Constitutional trisomy 8 as first mutation in multistep carcinogenesis: Clinical,cytogenetic, and molecular data on three cases

Three patients, with constitutional trisomy 8 mosaicism (CT8M), who developed a malignancy are reported. The diagnoses were refractory anaemia, acute lymphoblastic leukaemia, and idiopathic myelofibrosis. In the child with acute leukaemia, the CT8M was diagnosed at birth due to severe dysmorphisms and malformations; the other two patients showed a milder phenotype, and the CT8M was diagnosed only after the finding of trisomy 8 in neoplastic cells. The review of eight similar, previously reported cases and the clinical, cytogenetic, and molecular studies performed in our patients led us to make the following observations: (1) CT8M predisposes to neoplasms, preferentially to myelo- or lymphoproliferative diseases; (2) a gene dosage effect for glutathione reductase in red blood cells was seen in two of our patients; (3) the wide phenotypic variation of CT8M was confirmed: trisomy 8 in neoplastic cells of phenotypically near-normal cases may be misinterpreted as acquired; and (4) molecular studies suggested a postzygotic origin of the trisomy in our three cases, with the supernumerary chromosome being of paternal origin in one case and of maternal origin in the other two. We postulate that the trisomy 8 in neoplasms may often occur by mitotic nondisjunction in an early embryonic multipotent cell and that what is usually interpreted as an acquired trisomy 8 may in fact be CT8M. The constitutional trisomy 8 would act as a pathogenetically important first mutation in multistep carcinogenesis. Whenever trisomy 8 is found in malignancies, the patient should be reevaluated clinically to exclude CT8M, and CT8M patients should be monitored for the possible development of malignancies. Genes Chromosom Cancer 17:94–101 (1996). © 1996 Wiley-Liss, Inc.     

Characterization of a Wilms tumor in a 9-year-old girl with trisomy 18

This is a report of a trisomy 18 patient who developed Wilms tumor in conjunction with perilobar nephroblastomatosis (NB) at 9 years and 5 months of age. Review of the literature revealed that most patients with trisomy 18 who develop Wilms tumor, do so at a later than expected age for a tumor related to NB, and are females. In this case, no chromosome 11 WT1 mutation was detected by PCR/SSCP analysis, but the tumor had in addition to the trisomy, an isochromosome 7q and loss of heterozygosity at 16q, two mutations that have been linked independently to Wilms tumorigenesis.     

Wilms tumor in a patient with 22q11.2 microdeletion

22q11.2 deletion syndrome is the most common microdeletion syndrome. Wilms tumor is one of the most common solid tumors in childhood yet 22q11.2 deletion and Wilms tumor only once have been reported in the same patient. Here we describe a young patient with subtle clinical findings suggestive of 22q11.2 at the time of diagnosis who subsequently developed Wilms tumor. We assert the importance of a low threshold for screening for 22q11.2 deletion and the associated phenotypes and maintaining vigilance in screening for common primary malignancies in patients with known 22q11.2 deletion.     

Serous tumor of low malignant potential with early stromal invasion (serous LMP with microinvasion)

Eighteen examples of serous carcinoma arising in a background of a serous tumor of low malignant potential (SLMP with microinvasion) are reported. Nine of the 18 patients were less than 35 yr of age, and 5 were pregnant. In one patient, the microinvasive tumor was bilateral. The contralateral ovary had a serous tumor of low malignant potential (SLMP) in 9 additional women. Twelve patients presented with Stage I tumors, while 6 (33%) had tumors in Stages II and III. The tumors in all patients below the age of 30 were Stage I, and all three patients with Stage III tumors were older than 50. Two cell types were identified in all 18 tumors. The more dominant cell type was similar to those found in the typical SLMP tumors. The second cell type was larger with abundant eosinophilic cytoplasm, round nuclei, and prominent nucleoli; these were the cells that invaded the stroma of the papillary stalks in every case. Only one patient died of her disease, and she had Stage III tumor with massive ascites at presentation. All other patients are alive and well without evidence of disease from 2.5 to 5.5 yr after the diagnosis.     

Malignancies associated with systemic sclerosis

The outcome of systemic sclerosis (SSc) has become more favorable during the past years. Respiratory failure or renal crisis became less frequent, therefore more attention should be paid to long-term comorbidities, such as malignancies secondary to scleroderma. The incidence of malignant lymphoproliferative diseases, as well as that of solid tumors are higher in a number of rheumatic diseases including SSc. Some cytotoxic agents, primarily cyclophosphamide used in the treatment of SSc, as well as exposure to chemicals or smoking may further increase cancer risk. We also present malignancies in 218 scleroderma patients undergoing follow-up in our department were assessed for secondary malignancies. Although the number of SSc patients with tumor is relatively small, we compared our cohort to the Health for All Hungarian database and calculated standard incidence ratios (SIR). We identified 11 cases of malignancy in 10 SSc patients (4.6%). One patient had two types of tumor: breast cancer before the onset of SSc and later malignant lymphoma. Half of SSc patients with cancer belonged to the diffuse cutaneous (dcSSc) subtype. The mean age at onset of SSc was 54.6years, while that at the diagnosis of malignancy was 61.5years. The mean disease duration of scleroderma at the time of cancer diagnosis was 6.6years. Five patients died, 4 due to the underlying malignancy. Among the five surviving patients, the mean survival time was 4.9years. Altogether 3 patients had non-Hodgkin's lymphoma, 2 had bronchial cancer, 2 had breast cancer, one had leiomyosarcoma of the leg, one had esophageal cancer, one had cervix cancer and one had skin cancer. In comparison to the Health for All database, the overall SIR of all malignancies in SSc was 1.07 (CI: 0.82-1.38) varying between 5.8 and 52.4 in different tumor types. Only one cancer patient received cyclophosphamide therapy. In conclusion, secondary tumors including lung, skin and breast cancer, as well as lymphomas are more common in SSc than in the general population. The adequate treatment and follow-up of scleroderma patients may help us to lower the risk of malignancies secondary to SSc.     

Hepatocellular carcinoma metastatic to the ovary: a report of three cases discovered during life with discussion of the differential diagnosis of hepatoid tumors of the ovary.

Three cases of hepatocellular carcinoma with ovarian metastases discovered during the patient's life are reported. A 31-year-old woman presented with back pain, and radiographic studies disclosed massive liver enlargement and bilateral ovarian tumors. The second patient, a 38-year-old woman, had an enlarged liver at the time of laparoscopic tubal ligation, and subsequently underwent right hepatic lobectomy for hepatocellular carcinoma. Three months later a left ovarian tumor was detected and a total abdominal hysterectomy with bilateral salpingo-oophorectomy performed. The third patient, a 68-year-old woman, presented with gastrointestinal symptoms and weight loss, and had bilateral ovarian tumors and widespread tumor at laparotomy. Two patients died of their disease at 18 months and 4 years 7 months; the third patient is alive with residual tumor at 7 months. The ovarian tumors, which were bilateral and multinodular in two cases and focally cystic in one case, ranged from 4 to 11 cm in maximum dimension, and had yellow-green or yellow sectioned surfaces. On microscopic examination, they were composed of cells with moderate to abundant eosinophilic cytoplasm growing diffusely and in nodules, nests, and trabeculae; cysts or glands were conspicuous in two cases. Bile was present in one tumor. The main differential diagnostic considerations were hepatoid yolk sac tumor and hepatoid carcinoma, primary or metastatic in the ovary. A variety of features, including the age of the patient, unilaterality or bilaterality of the ovarian tumors, distribution of disease, and microscopic features of the neoplasm, including the identification of bile, established the diagnosis. Metastatic hepatocellular carcinoma must be included in the differential diagnosis of oxyphil cell tumors of the ovary.     

Cytogenetic investigation of transitional cell carcinomas of the upper urinary tract.

Cytogenetic investigation was attempted on 44 tumors from 44 patients with transitional cell carcinoma (TCC) of the upper urinary tract (pelvis and ureter), and karyotypes were obtained in 27 tumors. Numerical changes prevailed, but are not specific for this type of tumor (trisomy 7, -Y, or both). In the light of previously reported data on TCC, the finding of a del(9q) as the only anomaly in one of the cases may be meaningful. Patients showing -Y and/or trisomy 7 had a poor prognosis.     

Low frequency mosaicism of normal cells in a 16-year-old girl with trisomy 18

A 16-year-old girl with mosaicism of trisomy 18 has been followed from birth in our department. She had stigmata characteristic for trisomy 18. Chromosome analysis of lymphocytes showed trisomy 18 both at birth and at age 15, whereas analysis of fibroblasts at age 16 showed trisomy 18 with low frequency mosaicism of normal cells (4%). In most case reports, karyotype analyses have been performed in lymphocytes only. The low frequency mosaicism of normal cells found in fibroblasts from the present patient may raise the question of mosaicism in other long-living patients previously reported to be non-mosaic trisomy 18. The main disorders in the present patient were limited to severe mental deficiency, structural cerebral malformations and skeletal deformities, including bilateral equinovarus deformities. At birth, she had a ventricular septal defect which closed spontaneously. Frequent respiratory infections subsided after age 2. At age 7 she developed a seizure disorder. Since then, her medical condition has been stable. Even though patients with trisomy 18 rarely survive early childhood, the possibility that they may reach their teens must be kept in mind when treatment is planned. In our case, the decision not to treat her equinovarus deformities means that she cannot stand, a major problem in her everyday life.     

Further chromosome studies on Wilms' tumor cells of patients without aniridia

We studied chromosomes in Wilms' tumor cells of two patients without aniridia who had a normal constitutional karyotype. In both tumors, trisomy for 1q occurred as the result of a t(1;16), although the breakpoints in each chromosome differed in the two tumors. No 11p rearrangements could be detected, whereas in our previous patient an interstitial deletion of 11p13 was present in all tumor cells. Thus, trisomy for 1q may be another pathway leading to the development of Wilms' tumor, although the effect of the deletion of 16q cannot be assessed at present.     

Chromosome analyses in chronic lymphocytic leukemia and related B-cell neoplasms

Chromosome analyses were performed by routine G-banding in 29 patients with B-cell chronic lymphocytic leukemia (B-CLL), six with immunocytoma (IC), three with centroblastic-centrocytic (cb-cc) lymphoma, and one with hairy cell leukemia (HCL). Ages of the patients were between 46 and 81 years (mean, 63 years). 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was used as a mitogen to stimulate leukemic B-cells in 72-hour cultures. Twenty-one patients had one or more chromosomal abnormalities; and in 13 patients, they were clonal; 18 patients had a normal karyotype. Seven patients had trisomy 12 (three B-CLL, two IC, two cb-cc lymphoma); two (B-CLL) had it as the sole abnormality. One patient with B-CLL had trisomy 18 as the sole abnormality, and one with IC had trisomy 18 in combination with trisomy 19. One patient with B-CLL had t(1;6)(p36;p21) as a clonal structural abnormality. A t(11;14)(q13;q32) was consistently observed in one patient with cb-cc lymphoma together with inv(1) (p22p36), der(4)t(4;?)(p16;?), del(6)(q13) and other variable changes. One patient with morphologically atypical B-CLL had t(1;11)(p36;q13) together with der(X)t(X;?)(q26;?), der(3)t(3;?)(q29;?), der(8)t(4;8)(q12;q24.1) and additional variable changes. Both patients with these complex karyotypes were in an advanced stage of disease (Binet stage C) and died within 3-6 months after chromosome analysis.     

Two cases of partial trisomy 21 (pter-q22.1) without the major features of Down syndrome

We report two cases of partial trisomy 21 with clinical features distinct from Down syndrome (DS). These patients presented with moderate mental retardation and short stature, but the typical facial appearance of DS was not observed. Each patient had a similarly sized extra chromosome 21. We performed FISH analysis to examine whether deletions of reported approximately 5 Mb DS critical region (DSCR) might be associated with unusual clinical features in these cases. The results showed that each of their extra chromosomes 21 contained a distal part of chromosome 3p or 14q at the telomeric region of chromosome 21q. The translocation breakpoint of 21q for each patient was located on the centromeric side of DSCR (DSCR was deleted) and the sizes of partial trisomy 21 in respective patients are approximately 34.5 (21pter-q22.12) and approximately 33.0 Mb (21pter-q22.11). In one patient, the additional region of the short arm of chromosome 3 was 3pter-p26.1 from maternal origin, measuring approximately 9 Mb in size. The second patient had an extra 14q32.1-qter of maternal origin, measuring approximately 14 Mb in size. These are one of the shortest partial distal trisomy among reported cases. Taken together, two patients with partial trisomy 21 lack all of DSCR on 21q22, and their distinct clinical features are likely caused by the genes located at 21pter-q22.1 and the distal part of chromosome 3p or 14q.     

Trisomy 19 in a patient with myelodysplastic syndrome and thrombocytosis

A patient with refractory anemia with excess blasts, ringed sideroblasts, and thrombocytosis was found on cytogenetic analysis to have trisomy 19 as the sole abnormality. Although trisomy 19 in combination with other chromosomal anomalies has been encountered in association with a variety of hematologic malignancies, many solid tumors, and the myelodysplastic syndrome, its occurrence as the only cytogenetic aberration is rare and has not been reported in association with thrombocythemia.     

Prevalence of serologic markers in celiac disease in trisomy 21 in Tunisia

PURPOSE: This study was aimed to investigate the prevalence of serologic markers of celiac disease in Tunisian patients with trisomy 21. METHODS: Twenty seven patients with trisomy 21 were prospectively screened by indirect immunofluorescence for anti-reticulin and anti-endomysium antibodies, and by an ELISA method for anti-gliadin and anti-transglutaminase antibodies. None of the 27 patients had known celiac disease at the time of the study. RESULTS: Anti-reticulin, anti-endomysium, anti-gliadin and anti-transglutaminase antibodies were found in respectively 11%, 11%, 18.5%, and 14.8% of cases. Only one patient with all serologic markers of celiac disease underwent biopsy which shows a villous atrophy. CONCLUSION: Anti-endomysium and anti-transglutaminase antibodies are good immunologic markers for the screening for celiac disease, a screening which is justified in patient with trisomy 21.     

Mcl-1 expression is up-regulated in malignancies of the parotid gland

The anti-apoptotic protein Mcl-1 is highly expressed in various types of malignant tumors. Overexpression is reported to correlate with poor prognosis and disease progression. We report the expression levels of Mcl-1 in tumor samples of the parotid gland. A retrospective study containing 108 patients was performed. A tissue microarray of six malignancies of the parotid gland and pleomorphic adenoma as control was constructed. Parotid gland tumor samples were immunohistochemically stained for Mcl-1 and expression intensities were assessed. Statistical analysis included correlation to patients' clinical data and comparison of malignancies to the adenoma. All malignancies had significantly higher expression of Mcl-1 than the pleomorphic adenomas. The intensity, however, had no significant correlation to overall survival. Our immunohistochemical findings indicate that parotid gland malignancies produce high levels of Mcl-1 protein. Therefore, Mcl-1 might serve as a predictive co-marker in tumors of the parotid gland.     

Tetrasomy 12 in ovarian tumors of thecoma-fibroma group: A fluorescence in situ hybridization analysis using paraffin sections

Recent cytogenetical studies have indicated that trisomy 12 is a feature of ovarian tumors in the thecoma-fibroma group. Ten cases of these ovarian tumors were studied in total, including two thecomas, two fibrothecomas, four fibromas, one cellular fibroma and one fibrosarcoma, to clarify the relationship between polysomy 12 and proliferative activity in these tumors. Each formalin-fixed, paraffin-embedded tumor tissue was examined by fluorescence in situ hybridization to determine copy numbers of chromosome 12 and by immunohistochemical staining of Ki-67 for evaluation of tumor cell proliferation. Gains of trisomy 12 were found in seven of the 10 cases, and the percentage of cells with tetrasomy 12, but not that of cells with trisomy 12, was significantly and positively correlated with percentage of Ki-67-positive cells, but significantly and inversely correlated with patient age. These findings suggest that tetrasomy 12 is an age-related aberration of chromosome 12 in ovarian tumors of the thecoma-fibroma group, and that such tumors exhibit more active proliferation in younger patients.     

Multiple gastrointestinal stromal tumors in type I neurofibromatosis: a pathologic and molecular study.

Multiple gastrointestinal stromal tumors typically occur in familial form associated with KIT receptor tyrosine kinase or platelet-derived growth factor receptor-alpha (PDGFRA) germline mutations, but may also develop in the setting of type 1 neurofibromatosis. The molecular abnormalities of gastrointestinal stromal tumors arising in neurofibromatosis have not been extensively studied. We identified three patients with type 1 neuro-fibromatosis and multiple small intestinal stromal tumors. Immunostains for CD117, CD34, desmin, actins, S-100 protein, and keratins were performed on all of the tumors. DNA was extracted from representative paraffin blocks from separate tumor nodules in each case and subjected to a nested polymerase chain reaction, using primers for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18, followed by direct sequencing. The mean patient age was 56 years (range: 37-86 years, male/female ratio: 2/1). One patient had three tumors, one had five, and one had greater than 10 tumor nodules, all of which demonstrated histologic features characteristic of gastrointestinal stromal tumors and stained strongly for CD117 and CD34. One patient died of disease at 35 months, one was disease free at 12 months and one was lost to follow-up. DNA extracts from 10 gastrointestinal stromal tumors (three from each of two patients and four from one patient) were subjected to polymerase chain reactions and assessed for mutations. All of the tumors were wild type for KIT exons 9, 13, and 17 and PDGFRA exons 12 and 18. Three tumors from one patient had identical point mutations in KIT exon 11, whereas the other tumors were wild type at this locus. We conclude that, although most patients with type 1 neurofibromatosis and gastrointestinal stromal tumors do not have KIT or PDGFRA mutations, KIT germline mutations might be implicated in the pathogenesis of gastrointestinal stromal tumors in some patients.     

Isolated trisomy 15: a clonal chromosome abnormality in bone marrow with doubtful hematologic significance

We identified 18 patients with an isolated bone marrow clonal chromosomal abnormality, trisomy 15 (with or without -Y), who did not have any morphologic or clinical features of hematologic disease at initial examination. All but 1 patient was older than 65 years. Fourteen patients had underlying nonhematologic, chronic diseases. Four patients had histories of hematologic malignancies. Eleven of the patients also had a -Y. All but 1 case had a marrow cellularity of less than 50%. Extensive morphologic review of the specimens showed no features of myelodysplastic syndrome (MDS). Clinical follow-up was available for all patients and ranged from 1 month to 16.3 years (median, 4.0 years). No subsequent clinical or hematologic manifestations of MDS were identified in any of these patients. Clonal trisomy 15 in isolation or in combination with -Y is an uncommon cytogenetic finding that does not seem to be associated with definitive morphologic or clinical features of MDS or any other malignant process.     

Trisomy 13 in bone marrow cells in acute myelocytic leukemia and myelofibrosis

We have identified trisomy 13 in two additional patients with hematologic malignancies involving the hematopoietic stem cell: a 75-year-old female with acute myelocytic leukemia and a 64-year-old female with agnogenic myelofibrosis and myeloid metaplasia. Chromosome analysis of the direct bone-marrow preparation showed 100% of cells with trisomy 13 in the first and 10% of cells in the second. We also previously reported a patient with Ph1 negative chronic myelogenous leukemia in whom 100% of the marrow cells showed an identical trisomy. The probability of finding three such patients in our case material was calculated to be 0.05--0.08, implying that trisomy 13 may be another nonrandom chromosomal aberration associated with malignancies of hematopoietic pluri-potent stem cell.     

Adherence of cell-free DNA noninvasive prenatal screens to ACMG recommendations

PurposeNoninvasive prenatal screening (NIPS) for fetal aneuploidy via cell-free DNA has been commercially available in the United States since 2011. In 2016, the American College of Medical Genetics and Genomics (ACMG) issued a position statement with specific recommendations for testing laboratories. We sought to evaluate adherence to these recommendations.MethodsWe focused on commercial laboratories performing NIPS testing in the United States as of 1 January 2018. Sample laboratory reports and other materials were scored for compliance with ACMG recommendations. Variables scored for common and sex chromosome aneuploidy detection included detection rate, specificity, positive and negative predictive value, and fetal fraction. Labs that performed analysis of copy-number variants and results for aneuploidies other than those commonly reported were identified. Available patient education materials were similarly evaluated.ResultsNine of 10 companies reported fetal fraction in their reports, and 8 of 10 did not offer screening for autosomal aneuploidies beyond trisomy 13, 18, and 21. There was inconsistency in the application and reporting of other measures recommended by ACMG.ConclusionsLaboratories varied in the degree to which they met ACMG position statement recommendations. No company adhered to all laboratory guidance.