Gastrointestinal stromal tumor presenting as a rectovaginal mass. Clinicopathologic and molecular-genetic characterization of a rare tumor with a literature review.

Rectal gastrointestinal stromal tumors are rare. To date, 12 gastrointestinal stromal tumors have been reported as pelvic vaginal masses. We describe a rectovaginal tumor in a 39-year-old woman. The tumor frequently recurred after multiple surgical excisions and interrupted imatinib treatment without metastasizing. Magnetic resonance tomography demonstrated a partial response under imatinib. The patient was alive with stable disease under imatinib 44 months from initial diagnosis. Molecular analysis showed a somatic 6-base pair deletion in exon 11 of c-KIT (W557_K558del) in both the primary tumor and the third recurrence; the recurrence had an additional exon 17 mutation (N822K). Comparative genomic hybridization analysis of the primary tumor showed loss of 14q and gain of 1q. Recurrence showed complete loss of nuclear p16 expression. Molecular studies and p16 status confirmed the typical characteristics of gastrointestinal stromal tumors with an aggressive phenotype underscoring the need for a special interdisciplinary treatment and for achieving complete local excision with free margins.

Gastrointestinal stromal tumors of the vermiform appendix: clinicopathologic, immunohistochemical, and molecular study of 2 cases with literature review.

Gastrointestinal stromal tumors (GIST) are rare in the vermiform appendix. Only 5 cases have been reported so far, all being 14 mm or less, and they have yet not been investigated at the molecular level. Here, we report 2 appendiceal gastrointestinal stromal tumors in a 78-year-old woman and a 72-year-old man with a history of endometrial adenocarcinoma and urinary bladder carcinoma, respectively. The first patient had a history of pelvic irradiation. Both gastrointestinal stromal tumors were incidental findings at surgery for appendicitis-like symptoms and on follow-up for bladder carcinoma, respectively. Tumors were 5 and 25 mm and were located in the mid portion and the tip, respectively. The larger gastrointestinal stromal tumor was pedunculated. Both revealed a spindle cell histology with variable stromal hyalinization and occasional skeinoid fibers in 1 case. Immunohistochemistry showed reactivity for CD117 and CD34 and loss of p16 in both. Case 2 overexpressed the catalytic subunit of the human telomerase reverse transcriptase immunohistochemically. Molecular analysis of KIT revealed a missense mutation K558R in case 1 and an in-frame deletion I571_R588 in case 2, both in the juxtamembrane domain (exon 11). Comparative genomic hybridization was successful in case 2 (larger lesion) and revealed no chromosomal imbalance. We suggest that the molecular pathogenesis of appendiceal gastrointestinal stromal tumors beyond initiating KIT mutations might be different from their gastric and intestinal counterparts. The coincidence of loss of p16 and overexpression of human telomerase reverse transcriptase seems to be in contradiction to the small size, the benign nature, and the limited growth potential of appendiceal gastrointestinal stromal tumors.

Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: a report of three new cases with mutational analysis and comparative genomic hybridization.

Carney triad is a rare non-hereditary condition affecting young females and characterized by metachronous or synchronous occurrence of epithelioid gastrointestinal stromal tumours (GISTs), pulmonary chondroma and extra-adrenal paraganglioma. The genetic alterations in Carney triad-related GISTs have not been well studied. We evaluated GISTs from three females with incomplete Carney triad for KIT and PDGFRA mutations and studied the DNA by comparative genomic hybridization (CGH). All GISTs originated in the antrum and had a monotonous epithelioid morphology. Two patients had GISTs and pulmonary chondroma and one had GISTs and paraganglioma. Initial manifestation was GIST (n=1), pulmonary chondroma (n=1) and bladder paraganglioma (n=1). Time to the second component was 2-13 years. Two patients were alive at 108 and 168 months (one with metastases) and one died of the disease 3 years later. All cases were wild-type for KIT exons 9, 11, 13, 17 and PDGFRA exons 12 and 18. CGH revealed 14 aberrations (mean, 4.7/tumour) including 11 gains (X, 1q, 5p, 8q, 9p, 12p, 13q, 18p, 19q), 2 amplifications (1q, 19p) and one loss (13q). Carney triad-related GISTs do not only lack conventional KIT and PDGFRA mutations, but they also lack the non-random loss of 14q and 22q characteristic of their sporadic counterparts, suggesting an origin through a distinct pathogenetic pathway.

Novel chromosomal aberrations in a recurrent malignant meningioma.

The molecular basis of tumorigenesis and tumor progression in meningiomas is not fully understood. Here we present results of conventional cytogenetic, fluorescence in situ hybridization (FISH), and comparative genetic hybridization (CGH) analyses in a patient with recurrent anaplastic meningioma. We found complex aberrant karyotype alterations previously described in anaplastic meningiomas, such as 1p, 14q aberration, and a possibly tetraploid karyotype. Loss of chromosome 22q was detected by conventional cytogenetic analysis. Additional chromosomal aberrations not previously reported included a near-triploid karyotype and alterations such as 4p+, 5p-, 7p+, 8q+, and gain of chromosome 19. FISH with LSI 9p21, CEP9, LSI PML/RARA, and CGH confirmed the karyotype complexity in this case. Our findings of several previously unreported cytogenetic alterations suggest that complex karyotype alterations are a characteristic feature in anaplastic meningiomas. High chromosomal complexity might be associated with a highly aggressive meningioma phenotype.

High incidence of familial breast cancer segregates with constitutional t(11;22)(q23;q11).

In a family with a high incidence of postmenopausal breast cancer and a case of glioblastoma, the constitutional translocation t(11;22)(q23;q11.2) was shown to segregate with the malignancies. The breakpoints in this family coincided with the common breakpoints in t(11;22) as shown by a translocation-specific PCR assay. Loss of heterozygosity analysis of breast tumor tissue revealed deletion of the normal chromosome 22, but retention of der(22) in the tumor cells, suggesting a predisposing effect of the der(22) for breast and brain tumor development in this family.

Establishment and characterization of the permanent human cell line C3842 derived from a secondary chondrosarcoma in Ollier's disease.

The permanent human cell line C3842 was established from a secondary chondrosarcoma in a typical case of Ollier's disease. In the present study, we analyzed the morphological, cytogenetic and molecular biological characteristics of the cultured cells in comparison with the original tumor and investigated the invasion properties of the tumor model using functional imaging of proteolysis, matrigel assay and chick chorioallantoic membrane assay. C3842 cells exhibit the typical features of malignant cartilage tumor cells in vitro, including the expression of collagen types II, IX, XI and aggrecan. The proteolytic ability of C3842 cells is attributed to the expression of several proteases, such as cathepsin B, urokinase plasminogen activator and matrix-metalloproteinase-2, which enable the cells to degrade collagen type I and to permeate matrigel matrix. In accordance with the biological features in vivo, C3842 cells are not able to invade through the epithelium of the chick chorioallantoic membrane. In conclusion, the cell line C3842 provides the first model of a secondary chondrosarcoma in Ollier's disease in vitro, which is characterized by distinct features of such malignant cartilage tumors.

Jumping translocation of 1q in a BCR/ABL-positive acute lymphoblastic leukemia.

Jumping translocations (JT) are rare chromosomal abnormalities in which an identical copy of a chromosomal region (donor) is translocated to a different chromosome (acceptor). Chromosome 1 is often involved as donor chromosome. JTs of the long arm of chromosome 1 (1q) or parts of it are associated with a poor outcome. We report on a 72-year-old male patient with a BCR/ABL1 rearrangement positive acute lymphoblastic leukemia (common ALL, or c-ALL; FAB L2 morphology) and with additional structural and numeric aberrations. Four aberrant clones were observed after conventional cytogenetic analysis. Three of the four clones showed a JT with 1q as donor and 3q, 8q, and 22q as acceptors. To the best of our knowledge, neither JT between 1q and chromosome 3 nor JT between 1q and chromosome 22 have been described in c-ALL. This report emphasizes the frequent involvement of 1q in JT and the association with a poor prognosis.

Re-analysis of the cell line NALM-1 karyotype by GTG-banding, spectral karyotyping, and whole chromosome painting.

Chronic myelogenous leukemia (CML) is a clonal bone marrow disease with progression from a chronic phase to an aggressive blast crisis. The cell line NALM-1 was originally established by Minowada and coworkers from the peripheral blood of a patient in CML blastic crisis. A karyotype analysis of the NALM-1 cell line was performed in the 1970s. To the best of our knowledge, this karyotype was not re-analyzed by molecular cytogenetic techniques, although this cell line is the source of many molecular investigations including expression studies. To establish this cell line as a CML control in our own laboratory, NALM-1 was analyzed by GTG banding, fluorescence in situ hybridization, and spectral karyotyping. Our results differ from the original publication of Sonta and coworkers. We describe for the first time the karyotype of the NALM-1 cell line: 44,X,-X,der(7)t(7;9;15)(q10;?;q15),der(9)t(9;9)(p24;q33 approximately q34)t(9;22)(q34;q11),der(15)t(7;9;15) (?;?;q15),der(22)t(9;22)(q34;q11).

Complete molecular remission in a patient with Philadelphia-chromosome positive acute myeloid leukemia after conventional therapy and imatinib.

Philadelphia-chromosome (Ph)-positive acute myeloid leukemia (AML) is rare and prognosis is poor with a median survival of six to seven months only. We report on a patient with Ph-positive AML (FAB M2, major BCR/ABL1 mRNA transcript, b2a2), who is in sustained complete cytogenetic and molecular remission for 15 months. Cytarabine-based chemotherapy was discontinued after two courses due to infectious complications. Since the b2a2 transcript was still detectable, imatinib was started with quantitative RT-PCR monitoring. This result is promising and worth further evaluation to establish the role of imatinib in patients with Ph-positive AML.

Sex chromosomal mosaicism in the gonads of patients with gonadal dysgenesis, but normal female or male karyotypes in lymphocytes.

OBJECTIVES: In most cases, XX or XY gonadal dysgenesis remains genetically unexplained. In this pilot study we searched for sex-chromosomal mosaicism in gonads of patients with XX or XY gonadal dysgenesis of undetermined origin. STUDY DESIGN: Gonadal tissues were analyzed by cytogenetic and interphase fluorescence in-situ hybridization (FISH) analyses in four patients with gonadal dysgenesis and normal female (46,XX) or male (46,XY) karyotypes in lymphocytes. RESULTS: Cytogenetic and FISH analyses of the gonads demonstrated in three patients a sex-chromosomal mosaicism. Cytogenetic analysis of gonadal tissue of the fourth patient confirmed the result of the lymphocytes with 46,XX, but FISH analysis revealed in 17% of nuclei only one X-chromosome. CONCLUSION: Our data indicate that sex-chromosomal mosaicism in gonads may be a frequent cause of gonadal dysgenesis despite of normal karyotypes in lymphocytes. Therefore, cytogenetic and FISH analyses of gonadal tissue can provide important information in unexplained cases of gonadal dysgenesis.