Magnus Hallén

Frequent rearrangements of chromosomes 1, 7, and 8 in primary liver cancer

Fifteen primary liver carcinomas (PLCs), including 12 hepatocellular carcinomas and three cholangiocellular carcinomas, were investigated cytogenetically after short‐term culture. Ten tumors displayed clonal chromosomal abnormalities, whereas only normal karyotypes were detected in four cases, and one sample failed to grow in vitro. Structural rearrangements most often involved chromosomes 1, 7, and 8 and chromosome bands 1p36, 1q25, 3q10, 5q13, 6p10, 7p15, 7q22, 7q32, 8q10, 8q13, 14q10, and 17p11. Frequent genomic imbalances included gains of 1q, 3q, 6p, 7p, and 8q and losses of 1p, 8p, 10q, 14p, 17p, and 19p. A compilation of findings for all 19 cytogenetically abnormal PLCs reported to date, including the present cases, reveals that structural aberrations particularly affect 1p11, 1p22, 1p32, 1p34, 1p36, 1q25, 7p15, 7q22, 8q10, 8q13, 14q10, 16q24, and 17p11, and that the abnormalities frequently result in overrepresentation of 1q, 3q, 6p, 7p10–14, 8q, and 17q and underrepresentation of 1p34–36, 6q27, 7q32–qter, 8p, 13p, 14p, 16q24, and 17p. These genomic regions are likely to harbor genes of importance in hepatocarcinogenesis, and the present cytogenetic mapping may hence be of value for further molecular genetic investigations of PLC. Genes Chromosomes Cancer 23:26–35, 1998.

Laparoscopic extraperitoneal inguinal hernia repair versus open mesh repair : long-term follow-up of a randomized controlled trial

BACKGROUND We have conducted a randomized controlled trial of totally extraperitoneal hernia repair (TEP) versus tension-free open repair (Lichtenstein repair); we have presented the results previously up to 1 year after the operation. The aim of this study was to compare patient outcome in both groups at a median follow-up of 7.3 years after operation. METHODS Of 168 patients included in a prospective, randomized controlled trial designed to compare TEP with an open tension-free technique, 154 patients (92%) answered a questionnaire and 147 patients (88%) were followed up at an outpatient clinic after a minimum of 6 years after operation. RESULTS Overall, 89% of patients in the TEP group and 95% of patients in the open group reported complete long-term recovery (P = .23). Permanent impaired inguinal sensibility was more common in the open group (P = .004), whereas the proportion of patients with reported testicular pain was higher in the TEP group (P = .003). Three recurrences were found in the TEP group, and 4 recurrences were found in the open group (P = .99). Four patients in the TEP group underwent operations for complications related to the hernia repair (small bowel obstruction, umbilical hernia, testicular pain, and neuralgia). CONCLUSION Overall, both groups showed good long-term results with low rates of recurrences. However, the TEP group was associated with a higher proportion of patients with long-term testicular pain, whereas impaired inguinal sensibility was more common in the open group.

Clonal chromosomal abnormalities in congenital bile duct dilatation (Caroli’s disease)

BACKGROUND Caroli’s disease is a rare congenital disorder characterised by cystic dilatation of the intrahepatic bile ducts and an increased risk of cholangiocellular carcinoma. The cause is unknown, but occasional familial clustering suggests that some cases are inherited, in particular when occurring in association with polycystic kidney disease and germline PKD1 gene mutations. To date, no gene responsible for familial isolated Caroli’s disease has been identified, and no genetic investigations of liver tissue from patients with Caroli’s disease have been reported. PATIENT/METHOD A liver biopsy specimen from a patient with isolated Caroli’s disease, without any signs of cholangiocellular carcinoma, was short term cultured and cytogenetically investigated after G banding with Wright’s stain. RESULT Cytogenetic analysis disclosed the karyotype 45-47,XX,der(3)t(3;8)(p23;q13), +2mar[cp6]/46,XX[18]. CONCLUSIONS The finding of an unbalanced translocation between chromosomes 3 and 8 suggests that loss of distal 3p and/or gain of 8q is of pathogenetic importance in Caroli’s disease. Alternatively, structural rearrangements of genes located in 3p23 and 8q13 may be of the essence. These chromosomal breakpoints may also pinpoint the location of genes involved in inherited forms of Caroli’s disease not associated with polycystic kidney disease.

Cytogenetic abnormalities and clonal evolution in an adult hepatoblastoma

Hepatoblastomas usually occur in children < 3 years of age, and only occasional adult cases have been described. To date, 20 cytogenetically abnormal childhood hepatoblastomas have been reported. Karyotypic investigations have shown that most hepatoblastomas are diploid or hyperdiploid, often displaying trisomies for chromosomes 2 and 20. We have cytogenetically investigated an adult hepatoblastoma for which no previous karyotypic data exist. A hypertriploid stemline with multiple numerical and structural chromosomal aberrations, including +2 and +20, was found. In addition, the tumor displayed extensive clonal evolution with 11 subclones. Although the tumor thus displayed some chromosomal abnormalities commonly observed in childhood tumors, providing further support for the importance of these abnormalities in the development of hepatoblastoma, the level of genomic complexity seen in the present case has never been described in childhood hepatoblastomas and may suggest a different etiology or pathogenesis.

Cytogenetic analyses of secondary liver tumors reveal significant differences in genomic imbalances between primary and metastatic colon carcinomas

To investigate if karyotypic features of secondary liver tumors may provide diagnostic information and if the cytogenetic patterns of primary and metastatic colorectal carcinomas (CRC) are different, 33 liver metastases were analyzed: 25 CRC, 4 small intestine carcinoids, 1 ovarian carcinoid, 1 lobular breast cancer, 1 head-and-neck squamous cell carcinoma, and 1 uveal malignant melanoma. Chromosomal aberrations were detected in 24 cases, whereas 5 had normal karyotypes and 4 were uninformative due to lack of mitoses. Trisomy 12 was detected in 2 small intestine carcinoids, suggesting that +12 may be of pathogenetic importance in this tumor type. The breast and head-and-neck carcinomas and the uveal melanoma displayed aberrations previously reported as characteristic in primary tumors, e.g., der(1;16) and deletion of 3p in the breast cancer, losses of 3p and 8p and partial gain of 8q in the head-and-neck carcinoma, and monosomy 3 and i(8)(q10) in the uveal melanoma, indicating that cytogenetic investigations provide important diagnostic information in secondary liver tumors. In the 18 CRC metastases with chromosomal abnormalities, the cytogenetic findings agreed well with previously reported primary CRC. Common numerical abnormalities included gains of chromosomes 7, 11, 13, and 20, and losses of Y, 4, 18, 21, and 22. Structural rearrangements most often affected chromosome bands 1p13, 1q10, 3p21, 5q10, 5q11, 7q10, 8q10, 8q11, 12q13, 16p13, 17p11, 20p13, 20p11, and 20q10, and frequently resulted in losses of 1p, 8p, and 17p, and gains of 5p, 6p, 7p, 8q, and 20q. Comparing the present cases with primary CRC previously analyzed in our department revealed that additional gains of 6p, 6q, 7p, and 20q, and losses of 1p, 4p, 4q, 8p, 18p, 18q, and 22 were more common (P<0.05) in the metastases, suggesting that these genomic sites harbor genes of importance in the metastatic process of CRC.

Male infertility after mesh hernia repair: A prospective study

BACKGROUND Several animal studies have raised concern about the risk for obstructive azoospermia owing to vasal fibrosis caused by the use of alloplastic mesh prosthesis in inguinal hernia repair. The aim of this study was to determine the prevalence of male infertility after bilateral mesh repair. METHODS In a prospective study, a questionnaire inquiring about involuntary childlessness, investigation for infertility and number of children was sent by mail to a group of 376 men aged 18-55 years, who had undergone bilateral mesh repair, identified in the Swedish Hernia Register (SHR). Questionnaires were also sent to 2 control groups, 1 consisting of 186 men from the SHR who had undergone bilateral repair without mesh, and 1 consisting of 383 men identified in the general population. The control group from the SHR was matched 2:1 for age and years elapsed since operation. The control group from the general population was matched 1:1 for age and marital status. RESULTS The overall response rate was 525 of 945 (56%). Method of approach (anterior or posterior), type of mesh, and testicular status at the time of the repair had no significant impact on the answers to the questions. Nor did subgroup analysis of the men ≤40 years old reveal any significant differences. CONCLUSION The results of this prospective study in men do not support the hypothesis that bilateral inguinal hernia repair with alloplastic mesh prosthesis causes male infertility at a significantly greater rate than those operated without mesh.

Mesh hernia repair and male infertility: A retrospective register study.

BACKGROUND Previous studies have suggested that the use of mesh in groin hernia repair may be associated with an increased risk for male infertility as a result of inflammatory obliteration of structures in the spermatic cord. In a recent study, we could not find an increased incidence of involuntary childlessness. The aim of this study was to evaluate this issue further. METHODS Men born between 1950 and 1989, with a hernia repair registered in the Swedish Hernia Register between 1992 and 2007 were cross-linked with all men in the same age group with the diagnosis of male infertility according to the Swedish National Patient Register. The cumulative and expected incidences of infertility were analyzed. Separate multivariate logistic analyses, adjusted for age and years elapsed since the first repair, were performed for men with unilateral and bilateral repair, respectively. RESULTS Overall, 34,267 men were identified with a history of at least 1 inguinal hernia repair. A total of 233 (0.7%) of these had been given the diagnosis of male infertility after their first operation. We did not find any differences between expected and observed cumulative incidences of infertility in men operated with hernia repair. Men with bilateral hernia repair had a slightly increased risk for infertility when mesh was used on either side. However, the cumulative incidence was less than 1%. CONCLUSION Inguinal hernia repair with mesh is not associated with an increased incidence of, or clinically important risk for, male infertility.

Nonrandom chromosomal aberrations and cytogenetic heterogeneity in gallbladder carcinomas.

Chromosome banding analysis of 11 short‐term cultured gallbladder carcinomas revealed acquired clonal aberrations in seven tumors (five primary and two metastases). Three of these had one clone, whereas the remaining four were cytogenetically heterogeneous, displaying two to seven aberrant clones. Of a total of 21 abnormal clones, 18 had highly complex karyotypes and three exhibited simple numerical deviations. Double minutes and homogeneously staining regions were observed in one and two carcinomas, respectively. To characterize the karyotypic profile of gallbladder cancer more precisely, we have combined the present findings with our three previously reported cases, thereby providing the largest cytogenetic database on this tumor type to date. A total of 287 chromosomal breakpoints were identified, 251 of which were found in the present study. Chromosome 7 was rearranged most frequently, followed by chromosomes 1, 3, 11, 6, 5, and 8. The bands preferentially involved were 1p32, 1p36, 1q32, 3p21, 6p21, 7p13, 7q11, 7q32, 19p13, 19q13, and 22q13. Nine recurrent abnormalities could, for the first time, be identified in gallbladder carcinoma: del(3)(p13), i(5)(p10), del(6)(q13), del(9)(p13), del(16)(q22), del(17)(p11), i(17)(q10), del(19)(p13), and i(21)(q10). The most common partial or whole‐arm gains involved 3q, 5p, 7p, 7q, 8q, 11q, 13q, and 17q, and the most frequent partial or whole‐arm losses affected 3p, 4q, 5q, 9p, 10p, 10q, 11p, 14p, 14q, 15p, 17p, 19p, 21p, 21q, and Xp. These chromosomal aberrations and imbalances provide some starting points for molecular analyses of genomic regions that may harbor genes of pathogenetic importance in gallbladder carcinogenesis. Genes Chromosomes Cancer 26:312–321, 1999.

Phenotypic heterogeneity in hereditary nonpolyposis colorectal cancer: identical germline mutations associated with variable tumor morphology and immunohistochemical expression.

Background: Hereditary non-polyposis colorectal cancer (HNPCC) is associated with high risks for colorectal and endometrial cancer, young age at onset and an increased risk of multiple primary tumours. Colorectal cancer in HNPCC is characterised by poor tumour differentiation, an expanding growth pattern, and a pronounced lymphocytic reaction with tumour-infiltrating lymphocytes. Aims and Methods: The mutation spectrum in HNPCC is diverse and in order to clarify whether the HNPCC tumour phenotype is influenced by the underlying genetic alteration, 29 colorectal cancers and 12 adenomas from 24 individuals in two HNPCC families were morphologically and immunohistochemically characterised. Results: The tumour morphology as well as the immunohistochemical expression of β-catenin varied extensively within the families as well as between synchronous/metachronous colorectal cancers from the same individual. Poor tumour differentiation, an expanding growth pattern, and tumour-infiltrating lymphocytes occurred at higher frequencies in proximal tumours, whereas distal colorectal cancers often lacked distinct HNPCC-associated morphological features. Conclusions: The clinical, morphological and immunohistochemical variability observed within these families indicates that other mechanisms than the underlying germline mutation influence the HNPCC phenotype. Since morphological features linked to HNPCC are less frequent in distal cancers, it may be particularly relevant to obtain family history and age of onset in these tumours in order to identify individuals with HNPCC.

Cytogenetic abnormalities in a hemangiopericytoma of the spleen

To date, only 16 cytogenetically abnormal hemangiopericytomas (HP) have been reported. Despite this low number, some characteristic karyotypic features have already emerged: most HP are near-diploid and breakpoints in 12q13, 12q24, and 19q13 seem to be common, with t(12;19)(q13;q13) being a recurrent translocation. Here, we report the first case of a probably benign splenic HP with chromosomal abnormalities. The abnormal karyotype was 47,XX,t(5;22;11)(q31;q11;q13),+10. None of these abnormalities have previously been reported in HP, suggesting that the karyotypic pattern of splenic HP may differ from soft tissue HP.