Carl-Magnus Kullendorff

Cytogenetics of hepatoblastoma: further characterization of 1q rearrangements by fluorescence in situ hybridization: an international collaborative study

BACKGROUND Hepatoblastoma (HBT) is the most common hepatic neoplasm in children. This notwithstanding, little is known about pathogenetic factors, such as genetic abnormalities, of importance for the development and progression of this tumor type. To date, only 33 cytogenetically abnormal HBT have been published, and trisomies for chromosomes 2 and 20 have been shown to be the most frequent aberrations. Recently, unbalanced translocations involving proximal 1q have been described in several HBT, suggesting that a pathogenetically important gene maps to 1q. PROCEDURE Six primary and one recurrent HBT were cytogenetically analyzed after short-term tissue culture. In addition, fluorescence in situ hybridization (FISH) studies, using locus-specific probes, were performed on three of these pediatric HBT as well as on one previously reported adult HBT. RESULTS Total or partial trisomy 8, gain of chromosome 20, and structural rearrangements of chromosome 1 were detected in three HBT, and overrepresentation of chromosome 2 material was found in two HBT. The adjacent chromosome bands 1q12 and 1q21 were involved in three translocations, t(1;2), t(1;4), and t(1;11), which were all unbalanced and resulted in gain of 1q material. The previously reported adult HBT displayed 1q deletions with breakpoints at 1q12-21. FISH analyses of the 1q rearrangements revealed that all breakpoints were within the heterochromatic region. CONCLUSIONS These findings provide further support for the importance of trisomies 2, 8, and 20 and rearrangements of 1q in the development of HBT. Furthermore, the consistent localization of breakpoints within the heterochromatic segment of chromosome 1 suggests that the important pathogenetic consequence of 1q abnormalities is the resulting genomic imbalance rather than a specific gene rearrangement.

Cytogenetic and molecular cytogenetic findings in lipoblastoma

Lipoblastoma is a rare benign tumor that arises from embryonic adipose tissue and usually occurs in young children. Here, we present a review of available cytogenetic data and the karyotypes of 10 new cases of lipoblastoma, of which 7 could be studied further by fluorescence in situ hybridization (FISH) with regard to the involvement of the PLAG1 gene. All seven tumors with clonal aberrations harbored breakpoints in 8q11 approximately q13, in agreement with literature data. Including previously published cases, 33/40 (82%) lipoblastomas had rearrangement of the 8q11 approximately q13 region. These rearrangements target the PLAG1 gene, which becomes upregulated through promoter swapping. FISH revealed that five of seven cases in our series had a rearrangement of the PLAG1 gene. Occasionally, there can be difficulties in distinguishing a lipoblastoma from a conventional lipoma or a myxoid liposarcoma. As 8q11 approximately q13 rearrangements have been reported in only 3% of conventional lipomas and never in myxoid liposarcoma, cytogenetic analysis or FISH for the PLAG1 gene can provide useful differential diagnostic information.

Chromosomal aberrations in a consecutive series of childhood rhabdomyosarcoma

BACKGROUND AND PROCEDURE During a 13-year period, 22 children were treated for rhabdomyosarcoma (RMS). In 18 of these patients chromosome analysis was attempted on material from tumor biopsies, fine needle aspiration biopsies and/or bone marrow samples. RESULTS Clonal chromosome aberrations were detected in 14 cases; 7 of 9 embryonal RMS, 6 of 8 alveolar RMS and in the single case of pleomorphic RMS cytogenetic failures were more frequent in fine needle aspiration biopsies than in tumor biopsies. The characteristic t(2;13) translocation was seen in 2 alveolar RMS but not in any of the other subtypes. In 3 of the embryonal RMS hyperdiploid or hypertetraploid karyotypes with few or no structural rearrangements were seen. In all 3 cases the clinical course was relatively benign, suggesting that certain karyotypic patterns in RMS may be of prognostic significance. CONCLUSIONS Our results add to the evidence that cytogenetic analysis should be an integral part of the diagnostic examinations of children with RMS.

Cytogenetic aberrations in Ewing sarcoma: are secondary changes associated with clinical outcome?

BACKGROUND Ewing sarcoma is associated with a nonrandom pattern of primary and secondary chromosomal aberrations. Whereas the finding of rearrangements of chromosome 22, usually in the form of a balanced translocation t(11;22)(q24;q12), is important diagnostically, nothing is known about the potential prognostic impact of the secondary chromosomal aberrations. PROCEDURE During a 1 3-year-period, short-term cultured tumor samples from 21 children and young adults with Ewing sarcoma were cytogenetically analyzed successfully. RESULTS Clonal chromosome aberrations were detected in 18 patients, 17 of whom had the characteristic t(11;22)(q24;q12) or variants thereof. The most frequent secondary change was +8, followed by +12, +2, +5, +9, +15, and gain of material from the long and short arms of chromosome 1. The only recurrent secondary change that was restricted to tumors from the ten patients that were dead at latest follow-up was gain of 1q material. Furthermore, all three patients with tumors with chromosome numbers over 50 had died, and the only patient with a tumor karyotype lacking chromosome 22 rearrangement was alive without evidence of disease. CONCLUSIONS These data and previously published results indicate that the karyotypic pattern not only may be of diagnostic significance but also may be important prognostically.

A Microsurgical Method for Denervation of the Liver in the Rat

The role of the nerves in the hepato-duodenal ligament should be of special surgical interest, since these nerves are often injured in hepatic and biliary tract surgery. We have developed a microsurgical procedure for liver denervation. All visible nerves were resected after staining. Norepinephrine values in central liver tissue of denervated rats were only 18% of the corresponding values in innervated liver tissue, indicating an appreciable degree of sympathetic denervation. No detectable immunoreactivity of gastrin, cholecystokinin, vasoactive intestinal polypeptide, substance P, somatostatin or enkephalin were found within resected hepatic nerves. The described denervation procedure is simple and reproducible. It can be used to obtain additional information about the nervous regulation of various liver functions.

Granulocytic sarcomas in body cavities in childhood acute myeloid leukemias with 11q23/MLL rearrangements

Three childhood acute monoblastic leukemias (AML M5) with granulocytic sarcomas (GSs) are described. All displayed 11q23/MLL abnormalities, t(9;11)(p22;q23) in two cases and t(11;17)(q23;q21) in one case, constituting around 20% of all 11q23‐positive AML cytogenetically investigated in our department. Two of the patients had GS in multiple locations, and all three had abdominal GS. In two of them, t(9;11)‐positive GS was diagnosed prior to the diagnosis of AML. Fourteen (1.9%) of 752 published AML cases with 11q23 aberrations have had GS, either as a presenting feature or during disease progression. The incidence of GS has varied significantly (P < 0.05) between children (3.8%) and adults (0.8%). The most common AML subtype has been AML M5 (∼ 75%) and the most frequent GS sites have been the skin, abdomen, orbit, and thorax. Considering the possibility of underreporting of GS in published cases and the relatively high frequency in our own series, we believe that 11q23/MLL rearrangements may predispose to GS development. Although extramedullary infiltrates in the skin are known to be frequent in cases of AML M5, which is often associated with 11q23 aberrations, the present findings indicate that GS in the abdomen, orbit, and thorax may also be common, especially in pediatric AML. Thus, the possibility of 11q23/MLL‐positive GS should be suspected when tumors of uncertain derivation occur in these sites. Finally, the identification of 11q23/MLL abnormalities in GSs in two patients without overt AML underscores the importance of using cytogenetic and molecular genetic investigations as a diagnostic approach in the evaluation of tumorous lesions of unknown origin. Genes Chromosomes Cancer 27:136–142, 2000.

Laparoscopic aided cholecystostomy as a treatment of inspissated bile syndrome.

We report a case of a newborn girl with inspissated bile syndrome (IBS) that did not respond to treatment with oral ursodeoxycholic acid (Ursofalk). A solution was found using laparoscopic aided cholecystostomy with an indwelling catheter for local Ursofalk flushing in the gallbladder and the choledochus. This is the first report of a laparoscopic aided management of IBS without cholecystectomy or exploration of the bile ducts. This minimal invasive approach showed a clear advantage for the patient. There were no complications. The method is recommended in the treatment of IBS.

Membranous duodenal stenosis

The experience of our 16 patients treated for membranous duodenal stenosis is reported. Their treatment and course was analysed in a retrospective study. Eight patients were operated on within the first 16 days of life and in the remaining group surgery was performed at 1 month to 4 y of age. The presenting symptom leading to diagnosis was, in all but one case, non‐bile‐stained vomiting. Associated malformations were found in all but four patients, mostly morbus Down. The operative procedure performed was a partial excision of the duodenal membrane and a duodenoplasty in 10 patients, a duodenojejunostomy in 5 patients, and a duodenoplasty only in 1 patient. The postoperative course was without lethal complications. One late stricture in an anastomosis occurred. We conclude that in its presentation, duodenal stenosis differs from duodenal atresia, and can often be misinterpreted, resulting in a late diagnosis, and should be reported as a separate entity.

Continuous Double U-stitch Gastrostomy in Children.

BACKGROUND In children, a gastrostomy button was placed as the initial feeding tube, using laparoscopy and a modified surgical technique. The aim of this study was to test the hypothesis that a new surgical procedure developed at our institution would result in fewer postoperative complications. PATIENTS AND METHODS Sixty-two consecutive children with nutritional problems underwent a video-assisted gastrostomy operation (VAG). The technique requires the use of a 2 or 3 mm laparoscope optic and a 5 mm trocar placed at the exit site chosen for the gastrostomy. A continuous double U-stitch absorbable suture created a purse string suture around the gastrostoma on the stomach and fixated the stomach to the abdominal wall. For comparison, we used a control group of 68 children with nutritional problems operated on with our previously published VAG technique. After surgery, the children were followed up at one and six months and all complications were documented according to a protocol. RESULTS The two groups of children were comparable with regard to their demographic data. There were no serious intra-operative or postoperative intra-abdominal complications requiring reoperation. There was a significantly lower incidence of the minor complication of granuloma around the gastrostoma in the study group compared with the control group. CONCLUSION This variation of the surgical technique is simple and effective. It allows primary placement of a gastrostomy button that is functionally and cosmetically comparable to a gastrostomy tube surgically placed by other methods. In this study, the patients had fewer postoperative problems than the control group.

Complex Karyotype in a Childhood Adrenocortical Carcinoma

Cytogenetic analysis of short-term cultured cells from an 11-cm adrenocortical carcinoma in a 3.5-year-old girl revealed the karyotype 46,XX,inv(9)(p11q12)c/[2]/56-57,XX,+2,+4,+5,+7,+8,inv(9)c,+10,+add (13)(p11), +14,+15,+19,+20,+20,+mar[cp19]. To our knowledge, this is the first description of an abnormal karyotype in a pediatric adrenocortical tumor. Inasmuch as the distinction between benign and malignant adrenocortical tumors is often difficult to make from clinical and histopathologic data alone, the present findings suggest that cytogenetic analysis may be a valuable adjunct in the differential diagnosis.