosome 12p13.

o The NTRK3 neurotrophic tyrosine kinase receptor type 3 gene, also called TRK-C gene, is located on chromosome 15q25.3.

o The complex t(12;15)(p13;q25) rearrangements (translocations, deletions) in cellular CMN antedate the acquisition of chromosomes 8, 11, 17, and 20 polysomies (Rubin et al, 1998).

o The t(12;15)(p13;q25) rearrangements may represent the “first hit”, and the chromosomes 8, 11, 17, and 20 polysomies, the “second hits”, according to the Knudson “two-hit hypothesis” of tumorigenesis.

o By virtual of their common molecular genetics, the t(12;15)(p13;q25)-associated ETV6-NTRK3 gene fusion, cellular CMN which occurs in the kidney, and the histologically similar congenital infantile fibrosarcoma which does not occur in the kidney, are pathogenetically related and may represent a single neoplastic entity.

PDF File #15: DETAILED DESCRIPTION OF THE EXPERIMENTAL PATHOLOGY FINDINGS OF CMN.

• Crocker and Vernier have observed nephrogenesis with tubular epithelium formation in CMN cell cultures. Garvin et al have shown epithelial differentiation in cell cultures in form of islands epithelial cells

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overlaying the spindle cell population, characteristic of classic CMN. o A benign canine variant of CMN has been described (Takeda et al,

1989).

o An acidic fibroblast growth factorlike activity, which stimulates DNA synthesis in mouse fibroblasts and bovine endothelial cells, is present in CMN and in lesser amounts in immature human kidney. This suggests that the acidic fibroblast growth factorlike activity expressed in developing kidney may persist in some renal tumors (Witte et al, 1989).

o Renal neoplasms, similar to human CMN, have been induced by ethylnitrosourea with radiation in a rat experimental model in up to 18.4% of cases (Hasgekar et al, 1989).

o Rat renal mesenchymal tumors induced by ethylnitrosourea with radiation could be an experimental model for human CMN (Deshpande et al, 1989).

o NIH3T3 cell cultures are transformed by a chimeric protein tyrosine kinase encoded by the ETV6-NTRK3 fusion gene, when infected with a recombinant retroviral vector that carried full-length ETV6-NTRK3 cDNA (Wai et al, 2000). These transformed cells grow macroscopic colonies in soft agar and form tumors in severe combined immunodeficient (SCID) mice, confirming the transforming protein function of the ETV6-NTRK3 chimeric protein. The ETV6-NTRK3 protein requires both an intact dimerization domain and a functional protein tyrosine kinase domain for its transformation activity. The chimeric protein mediates transformation by dysregulating the NTRK3 signal transduction pathways via ligand-independent dimerization and protein tyrosine kinase activation.

PDF File #15: DETAILED CHRONOLOGY OF THE EXPANSION OF KNOWLEDGE ABOUT CMN IN THE LAST 30 YEARS:

• Advances before 1980 - Clinical and treatment studies of CMN:

o 1967: Bolande et al reported of 8 cases of CMN of infancy as a distinct neoplasm, classifying it as a form of Wilms tumor.

o 1973: Block et al reported the first case of CMN in an adult female.

o 1973: Fu and Kay reported a case of CMN of unstated histologic classification that recurred.

o 1973: Joshi et al reported the unusual clinical behavior of a case of CMN of unstated histologic classification that recurred massively causing the patient’s death.

o 1974: Walker and Richard reported the recurrence of CMN of

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unstated histologic classification that caused the patient’s death.

o 1975: Eidelman et al recommended that CMN be treated surgically and not by adjuvant chemotherapy and radiation therapy.

o 1976: D'Angio et al, reporting for the National Wilms Tumor Study (NWTS) initiated in 1969, stated that the frequency of CMN in the 606 registered NWTS patients.

o 1977: Sussman et al reported a case of CMN in infancy.

o 1977: Bretagne et al described the diagnostic trap posed by hematuria in an infant with CMN.

o 1978: Blank et al reported 3 cases of CMN presenting with polyhydramnios and premature delivery.

o 1979: Bauer et al reported CMN presenting with primary reninism.

o 1979: Noronha et al reported acquired von Willebrand disease associated with Wilms tumor.

• Advances before 1980 - Pathology, biology and histogenesis of CMN:

o 1969: Wigger further defined CMN as a clinicopathological entity but considered it as a fetal hamartoma with excellent prognosis that is unrelated to Wilms tumor.

o 1970: Beckwith included CMN among the mesenchymal renal neoplasms of infancy.

o 1972: Knudson and Strong proposed a mutational oncogenesis model for the development of Wilms tumor.

o 1973: Bolande reviewed CMN in infancy for Perspectives in Pediatric Pathology.

o 1974: Beckwith proposed a pathologic spectrum with benign CMN at one extreme, ranging through potentially more aggressive intermediate “gray zone” lesions of indeterminate biologic significance, to unequivocally malignant "crossover" lesions like spindle cell sarcoma at the other extreme.

o 1974: Nickey commented on CMN in a letter to the editor of the Archives of Pathology.

o 1974: Bolande replied about CMN in a letter to the editor of the Archives of Pathology.

o 1976: Bohm and Riede reported the pathology, ultrastructure and DNA cytophotometry of a semi-malignant fibroleiomyomatous CMN in a newborn infant.

o 1979: Nogueira March et al emphasized the difference between CMN and Wilms tumor.

o 1979: McAlister et al reported cystic CMN containing epithelial

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spaces similar to dysplastic tubules and glomeruli.

o 1979: Wockel et al reported CMN associated with nodular renal blastema in an infant.

• Advances in 1980 - Clinical and treatment studies of CMN:

o Reddemann et al reviewed the literature on 74 cases of infantile CMN of unstated histologic classification, 7 of which recurred.

o Babaya et al reported 2 cases of neonatal CMN.

o Arensman and Belman successfully treated a ruptured CMN with adjuvant chemotherapy and radiation after nephrectomy.

o Sty and Oechler reported the 99mTc-glucoheptonate renal imaging of CMN.

o Gilly et al emphasized the necessity to avoid radiotherapy or chemotherapy without histologic diagnosis in CMN. These therapies caused severe complications adversely affecting the excellent prognosis of CMN treated with nephrectomy alone. They proposed thar, in exceptional cases, adding other forms of therapy may be useful when the tumor proved to be more aggressive than usual either macroscopically or microscopically.

• Advances in 1980 - Pathology, biology and histogenesis of CMN:

o Shen and Yunis reported the ultrastructure of 10 cases of CMN—5 classic, 2 cellular, and 3 mixed lesions—which showed mesenchymal cells with varying degrees of fibroblastic and/or myofibroblastic differentiation.

o Gilly et al reported 6 cases of CMN with myomatous or fibromyomatous proliferation that entrapped normal or dysplastic glomerular or tubular structures. Some lymphatic capsular ectasia or lymphoid infiltration or cartilaginous islets were seen in the periphery.

o Gonzalez-Crussi et al reported a tumor they called malignant mesenchymal nephroma that metastasized to the lungs of the patient.

• Advances in 1981 - Clinical and treatment studies of CMN:

o Rosa et al reported 5 cases of CMN and review of the literature.

o Gerber et al reported 2 cases of infantile CMN cured by nephrectomy.

o Hartman et al reported the radiologic-pathologic correlation in 20 cases of CMN. Urograms demonstrated an intrarenal mass 2-7 times larger than the contralateral kidney, with contrast medium occasionally demonstrated within the tumor that represented trapped functioning nephrons. Sonography correlated well with the gross morphology and established the relation of the tumor to the

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kidney. Angiography showed hypervascular in most and neovascularity in some tumors. Prognosis after complete excision was excellent and adjunctive therapy was unnecessary.

• Advances in 1981 - Pathology, biology and histogenesis of CMN:

o Ganick et al reviewed the pathology of CMN.

o Tinaztepe et al report a comparative histological study of 3 cases of CMN at different ages.

o Grider et al reported CMN with a cystic component.

o Snyder et al proposed in a schema in which the developing renal blastema at the premetanephric stage is the site of the first mutational event in the tumorigenesis of CMN, analogous to Knudson and Strong’s two-step tumor induction hypothesis for Wilms tumor.

o Willnow called CMN a dysontogenetic tumor with low grade of malignancy since its [3H]thymidine labeling, DNA synthesis time, mean generation time, growth fraction and doubling time differed from those of Wilms tumors, which characterized a rapidly growing tumor.

• Advances in 1982 - Clinical and treatment studies of CMN:

o Yazaki et al reviewed 90 cases of CMN in the English and Japanese literature.

o Howell et al, reporting the therapy and outcome of 51 children with CMN of unstated histologic types recorded in the NWTS (2.8% of 1905 renal tumors submitted), described no recurrence but one patient who died from sepsis as a complication of chemotherapy.

o Slasky et al reported a cystic CMN with a large peripheral cystic component and a solid central core on ultrasonography.

o Bitter reviewed the computerized tomography finding of CMN.

o Williams reported a CMN in an infant with crossed renal ectopia (ie, horse-shoe kidney).

o Levin et al reported a classic CMN in a 19-year-old woman that recurred with invasion of the liver 21 years after resection. The recurrent tumor comprised fibroblastic cells surrounded by collagen and elastin-rich interstitial material.

• Advances in 1982 - Pathology, biology and histogenesis of CMN

o Beckwith and Yokomori presented at the Interim Meeting of the Pediatric Pathology Club in Vancouver, “Clear cell sarcoma: Is it derived from mesoblastic nephroma?”

• Advances in 1983 - Clinical and treatment studies of CMN:

o Ehman et al reported the prenatal sonographic detection of a CMN

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in a monozygotic twin pregnancy.

o Sacks et al reported on the scintigraphic and real-time sonographic diagnosis of CMN, distinguishing it from Wilms tumor.

• Advances in 1983 - Pathology, biology and histogenesis of CMN: o Beckwith reviewed for Human Pathology, “Wilms tumor and other

renal tumors of childhood: a selective review from the National Wilms Tumor Study Pathology Center” based on an archive of 2600 cases of childhood renal tumors.

• Advances in 1984 - Clinical and treatment studies of CMN:

o Steinfeld et al reported a case of recurrent and metastatic CMN. A review of 5 patients indicated that chemotherapy and radiotherapy could cure locally recurrent and metastatic CMN with unstated histologic types.

o Matsuki et al reported a large renal tumor in a 2-year-old boy that was treated as Wilms tumor with preoperative radiation and chemotherapy without a biopsy. The tumor extended to the renal pelvis and ureter with a polypoid growth pattern and was composed of compact interlacing bundles of elongated fibromyomatous cells with islands of entrapped glomeruli and tubules within the tumor.

• Advances in 1984 - Pathology, biology and histogenesis of CMN:

o Schmidt et al segregated renal tumors in the first 6 months of life into two groups, one with a better prognosis which included CMN, fetal rhabdomyomatous nephroblastoma, and cystic partially differentiated nephroblastoma, and one with a poorer prognosis group which included rhabdoid tumor and clear cell sarcoma that had a propensity to metastasizing to bone.

o Haas et al proposed clear cell sarcoma as the malignant counterpart of CMN.

o Iraqi et al reported the histogenetic aspects of CMN in an adult.

• Advances in 1985 - Clinical and treatment studies of CMN:

o Geirsson et al reported the prenatal ultrasonography appearance of a CMN associated with polyhydramnios.

o Walter and McGahan reported the prenatal sonographic detection of CMN.

o Howey et al reported the ultrasonic findings and surgical excision of a CMN in a very-low-birth-weight infant.

o Kelly reported a case of cystic cellular CMN with renal vein invasion arising in an 8-month-old female.

o Terai et al reported a case of CMN in a 35-year old man

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presenting with flank pain and multiple renal calculi. The tumor had a mixed epithelial component with cysts and tubules and a mesenchymal component with loosely textured fibroblasts and smooth muscle cells.

• Advances in 1985 - Pathology, biology and histogenesis of CMN:

o Fernbach et al reported calcification and ossification within a CMN.

o Kumar et al reported the histogenesis of 4 nonmetastatic CMN that contained fibronectin but not laminin, whereas neonatal metastasizing spindle cell sarcoma was positive for laminin. During embryogenesis, primitive nephrogenic mesenchyme contained only fibronectin but not laminin, while mature renal metanephric blastema was positive for laminin.

• Advances in 1986 - Clinical and treatment studies of CMN:

o Chellama and Chacko reported 7 cases of CMN including one cellular CMN.

o Shanbhogue et al reported 4 cases of CMN and reviewed the literature.

o Sharma and Sharma reviewed CMN of infancy.

o Yambao et al reported the prenatal diagnosis of CMN by ultrasonography.

o Apuzzio et al reported the prenatal diagnosis of a fetal renal CMN.

o Plaja Roman et al reviewed the diagnostic procedures for CMN.

o Mufarrij and Ashkar reviewed the management of CMN.

o Shanbhogue et al reported a case of CMN presenting with hypercalcemia.

o Ferraro et al reported a case of cellular CMN presenting with hypercalcemia and reviewed the literature.

o Vido et al reported a hypercalcemic patient with CMN who had normal parathyroid hormone but raised urinary prostaglandins. A prostaglandin arteriovenous gradient was demonstrated at surgery. The CMN contained a large quantity of prostaglandin E that mediated the hypercalcemia.

• Advances in 1986 - Pathology, biology and histogenesis of CMN:

o Hrabovsky et al, reporting for NWTS, stated that 27 (0.8%) of the 3340 patients registered on NWTS in 1969-84 were aged 30 days or less. Of these 27 patients, 18 had CMN (0.5%), one, malignant rhabdoid tumor, four, favorable histology Wilms tumors, and four, nonneoplastic lesions.

o Marsden and Newton reviewed the pathology of 38 cases of CMN. They defined its mesoblastic origin based on the presence of

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cartilage, but also described the squamous epithelium seen within 3 tumors. The adjacent renal tissue showed vacuolated and dysplastic tubules, cysts and subcapsular epithelial tumourlets, findings common to both dysplastic kidneys and Wilms tumor. Classification of the tumors as normocellular and hypercellular was attempted, but they overlapped considerablely.

o Joshi et al characterized the pathologic features of cellular CMN as a potentially aggressive variant of classic CMN.

o Beckwith and Weeks discussed the question in an Editorial for the Archives of Pathology & Laboratory Medicine, “Congenital mesoblastic nephroma. When should we worry?”

• Advances in 1987 - Clinical and treatment studies of CMN:

o Chan et al described the clinicoradiologic findings in 17 cases, 9 classic and 8 cellular, that represented the pathologic spectrum of the disease.

o Chaouachi et al reviewed the literature of the 115 cases of CMN reported to date.

o Han et al reported asymptomatic von Willebrand disease in a young patient with Wilms tumor who recovered after nephrectomy.

o Bracey et al reported von Willebrand-type platelet dysfunction from hyaluronic acid associated with Wilms tumor that reversed after nephrectomy. The von Willebrand factor antigen was undetectable, ristocetin cofactor was diminished, factor VIII coagulant activity was reduced, and lacked platelet aggregation with ADP, epinephrine, collagen and arachidonic acid. These abnormalites were due to the high serum levels of hyaluronic acid that made the patient's serum hyperviscous, and hyaluronic acid was found in the tumor matrix.

• Advances in 1987 - Pathology, biology and histogenesis of CMN:

o Kovacs et al described a mixed CMN with classic fibromatous and cellular pleomorphic components. Cell cultures of the classic component showed mature mesenchymal cells with a normal chromosomal pattern. The cellular component consisted of immature mesenchymal cells showing aneuploidy with 54 chromosomes.

• Advances in 1988 - Clinical and treatment studies of CMN:

o Burtner and Willard reported a prenatal diagnosed case of CMN presenting with polyhydramnios.

o Zeilinger et al reported that CMN could not be differentiated from Wilms tumor ultrasonographically.

o Woolfield et al reported that hypercalcemia was a life-threatening

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complication of CMN.

• Advances in 1988 - Pathology, biology and histogenesis of CMN:

o Cook reported an immunohistochemical study of renin in CMN.

• Advances in 1989 - Clinical and treatment studies of CMN:

o Ohmichi et al reported a case of hydramnios from excessive urine production in a 28-week-gestation fetus with a rapidly growing CMN. At birth at 34 weeks gestation, 18% of the birth weight was lost in 2 days from polyuria.

o Kuo et al reported a case of maternal polyhydramnios associated with a prenatally detected classic CMN.

o Kirks and Kaufman reported that CMN was the only primary renal neoplasm with radiographically demonstrable functioning in nephrons trapped within the tumor, as demonstrated by excretion of contrast and radionuclide and confirmed pathologically.

o Boulot et al reported antenatal ultrasound diagnosis of CMN in a 33-week-gestation fetus. The pregnancy was associated with acute hydramnios and culminated in premature labor; the infant died of respiratory compromise.

o Bruet et al reported a CMN in a 69-year-old man.

o Ogawa et al reported a case of a giant 2500-gram classic CMN in a 24-year-old woman presenting with hematuria and flank pain.

o Malone et al reported 12 patients with CMN in whom 4 of the 5 measured had preoperative hypertension related to immunodetected renin production (10 of 12 cases) in renal cortex entrapped within CMN tumors and in perivascular spaces not associated with entrapped cortex. This suggested that hypertension also may be secondary to increased tumor-associated renin production in CMN.

o Gormley et al reviewed 38 patients with cellular CMN in the literature, segregating them into those who had recurrence (7 local recurrence and/or pulmonary metastasis at a mean duration of 5.4 months causing 3 deaths) and those who had no recurrence (31 cases). Positive surgical margin was the only statistically significant variable for recurrence; presenting age was not a significant variable, although the relative risk of recurrence doubles after the first 3 months of life and quadruples after 6 months of life. Clear surgical margins correlated with cure. Vincristine and dactinomycin failed to control local recurrence or distant metastasis in 4 of 5 children, but 2 subsequently responded to vincristine, cyclophosphamide, and doxorubicin.

o Smida et al reported a case of a CMN in an 18-year-old woman.

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• Advances in 1989 - Pathology, biology and histogenesis of CMN:

o Pettinato et al reviewed 16 cases of CMN, 6 classic (mean age 16 d; mean size 5.1 cm and 94 g), 7 cellular (mean age 5.3 mo; mean size 9.1 cm and 620 g), and 3 mixed (mean age 2.3 mo; mean size 10.5 cm and 150 g).

§ Grossly, cysts, hemorrhage and necrosis were only seen in the cellular variant.

§ Microscopically, mitosis ranged from 0-1 per 10 high-power fields (HPF) in classic and 25-30 per 10 HPF in cellular CMN, with clear cell sarcoma-like areas in 3 cellular CMN and regional extension in 10 into perirenal fat, psoas, renal vein wall and lumen.

§ On ultrastructural analysis, CMN showed features of myofibroblastic differentiation.

§ On flow cytometry, one classic CMN, one cellular CMN, and one mixed CMN’s classic areas were euploid, while its cellular areas were aneuploid.

§ Since no recurrences were seen in this series, the pathologic features did not correlate with the biologic behavior of CMN.

o Weeks et al, reviewing for American Journal of Surgical Pathology, in “Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms' Tumor Study Pathology Center”, reported that rhabdoid tumors showed no histogenetic relationship to Wilms tumor, although they might overlap with CMN and clear cell sarcoma. Their findings suggested that rhabdoid tumors might arise from primitive cells involved in formation of the renal medulla.

o Witte et al identified in a CMN acidic fibroblast growth factorlike activity, which stimulated DNA synthesis in mouse fibroblasts and bovine endothelial cells. Acidic fibroblast growth factorlike molecules were present in immature human kidney, although in leser amounts than in CMN. This suggested that the acidic fibroblast growth factorlike activity expressed in developing kidney persisted in some renal tumors.

o Taylor et al described in situ hybridization of the renin messenger RNA localized in cortical glomeruli and tubules entrapped within CMN, and in actin-positive tumor vessels and larger vascular spaces.

o Takeda et al described a benign canine variant of CMN.

o Hasgekar et al reported that renal neoplasms, similar to human CMN, have been induced by ethylnitrosourea with radiation in a rat experimental model in up to 18.4% of cases.

o Deshpande et al reported that rat renal mesenchymal tumors

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induced by ethylnitrosourea with radiation could be an experimental model for human CMN.

• Advances in 1989 - Genetics and molecular genetics of CMN:

o Varsa et al described the complex karyotype and diploid DNA index of a cellular CMN.

• Advances in 1990 - Clinical and treatment studies of CMN:

o Nicholson and Gupta reported a case of CMN occurring in a solitary kidney.

o Christmann et al reported a case of a CMN presenting as a hemorrhagic cyst.

o Walterhouse reviewed CMN of childhood.

o Trillo reported a 41-year-old woman with CMN composed of compact fibrocollagenous elements interspersed with areas containing immature tubules and occasional glomeruloid structures.

• Advances in 1990 - Pathology, biology and histogenesis of CMN:

o Van Velden et al reported a case of CMN in a 20-year-old woman that showed ultrastructurally the fibromyomatous nature of the stroma and the tubules that were integral to the tumor; they discussed its histogenetic relationship to Wilms tumor.

o Vujanic and Aleksandrovic reviewed the clinical and morphologic characteristics of 6 cases of CMN. Histologically, CMN was mostly leiomyomatous and less commonly cellular, with no implication for survival, except that cellular CMN must be distinguished from poor-prognosis clear-cell Wilms tumor.

• Advances in 1991 - Clinical and treatment studies of CMN:

o Angulo et al reported a case of cellular CMN with nephrocalcinotic hypercalcemia in a patient with hypertrophic pyloric stenosis.

o Angulo et al reported a case of CMN in a stillborn infant with hydrops fetalis.

o Zach et al reported a a newborn with cellular CMN who died of hemorrhagic shock and disseminated intravascular coagulation.

o Wootton et al reported the radiologic findings of CMN.

o Occhionorelli et al reported a young woman with an abdominal aortic aneurysm and stenosis due to truncus coeliacus compression. She had a previous nephrectomy for a ruptured renal arterial aneurysm and a CMN was incidentally found with angiomyolipomatosis indicating tuberous sclerosis. Tuberous sclerosis, first described by Bourneville in 1880, is a syndrome characterized by mental deterioration, seizures, cutaneous

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sebaceous adenoma, renal angiomyolipoma, and kidney and cardiovascular malformations.

• Advances in 1991 - Pathology, biology and histogenesis of CMN:

o Barrantes et al reviewed 211 cases of pediatric renal tumors recorded in the West Midlands Health Authority Region Registry from 1957 to 1986 and found 13 cases of CMN (6%), comprising 9 classic, 3 cellular, and 1 mixed. One aneuploid tumor was cellular and one, of the mixed histologic type. Eight diploid tumors were classic and one was cellular. The flow cytometric DNA content and histological subclassification could be useful for selecting patients with CMN who might benefit from postoperative therapy.

o Weeks et al reporting for the NWTS Pathology Center, reviewed 56 mostly pediatric renal neoplasms showing conspicuous filamentous cytoplasmic inclusions or macronucleoli, typical findings for renal rhabdoids, that resulted in confusion with the highly malignant rhabdoid tumor. Sixteen turned out to be Wilms tumor with favorable histology that contained diagnostic typical Wilms blastema or nephrogenic differentiation. The other 40 turned out to be CMN, anaplastic Wilms tumor, renal cell carcinoma, transitional cell carcinoma, collecting duct carcinoma, oncocytoma, rhabdomyosarcoma, malignant neuroepithelial tumor, or lymphoma, in which careful attention to light microscopy, electron microscopy, and immunocytochemical details provided the correct diagnosis.

• Advances in 1992 - Clinical and treatment studies of CMN:

o Gaillard et al reviewed 78 renal tumors in French infants younger than 6 months and identified 35 CMN, comprising 14 classic (mean age 24 d), 17 cellular (mean age 70 d) and 4 mixed (mean age 11 d). Nine of the classic, 5 of the cellular, and 3 of the mixed CMNs extended to the perirenal fat (stage II). Five cellular CMNs ruptured (stage III). Nucleolar organizer region silver staining showed lower cellular proliferative activity in classic and mixed CMN than in cellular CMN, and very high cellular proliferative activity in a recurrent case of cellular CMN.

o Vujanic reported a case of cystic CMN.

o Kurosu et al reported a case of polyhydramnios associated with CMN.

o Stalens et al reported preoperative chemotherapy in a patient with cellular CMN to enable complete surgical resection.

o Desligneres et al reported a case of CMN in an adult older than 40 years.

o Chandeck et al reported a case of cellular, partially cystic CMN in

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a 27-year-old woman.

o Coppes et al reported acquired von Willebrand disease in 4 of 50 (8%) patients with Wilms tumor, 2 with Type II and 2 with Type I features, which responded to 1-desamino-8-D-arginine vasopressin (DDAVP).

• Advances in 1992 - Pathology, biology and histogenesis of CMN:

o Drut reported fine-needle aspiration of CMN that showed spindle and tadpole-shaped cells, with round to oval nuclei with small nucleoli and dense and homogeneously stained cytoplasm, in a mucoid fibrillar background. The findings appeared to be different enough to be diagnostic from other types of infantile renal tumors.

o Dey et al reported fine-needle aspiration cytology of a cellular CMN from a 4-month-old infant that showed clustered and dyshesive spindle cells with minimal nuclear atypia and mitosis and no epithelial, tubular, or glomeruloid differentiation.

o Boccon-Gibod and Ben Lagha reported that the cellular variant of CMN had no prognostic significance in infants younger than 3 months.

o Frank et al described a Sprague-Dawley rat renal transplacental 3,3-dimethyl-1-phenyltriazene carcinogenicity model that showed lesions similar to CMN and intralobar nephrogenic rests.

• Advances in 1992 - Genetics and molecular genetics of CMN:

o Tomlinson et al reported that the molecular characterization of CMN distinguished it from Wilms tumor in the following ways: (1) CMN, like Wilms tumor, demonstrated high-level expression of insulinlike growth factor II (IGF-2); (2) unlike Wilms tumors, CMN expressed neither the N-myc oncogene nor the putative Wilms tumor suppressor gene, WT1; and (3) unlike Wilms tumors, CMN showed no loss of heterozygosity at chromosomes bands 11p13 and 11p15.

o Parada et al reviewed the important functions of neurotrophins in the survival of embryonic and adult neuronal subpopulations. Identification of the TRK family of TRK-A, TRK-B and TRK-C (also called NTRK3) receptor tyrosine kinase neurotrophin receptors indicated that phosphotyrosine-mediated signal transduction was a principal mechanism for neurotrophin signaling. The early expression of TRK-C and TRK-B that persisted throughout embryogenesis in many nonneuronal cells besides motor neurons suggested that these receptors might act in other aspects of organogenesis and development in addition to neurotrophin activity.

o Tessarollo et al reported wide expression of the TRK-C (also called NTRK3) receptor tyrosine kinase neurotrophin receptor for

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neurotrophin 3 in developing nonneuronal as well as nervous tissues.

Advances in 1993 - Clinical and treatment studies of CMN:

o Brough et al reviewed the cases of CMN in the literature.

o Skoric et al reported that CMN represented 9% of their pediatric renal tumors in Belgrade.

o Matsumura et al reported a case of a huge CMN that caused fetal asphyxia and tumor rupture requiring emergency surgery.

o Sailer et al reported a case of disseminated intravascular coagulation and anemia caused by prenatal hemorrhage into a CMN that was diagnosed prenatally in the 32nd week of gestation.

o Heidelberger et al reported a case of benign classic CMN that metastasized to the brain from a single cellular nodule within the tumor. They also referred to 3 cases in which the tumor metastasized to the lung.

o Vujanic et al reported a case and reviewed the literature of CMN metastatic consecutively to the lungs and heart.

o Cowling et al described 2 cases of CMN imaged with 99mTcDMSA, which they suggested was sufficient to diagnose CMN correctly and allowed nephrectomy without biopsy.

o Coppes et al reviewed the Wilms-associated paraneoplastic syndromes, including hypertension, erythrocytosis, hypercalcemia, Cushing syndrome, and acquired von Willebrand disease; and the Wilms-associated biological markers, including erythropoietin, neuron-specific enolase, hyaluronic acid, hyaluronic acid-stimulating activity, and hyaluronidase.

• Advances in 1993 - Pathology, biology and histogenesis of CMN:

o Durham et al reported CMN in 3 adults aged 45, 64, and 66 years, all presenting with hematuria, and flank mass and pain. The tumors were solitary yellow-tan masses with solid and cystic areas involving renal cortex extending into the renal pelvis, calyces and ureter. They consisted of uniform spindle cell proliferations with entrapped dilated renal tubules with focal necrosis but no atypia or mitosis. The spindle cells were positive for vimentin, desmin, panmuscle actin and alpha-smooth-muscle actin, but negative for keratin, epithelial membrane antigen, and S-100. Electron microscopy revealed smooth-muscle differentiation in 2 cases and undifferentiated mesenchyme in one, and all tumors were diploid.

o Nadasdy et al reported on the differentiation of classic, cellular and mixed CMN by the following criteria: (1) along epithelial lines by the lectins Tetragonolobus purpureas, Phaseolus vulgaris erythroagglutinin, and Arachis hypogaea; (2) along epithelial lines

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by antibodies to epithelial membrane antigen, cytokeratin, and Tamm-Horsfall protein; (3) along mesenchymal lines by antibodies against vimentin, desmin, and muscle-specific actin; (4) along putative renal oncodevelopmental lines by an antibody to the embryonic polysialic acid long form on the neural cell adhesion molecule (NCAM); (5) along increased proliferative lines by an antibody to proliferating cell nuclear antigen (PCNA). Cellular CMN showed increased proliferative rate, and contained tubular structures with immature, dysplastic epithelium and occasional embedded epithelial cell clusters that showed epithelial and mesenchymal differentiation.

o Gonzalez Moran et al reported the immunohistochemical study of a CMN in a 60-year-old woman who presented with hematuria and flank pain. The epithelial lining of the tubular and cystic structures in the CMN was positive for keratin, and the fusocellular stroma was positive for desmin and vimentin.

o Tsuchida et al reported very high plasma renin in a cellular CMN with tissue renin localized predominantly in the juxtaglomerular apparatus adjacent to entrapped glomeruli but not in the tumor cells.

o Knudson made observations on the oncogenesis of CMN, Wilms tumor, clear cell sarcoma, malignant rhabdoid tumor, and renal carcinoma, which all arose from primary or secondary mesenchyme, blastema and epithelium. § Tumors in the non-Wilms group, CMN, and possibly clear

cell sarcoma, might have some genetic affinity with Wilms tumor, but rhabdoid tumor and renal carcinoma did not.

§ For Wilms tumor, the "two hit" model originally developed for retinoblastoma by Knudson only partially applied because of genetic heterogeneity of Wilms tumor, which is affected by at least 3 genes: (1) a Wilms tumor (WT1)-aniridia tumor suppressor gene compatible with the "two hit" hypothesis; (2) a Beckwith-Wiedemann Syndrome (BWS) putative oncogene imprinted in females and activated by a paternal allele gain or by loss of the inactive possibly trans-sensing maternal allele; and (3) a third unknown gene, unlinked to the WT1 and BWS genes, that shared with WT1 specificity for Wilms tumor, which was not true of the BWS gene. Activation of the IGF-2 gene may be a final common pathway for mutation in both WT1 and BWS.

• Advances in 1993 - Genetics and molecular genetics of CMN:

o Carpenter et al reported that CMN consisted of interlacing bundles of spindle-shaped cells with vimentin and actin reactivity, trisomy or tetrasomy 11, and an altered chromosome 12. This contrasted with

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the breakpoints in the q13-15 region of chromosome 12 commonly seen in leiomyomas, which are histologically similar to CMN.

o Roberts et al found 2 cell lines in a CMN, one 46,XY and the other hyperdiploid 51,XY with a 11p15 rearrangement. They questioned a histogenesis linkage between CMN and Wilms tumor since allelic loss of heterozygosity at polymorphic 11p15 loci was described in sporadic Wilms tumor, and cytogenetic and molecular 11p15 changes occurred in the Wiedemann-Beckwith syndrome with a predisposition to embryonal tumors particularly Wilms tumor.

o Schofield et al described chromosome aberrations in CMN. Using a D11Z1 centromeric probe, extra copies of chromosome 11 were detected in 7 of 10 cellular or mixed CMNs, whereas 6 of 6 classic CMNs were disomic. Fluorescence in situ hybridization, alpha satellite and centromeric probes showed that 5 of 10 cellular or mixed CMNs had extra copies of D8Z1, and 4 of 10 had extra copies of D17Z1, suggesting that gains in chromosomes 8 and 17 might be additional nonrandom cytogenetic events associated with the evolution of CMN. DNA aneuploidy was detected in 3 tumors with more than 4 chromosomal aberrations.

Advances in 1994 - Clinical and treatment studies of CMN:

o Goldberg et al reported a case of CMN that ruptured and presented with hemoperitoneum and shock.

o Mahalati et al reported a CMN that occurred in an 18-year-old man.

o Rieumont and Whitman reviewed the radiologic diagnosis of CMN.

o Lim et al reported von Willebrand disease with epistaxis in a Wilms tumor patient that improved after chemotherapy.

• Advances in 1994 - Pathology, biology and histogenesis of CMN:

o Kaw reported a case of classic CMN with scant cellularity, a clean background and a predominant naked spindle cell population arranged singly or in tight cohesive fragments, with trapped tubules and glomeruli.

• Advances in 1994 - Genetics and molecular genetics of CMN:

o Mascarello et al reported that the presence of trisomy 11 correlated with the cellular subtype of CMN.

o Escandon et al reported that the presence of TRK-A, TRK-B and TRK-C (also called NTRK3) receptor tyrosine kinase neurotrophin receptors in a wide variety of embryonic and postnatal neuronal and nonneuronal tissues, underlined the significant role of brain-derived neurotrophic factor, neurotrophin 3, and neurotrophin 4 and 5 in embryonic and postnatal development.

o Tessarollo et al reported that targeted mutation in the neurotrophin

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3 gene resulted in loss of sensory neurons and failure to thrive.

o Segal et al reported that expression of TRK-C (also called NTRK3) receptor tyrosine kinase neurotrophin receptor correlated with favorable outcome in medulloblastoma.

• Advances in 1995 - Clinical and treatment studies of CMN:

o Correia et al reported CMN associated with focal and segmental sclerosis of the kidney.

o Schlesinger et al reported another 2 cases of CMN that metastasized to the brain.

o Fung et al reported hypercalcemia-induced polyuria resulting in polyhydramnios in association with CMN.

o Mogilner et al reported acquired von Willebrand disease in a patient with CMN, noting that this was previously identified only with Wilms tumor but not with CMN.

o Yang et al reported a CMN found in a 12-year-old boy on routine physical examination.

o Chan et al reported successful preoperative vincristine monotherapy for stage 3 CMN that was too infiltrative and too advanced for primary excision.

• Advances in 1995 - Pathology, biology and histogenesis of CMN:

o Sharifah et al reported the IGF-2 gene transcript expressed abundantly in classic, cellular and mixed CMN, suggesting that CMN was derived from primitive mesenchymal nephrogenic cells that had a potential to differentiate into a stromal cell lineage. The transcript of the Wilms tumor gene (WT1) was absent.

o Becroft et al reported good prognosis in a case of CMN with hyperdiploidy and relaxation of the imprinting of the maternal IGF-2 gene. The tumor showed mosaic hyperdiploidy with 54 chromosomes in the hyperdiploid line. Genomic imprinting normally prevented transcription of the maternal IGF-2 gene. Relaxation of IGF-2 imprinting leading to abnormal transcription of the maternal gene was found in the majority of Wilms tumors and other malignant neoplasms. The biallelic transcription of IGF-2 in this case of CMN was consistent with abnormal transcription of the maternal allele. Relaxation of imprinting of the maternal IGF-2 gene or abnormal expression of the gene through other mechanisms might have a role in the genesis of CMN or its cellular subtype.

o Vujanic et al reported a large perilobar sclerosing nephrogenic rest between a CMN and the renal parenchyma in a 3-year-old girl. They suggested that this supported the theory that both CMN and Wilms tumor arose from the developing kidney but the key

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difference was the time point at which neoplastic induction occurred.

• Advances in 1995 - Genetics and molecular genetics of CMN:

o Lowery et al reported hyperdiploidy and a single structural abnormality involving a translocation between chromosomes 12 and 15 with a trisomy 11 in a monophasic CMN with prominent staghorn vascular spaces and extensive infiltration into adjacent kidney. Its composite karyotypic interpretation was 46- 47,XX,-X, +8, +11,t(12;15)(p12;q25), +17, +20[cp14].

o Nakagawara et al cloned the human TRK-B tyrosine kinase receptor (NTRK2) gene that encoded for at least 2 major sizes of TRK-B transcripts and a 822-amino acid protein, and showed 49% homology to TRK-A, and 55%, to TRK-C, the other two human central/peripheral nervous system developmental-regulatory neutrophins. The human TRK-B gene was localized to chromosome 9q22.1.

o Hoehner et al reported that TRK-C expression was most apparent in differentiated neuroblastoma tumor cells, as was TRK-A expression, while TRK-B expression was primarily localized to neuroblastoma fibrovascular stromal cells.

o Ryden et al reported that neurotrophin receptor TRK-C mRNA expression correlated with favorable neuroblastoma stage and good prognosis.

• Advances in 1996 - Clinical and treatment studies of CMN:

o Haddad et al reported the prenatal ultrasonographic diagnosis of a case of classic CMN presenting with acute polyhydramnios at 33 weeks of pregnancy, the 13th such case to be reported to date. The infant was delivered at 35 weeks.

o Liu et al reported the prenatal diagnosis of lethal hydrops fetalis in a fetus with CMN.

o Sane et al reviewed 4 Indian cases of cellular CMN, concluding that it was a potentially malignant variant of classic CMN. One case was associated with nephroblastomatosis in the non-involved part of the kidney.

o Bouvier et al reviewed the adult cases of CMN in the literature.

o Barr et al reported a case of Wilms tumor associated with von Willebrand disease at diagnosis that apparently responded completely to chemotherapy after multiple relapses.

o Jonge Poerink-Stockschlader et al reviewed the literature on acquired von Willebrand disease in children with Wilms tumor, noting previous 8 cases to which they added another 2 cases showing reduced factor VIII coagulant, von Willebrand factor

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antigen, and ristocetin cofactor activity.

• Advances in 1996 - Pathology, biology and histogenesis of CMN:

o O'Malley et al reported that cellular CMNs were composed mainly of primitive mesenchymal cells, with varying numbers of differentiating fibroblasts and myofibroblasts, thereby bearing a closer resemblance at the ultrastructural level of organization to infantile fibrosarcoma than to conventional fibrosarcoma.

o Charles reported on nephrogenic rests and CMN.

• Advances in 1996 - Genetics and molecular genetics of CMN:

o Sawyer et al reported that a novel reciprocal translocation t(14;15)(q11;q24) occurred in a predominantly classic CMN with small cellular islands of larger cells indicating early transformation to the cellular type.

o Yamashiro et al reported TRK-C receptor tyrosine kinase neurotrophin receptor expression in favorable neuroblastoma.

• Advances in 1997 - Clinical and treatment studies of CMN:

o Sutherland et al reported a case of classic CMN in a child with the Beckwith-Wiedemann syndrome.

o Kayemba Kay's et al reported a case of CMN discovered by prenatal diagnosis.

o Gemechu and Bezabeh reported a classic CMN presenting with flank pain and mass in a 54-year-old Ethiopian woman.

o Fallouh et al presented a 2-month-old infant with marrow, liver and thoracic soft tissue metastasis at diagnosis of a cellular CMN that responded to surgery, vincristine-etoposide-ifosfamide chemotherapy but was reported after a short follow-up.

o Freeby et al presented the spiral computerized tomography appearance of an adult with CMN.

o Zaidi and Mouriquand reported the diagnosis and therapy of CMN in a baby boy.

o Drubach et al reported the results of 4-hour and 24-hour imaging of CMN with 99mTcDMSA.

• Advances in 1997 - Pathology, biology and histogenesis of CMN:

o Beckwith reviewed for Cancer Investigation the new developments in the pathology of Wilms tumor and other pediatric renal tumors.

• Advances in 1997 - Genetics and molecular genetics of CMN:

o Brodeur et al reported that expression of TRK-C receptor tyrosine kinase neurotrophin receptor correlated with favorable outcome in neuroblastoma, as did TRK-A and TRK-B.

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o Svensson et al reported the co-expression of TRK-C and TRK-A mRNA in favorable neuroblastoma.

o Rubnitz et al reported ETV6 rearrangement was significantly favorable for childhood acute lymphoblastic leukemia, but 11q23/MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia) rearrangement was unfavorable, and homozygous p16 deletion was not prognostic.

• Advances in 1998 - Clinical and treatment studies of CMN:

o Yamashita et al reported a classic CMN presenting with asymptomatic hematuria in a 20-year-old Japanese man.

o Campagnola et al reported a case of cystic CMN of the cellular subtype with diffuse areas of hemorrhage and necrosis that invaded the surrounding structures and renal parenchyma but appeared biologically benign.

o Matias Garcia et al reported a case of CMN in a 17-year-old woman.

• Advances in 1998 - Pathology, biology and histogenesis of CMN:

o Truong et al reviewed 22 cases of adult CMN in the literature, adding 5 new cases.

§ The 22 patients had the following characteristics: (1) they were predominantly women (20 cases); (2) their ages ranged from 19-78 years; (3) they were asymptomatic or had a nonspecific mass effect; (4) twenty of the tumors were classic and 2 cellular; (5) tumors ranged from 2-24 cm in size and were well circumscribed, partially encapsulated, predominantly solid but partly cystic to almostly cystic; (6) most of the tumors extended to the renal sinus, some appearing entirely intrapelvic; (7) no gross and microscopic destruction or invasion of the pelvic wall was noted; and (8) tumors did not extend beyond the renal capsule.

§ Microscopically, tumors were composed of epithelial and stromal components with the following features: (1) epithelial component similar in classic and cellular variants with isolated or clustered tubules and cysts lined by differentiated epithelium; (2) stroma composed of fibroblasts, myofibroblasts and smooth muscle cells with low cellularity for the classic but high cellularity for the cellular variant; (3) hemorrhage, necrosis and high mitotic index in the stroma of the cellular, but not the classic, variant; (4) fibroblasts, myofibroblasts, smooth muscle cells, and prominent vessels identified immunologically in the stroma; and (5) cysts and tubules that profiled similar to the collecting duct.

§ Clinically, the 22 patients underwent total or partial

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nephrectomy without adjuvant chemotherapy or radiotherapy, with the following outcomes: (1) 19 patients, including the 2 with cellular CMN, were well at 8 months to 48-years follow-up; (2) follow-up was unavailable in 2 patients; and (3) one patient had surgical site recurrence 24 years after nephrectomy.

§ In conclusion, adult CMN is characterized by the following: (1) a distinctive morphologic spectrum paralleling childhood CMN; (2) successful outcome after complete excision; and (3) collecting duct-type differentiation expressed by most tubules and cysts, implying that the ureteric bud, exclusively the embryologic origin of the collecting duct, was important in adult CMN histogenesis.

• Advances in 1998 - Genetics and molecular genetics of CMN:

o Dal Cin et al reported a 1-month-old boy with a 48,XY, +10, +11 karyotypic CMN. They concluded that trisomy 11 stood out, whereas involvement of the long arm of chromosome 15 may be a nonrandomly occurring structural change.

o Knezevich et al reported a novel recurrent t(12;15)(p13;q25) rearrangement that induced a ETV6-NTRK3 gene fusion in congenital infantile fibrosarcoma, a good-prognosis, low-grade malignant, rarely metastatic fibroblastic tumor that occured in patients younger than 2 years.

§ ETV6-NTRK3 rearrangement was absent in the histologically identical aggressive poor-prognosis adult-type fibrosarcoma of adults and older children, and in a histologically similar but benign fibroblastic proliferation in young children called infantile fibromatosis.

§ The rearrangement fused the ETV6 gene (ETS variant gene 6, also known as TEL) from 12p13 with the 15q25 NTRK3 neurotrophin 3 receptor gene (neurotrophic tyrosine kinase receptor type 3, also known as TRK-C). ETV6-NTRK3 fusion transcripts encoded the helix-loop-helix protein dimerization domain of ETV6, fused to the protein tyrosine kinase domain of NTRK3. This suggested that the chimeric protein-tyrosine kinase expressed in congenital infantile fibrosarcoma might contribute to oncogenesis by abnormally activating receptor tyrosine kinase signaling pathways and dysregulating NTRK3 signal transduction pathways.

o Knezevich et al reported that cellular and mixed (classic plus cellular) CMN and congenital infantile fibrosarcoma both contained trisomy 11 and a t(12;15)(p13;q25)-associated chimeric fusion gene made up of the ETV6 gene and the NTRK3 gene. This established a histogenetic link between the “benign” renal cellular

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and mixed CMN and the virtually identical histologically nonrenal congenital infantile fibrosarcoma, a low-grade malignancy that also occurred in young infants. Classic CMN tested negative, as did Wilms tumor and clear cell sarcoma. The different molecular genetic features of classic and cellular CMN suggested their different histogenesis, with cellular CMN being histogenetically related to congenital infantile fibrosarcoma. Their data provided insight into potential mechanisms involved in the transformation of the classic CMN into cellular CMN. This suggested that the chimeric protein-tyrosine kinase expressed in the tumor cells might contribute to cellular transformation from normal to cancer cells by abnormally activating receptor tyrosine kinase signaling pathways.

o Rubin et al reported that the t(12;15)(p13;q25) translocation in CMN, and the associated chimeric ETV6-NTRK3 gene fusion, antedated the acquisition of polysomies of chromosomes 8, 11, 17, and 20. By virtual of their common molecular genetics, they speculated that CMN and the histologically similar congenital infantile fibrosarcoma are pathogenetically related, perhaps representing a single neoplastic entity.

• Advances in 1999 - Clinical and treatment studies of CMN:

o Willert et al reported CMN as a cause of perinatal anemia.

o Puvaneswary and Roy reviewed the MRI findings of CMN.

o Shibahara et al reported the prenatal sonographic diagnosis of a polyhydramnios and renal CMN that occurred after transfer of a cryopreserved embryo.

o Shiraishi et al reported a case of classic CMN found incidentally in a 50-year-old woman that was treated surgically.

• Advances in 1999 - Pathology, biology and histogenesis of CMN:

o Siracusano et al reported strong proliferating cellular nuclear antigen (PCNA), vimentin and actin positivity, but p53 negativity, in a case of classic CMN with benign biological behavior. PCNA positivity is generally considered to be a reliable marker of potential malignancy.

• Advances in 1999 - Genetics and molecular genetics of CMN:

o Eguchi et al determined by fluorescence in situ hybridization that fusion gene ETV6-TRKC, consisting of the ETS variant gene 6 ETV6 on 12p13, and the TRK-C gene on 15q25, produced by the t(12;15)(p13;q25) translocation, occurred in a case of adult acute myeloid leukemia.

§ TRKC, a receptor tyrosine kinase that was activated by neurotrophin type 3, was broadly expressed in neural tissues but not previously found in hematologic cells. The ETV6-TRKC chimeric transcript encoded the pointed domain of the

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TRKC chimeric transcript encoded the pointed domain of the ETV6 gene that fused to the protein-tyrosine kinase domain of the TRKC gene.

§ One fusion transcript was produced for the entire protein-tyrosine kinase domain of TRK-C, and another for the 3'-terminus 462 base pair of TRKC truncated at the protein-tyrosine kinase domain. This suggested that the chimeric protein-tyrosine kinase expressed in the myeloid leukemic cells might contribute to cellular transformation by abnormally activating receptor tyrosine kinase signaling pathways.

• Advances in 2000 - Clinical and treatment studies of CMN:

o Bisceglia et al reviewed the most significant literature on CMN.

o Irsutti et al reported the prenatal ultrasonographic and MRI features of 20 cases of CMN. Early and correct detection of this rare entity facilitated the management of severe obstetric and neonatal complications such as polyhydramnios and prematurity. They concluded that MRI might be required rarely to evaluate the origin and the morphologic features of a fetal abdominal mass.

o Schild et al reported the prenatal diagnosis of a CMN by 3-dimensional ultrasonography that gave a reliable estimation of the tumor size.

o Kumar and Jain diagnosed a 50-year-old woman’s renal mass by aspiration cytology that showed cellular cohesive interlacing fragments of spindle cells embedded in abundant pink fibrillary stromal matrix. Epithelial tubular components were seen, but not pleomorphism, mitosis, or necrosis.

o Nakano et al reported a case of CMN in a 52-year-old Japanese man with hematuria and back pain and reviewed 38 cases of adult CMN in the literature.

• Advances in 2000 - Pathology, biology and histogenesis of CMN:

o Bisceglia et al reviewed the morphological subtypes of CMN: classic or leiomyomatous CMN and cellular CMN, with mixed CMN combining the two patterns. They described a mixed lesion showing a high mitotic index, diploid DNA cellular component infiltrating perirenal fat, and an euploid-DNA classical component.

o Herman and Siegel reviewed the pathology of the cystic variant of CMN.

o Daniel et al reviewed the pathology of an asymptomatic CMN in a 54-year-old woman that showed immunohistochemical reactions similar to developing nephrons. Electron microscopy showed immature tubules with numerous intracytoplasmic intermediate

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filaments. Recent studies of the pathogenesis of CMN suggested its origin from collecting ducts, but this tumor showed a complex pattern of antigenic expression not restricted to the collecting ducts, but including the glycoprotein CD24 and neural cell adhesion molecule.

o Yanai et al reported two polypoid renal pelvic CMN in a 44-year-old man characterized by: (1) glandular components, some with ciliated epithelium similar to epididymal tubules, some resembling collecting ducts or mesonephric remnant of female genitalia, others containing psammoma bodies; (2) stromal components with smooth muscle differentiation on immunological and ultrastructural analysis. Adult CMN constituted clinicopathologically different entities originating from pediatric CMN. Differentiation of adult CMN from angiomyolipoma, leiomyoma, and nephrogenic adenofibroma was discussed.

o Vegunta et al reported an extremely rare CMN in contiguity with a neuroblastoma in an infant’s kidney, and discussed and reviewed childhood “collision tumors”.

o Miller and Kolon reported that hypertension and reninism were due either to the CMN or secondarily from compression and ischemia of the renal vascular pedicle.

• Advances in 2000 - Genetics and molecular genetics of CMN:

o Argani et al reported that the RNA of the ETV6-NTRK3 chimeric fusion gene, produced by the t(12;15)(p13;q25) translocation, which was characteristic of the cellular variant of CMN and congenital infantile fibrosarcoma, could be specifically detected by the reverse transcriptase polymerase chain reaction (RT-PCR), while classical CMN, rhabdoid tumors and clear cell sarcoma were negative.

o Bourgeois et al used RT-PCR, cytogenetic and immunohistochemical detection to determine that the t(12;15)(p13;q25) translocation, which gave rise to an ETV6-NTRK3 gene fusion, distinguished the relatively benign seldom-metastatic congenital infantile fibrosarcoma from other childhood spindle-cell tumors, including the benign infantile fibromatosis and myofibromatosis, and the malignant spindle-cell sarcoma and adult-type fibrosarcoma.

o Punnett et al reported the presence of the ETV6-NTRK3 fusion gene in a metastasizing case of the generally relatively benign low-grade fibroblastic neoplasm, congenital infantile fibrosarcoma.

o Okamoto et al used the absence of the t(12;15)(p13;q25) translocation-related ETV6-NTRK3 fusion gene mRNA transcript, to corroborate and distinguish childhood monophasic fibrous or

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biphasic subtype synovial sarcoma, which could be mistaken for the ETV6-NTRK3-bearing congenital infantile fibrosarcoma. The ETV6-NTRK3 genetic marker could be used to distinguish congenital infantile fibrosarcoma from synovial sarcoma, which was characterized by a t(X;18)(p11.2;q11.2) translocation-related SYT-SSX1 fusion gene, and from the other fibroblastic spindle-cell disorders including spindle-cell rhabdomyosarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.

o Wai et al reported that the t(12;15)(p13;q25) rearrangement spliced the ETV6 gene on chromosome 12p13 in-frame with the NTRK3 neurotrophic tyrosine kinase receptor type 3 gene on chromosome 15q25. The resultant ETV6-NTRK3 fusion transcripts encoded the helix-loop-helix dimerization domain of ETV6 fused to the protein tyrosine kinase domain of NTRK3. ETV6-NTRK3 homodimerized and heterodimerized with wild-type ETV6.

ETV6-NTRK3 had protein tyrosine kinase activity and was autophosphorylated on tyrosine residues. ETV6-NTRK3 fusion gene encoded a chimeric protein tyrosine kinase that transformed NIH/3T3 cells, which grew macroscopic colonies in soft agar, and formed tumors in severe combined immunodeficient (SCID) mice. Chimeric ETV6-NTRK3 proteins mediated transformation of normal cells to tumor cells by dysregulating the NTRK3 signal transduction pathways via ligand-independent dimerization and protein tyrosine kinase activation. ETV6-NTRK3 was a transforming protein that required an intact dimerization domain and a functional protein tyrosine kinase domain for transformation activity.

• Advances in 2001 - Clinical and treatment studies of CMN:

o Michiels et al depicted the acquired von Willebrand disease in Wilms tumor patients as “atypical” since: (1) symptoms of mucocutaneous bleeding were mild; (2) von Willebrand factor antigen, ristocetin cofactor and factor VIII coagulant activity were undetectable or low; (3) response to DDAVP was good in 2 but poor in 1 patient; (4) 3 patients showed the normal pattern of Type I, and 3 patients showed absence of multimers consistent with Type III acquired von Willebrand disease; (5) the higher functional versus antigen level with increased ratio of factor VIII coagulant activity/von Willebrand factor antigen and von Willebrand ristocetin cofactor/von Willebrand factor antigen remained unexplained and was inconsistent with Type I von Willebrand deficiency; (6) family history was absent; (7) parameters normalized after chemotherapy or nephrectomy; and (8) the causative agent might be hyaluronic acid secreted by Wilms tumor.

• Advances in 2001 - Pathology, biology and histogenesis of CMN:

o Arroyo et al reported from the NWTS Pathology Center the spectrum of 25 cases of metanephric adenofibroma, a bland

46

spectrum of 25 cases of metanephric adenofibroma, a bland spindle-cell tumor whose stroma resembled, but was distinguishable from, the stroma of CMN by the intratumoral angiodysplasia, concentric "onion skinning" cuffing of entrapped tubules and heterologous differentiation, and the wide range of appearances of its epithelial components.

• Advances in 2001 - Genetics and molecular genetics of CMN:

o Sheng et al detected the ETV6-NTRK3 fusion gene mRNA transcript in the relatively indolent non-renal congenital infantile fibrosarcoma that carried the reciprocal translocation t(12;15)(p13;q25), the same translocation and molecular genetic alteration that had also been found in CMN. The gene fusion occurred between ETV6 exon 5 and NTRK3 exon 13 and was mediated by the (12;15)(p13;q25) translocation. Other spindle-cell tumors tested negative for the fusion gene transcript; they expressed NTRK3 but not ETV6.

o Van Limbergen et al reported ETV6/ABL1-positivity in a case of adult chronic myelogenous leukemia and one of childhood T-lineage acute lymphoblastic leukemia. The ETV6 gene was located at 12p13, and deletions or translocations are common findings in hematologic malignancies. Various partner genes had been implicated in the formation of fusion genes with ETV6, including PDGFRB, JAK2, NTRK3, ABL2, and ABL1, each of which encoded for proteins with tyrosine kinase activity.

In leukemia, the formation of an ETV6/ABL1 fusion gene required at least 3 chromosomal breaks, and each of these translocations was the result of a complex chromosomal rearrangement. More than one mRNA transcripts could ensue from the ETV6/ABL1 gene fusion as a result of alternative splicing. ETV6/ABL1 and other fusion genes could lead to increased tyrosine kinase activity. The ETV6-NTRK3 fusion gene was found in two low-grade infantile malignancies, cellular CMN and congenital infantile fibrosarcoma.

o Pujana et al reviewed the rearrangements between 12p13 and 15q25 that caused congenital infantile fibrosarcoma. A new set of human chromosome 15q duplicons was recognized on 15q11-q13, 15q24 and 15q26. Several regions of sequence similarity existed with other chromosomes (6q, 7p, 12p) and with other 15q cytogenetic bands (15q11-q13, 15q24). The neurotrophin 3 receptor NTRK3 gene mapped to 15q25.3. The Bloom chromosomal fragility/leukemia-predisposing syndrome region mapped to 15q26.1. The Prader-Willi/Angelman overgrowth/dysmorphic syndrome imprinting center was close to 15q11-q13. The 12p similar sequence maps on 12p13, at a distance to ETV6 that is equivalent on 15q26.1 to the distance to NTRK3. Both ETV6 and NTRK3 were targets of congenital infantile

47

fibrosarcoma recurrent translocations, suggesting that misalignments between these two chromosomes regions could facilitate recombination. Low-copy repeat sequences, mainly at 15q24 and 15q26, were located close to a HERC2 sequence on the distal end of the Prader-Willi/Angelman region, 3 around the lysyl oxidase-like (LOXL1) gene on 15q24, and 3 on 15q26, one of which close to the IQ motif containing the GTPase-activating protein 1 (IQGAP1) gene on 15q26.1. These low-copy repeat sequences on chromosome 15 spanned between 13 and 22 kilobases and contained high identity with the golgin-like protein (GLP) and the SH3 domain-containing protein (SH3P18) gene sequences.

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