Maria Debiec-Rychter

A phase II trial with rosiglitazone in liposarcoma patients

Agents of the thiazolidinedione drug family can terminally differentiate human liposarcoma cells in vitro by activating genes responsible for lipocyte differentiation. One study has shown clinical activity of troglitazone treatment in liposarcoma patients. We sought to find further evidence for this result. In all, 12 patients with a liposarcoma received rosiglitazone 4u2009mg b.d. They were followed clinically and with repeated biopsies for histological and biological studies. At the molecular level the mRNA translation of three genes that are induced by this treatment (peroxisome proliferator-activated receptor γ (PPARγ), adipsin and fatty acid binding protein) was determined. Nine patients were eligible for evaluation. One patient had to stop treatment due to hepatotoxicity. The mean time to progression was 6 months (2u2009–u200916 months), with one patient still on treatment. We did not see any significant change in histologic appearance of the liposarcomas by the treatment. The level of gene expression changed significantly in two patients, but this did not result in a clinical response. Based on this study, rosiglitazone is not effective as an antitumoral drug in the treatment of liposarcomas. Increased PPARγ activity does not correlate with the clinical evolution.

Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors.

Benign peripheral nerve sheath tumors (PNSTs) are a characteristic feature of neurofibromatosis type I (NF1) patients. NF1 individuals have an 8–13% lifetime risk of developing a malignant PNST (MPNST). Atypical neurofibromas are symptomatic, hypercellular PNSTs, composed of cells with hyperchromatic nuclei in the absence of mitoses. Little is known about the origin and nature of atypical neurofibromas in NF1 patients. In this study, we classified the atypical neurofibromas in the spectrum of NF1‐associated PNSTs by analyzing 65 tumor samples from 48 NF1 patients. We compared tumor‐specific chromosomal copy number alterations between benign neurofibromas, atypical neurofibromas, and MPNSTs (low‐, intermediate‐, and high‐grade) by karyotyping and microarray‐based comparative genome hybridization (aCGH). In 15 benign neurofibromas (4 subcutaneous and 11 plexiform), no copy number alterations were found, except a single event in a plexiform neurofibroma. One highly significant recurrent aberration (15/16) was identified in the atypical neurofibromas, namely a deletion with a minimal overlapping region (MOR) in chromosome band 9p21.3, including CDKN2A and CDKN2B. Copy number loss of the CDKN2A/B gene locus was one of the most common events in the group of MPNSTs, with deletions in low‐, intermediate‐, and high‐grade MPNSTs. In one tumor, we observed a clear transition from a benign‐atypical neurofibroma toward an intermediate‐grade MPNST, confirmed by both histopathology and aCGH analysis. These data support the hypothesis that atypical neurofibromas are premalignant tumors, with the CDKN2A/B deletion as the first step in the progression toward MPNST.

Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience

BACKGROUNDnMajority of gastrointestinal stromal tumours (GISTs) are characterised by KIT-immunopositivity and the presence of KIT/platelet-derived growth factor receptor alpha (PDGFRA) activating mutations.nnnPATIENTS AND METHODSnSpectrum and frequency of KIT and PDGFRA mutations were investigated in 427 GISTs. Univariate and multivariate analysis of relapse-free survival (RFS) was conducted in relation to tumours clinicopathologic features and genotype.nnnRESULTSnMutations were found in 351 (82.2%) cases, including 296 (69.3%) KIT and 55 (12.9%) PDGFRA isoforms. Univariate analysis revealed higher 5-year RFS rate in women (37.9%; P = 0.028) and in patients with gastric tumours (46.3%; P < 0.001). In addition a better 5-year RFS correlated with smaller tumour size ≤ 5 cm (62.7%; P < 0.001), tumours with mitotic index ≤ 5/50 high-power fields (60%; P < 0.001), and characterised by (very) low/moderate risk (70.2%; P = 0.006). Patients with GISTs bearing deletions encompassing KIT codons 557/558 had worse 5-year RFS rate (23.8%) than those with any other KIT exon 11 mutations (41.8%; P < 0.001) or deletions not involving codons 557/558 (33.3%; P = 0.007). Better 5-year RFS characterised patients with KIT exon 11 point mutations (50.7%) or duplications (40%). By multivariate analysis, tumours with PDGFRA mutations and KIT exon 11 point mutations/other than 557/558 deletions had lower risk of progression than with KIT exon 11 557/558 deletions (both Ps = 0.001).nnnCONCLUSIONSnKIT/PDGFRA mutational status has prognostic significance for patients outcome and may help in management of patients with GISTs.

Extramammary myofibroblastoma is genetically related to spindle cell lipoma

Extramammary-type myofibroblastoma is a rare, benign spindle cell lesion, strictly resembling the breast counterpart, but occurring in extramammary sites, mainly in the inguinal/groin area. In this paper, we describe an extramammary-type myofibroblastoma in the groin of a 37-year-old male patient. The tumor showed a typical morphological and immunophenotypical profile, including staining for both CD34 and desmin. Dual-color interphase florescent in situ hybridization analysis revealed losses of RB/13q14 and FKHR/13q14 loci within tumor cells. The chromosome 13 rearrangements associated with the loss of the 13q14 chromosomal region are typically seen in spindle cell lipoma, and have been previously recognized in mammary myofibroblastoma, providing strong evidence for a pathogenetic link between these lesions.

Cellular angiofibroma: another mesenchymal tumour with 13q14 involvement, suggesting a link with spindle cell lipoma and (extra)mammary myofibroblastoma

1. Bjarnason I, Hayllar J, Macpherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104; 1832–1847. 2. Hanby AM, Wright NA. The ulcer associated cell lineage. The gastrointestinal repair kit? J. Pathol. 1993; 171; 3–4. 3. Muniz-Grijalvo O, Reina-Campos F, Borderas F. Could a fibroid polyp be a manifestation of enteropathy induced by nonsteroidal anti-inflammatory drugs? Am. J. Gastroenterol. 1997; 92; 170– 171. 4. Johnstone JM, Morson BC. Inflammatory fibroid polyp of the gastrointestinal tract. Histopathology 1978; 2; 349–361. 5. Daum O, Hes O, Vanecek T et al. Vaneks tumour (inflammatory fibroid polyp). Report of 18 cases and comparison with three cases of original Vaneks series. Ann. Diagn. Pathol. 2003; 7; 337– 347. 6. Pantanowitz L, Antonioli DA, Pinkus GS, Shahsafaei A, Odze RD. Inflammatory fibroid polyps of the gastrointestinal tract: evidence for a dendritic cell origin. Am. J. Surg. Pathol. 2004; 28; 107– 114. 7. Makhlouf HR, Sobin LH. Inflammatory myofibroblastic tumors (inflammatory pseudotumors) of the gastrointestinal tract: how closely are they related to inflammatory fibroid polyp. Hum. Pathol. 2002; 33; 307–315. 8. Burke AP, Sobin LH, Shekitka KM, Federspiel BH, Helwig EB. Intra-abdominal fibromatosis. A pathologic analysis of 130 tumors with comparison of clinical subgroups. Am. J. Surg. Pathol. 1990; 14; 335–341. 9. Yantiss RK, Nielsen GP, Lauwers GY, Rosenberg AE. Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery. A clinicopathologic study of five cases. Am. J. Surg. Pathol. 2003; 27; 532–540. 10. Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992; 327; 749– 754.

Clinical utility of the new American Joint Committee on Cancer staging system for gastrointestinal stromal tumors: current overall survival after primary tumor resection.

The objectives of the current study were to assess the reliability of the new revision of the American Joint Committee on Cancer (AJCC) staging system for gastrointestinal stromal tumors (GISTs) based on the National Comprehensive Cancer Network‐Armed Forces Institute of Pathology risk classification and to analyze the factors that influence after resection for primary GISTs in 2 AJCC groups: patients with GISTs originating from the stomach and omentum (G‐GISTs) and patients with other primary GISTs located mainly in the small bowel (nongastric GISTs [NG‐GISTs]).

Gastrointestinal stromal tumors II: medical oncology and tumor response assessment.

The finding of mutations of KIT in gastrointestinal stromal tumors (GISTs) and subsequent development of kinase-directed therapy in metastatic GIST serve as a touchstone for the translation of laboratory research into clinical therapeutics. A variety of novel developments have followed the discovery of clinical activity of kinase-directed therapy against GIST. Radiological assessment of GIST challenges the standard of care for assessing tumor responses, ie, Response Evaluation Criteria in Solid Tumors (RECIST). Furthermore, the determination of the relationship of specific KIT mutations and sensitivity and resistance to kinase-directed agents and the assessment of inhibitor levels and the quality of response to those agents have implications beyond the treatment of sarcomas. These discoveries and the next chapters in this developing story are discussed in this review.

Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST]

In contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits [SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate post-transcriptional regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30 gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region. Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wild-type gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type, SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do express SDHB. All cases with Carney triad within our cohort cluster together tightly.

Chondroid lipoma is characterized by t(11;16)(q13;p12–13)

Sir, Chondroid lipoma is a rare benign tumor of adipose tissue origin that may mimic myxoid chondrosarcoma and liposarcoma. Karyotypes from two chondroid lipomas have been reported so far, both with a t(11;16)(q13;p12– 13) [2, 7]. We report a chondroid lipoma with the same translocation, including ring chromosomes in a small fraction of metaphases. A 72-year-old female presented with diarrhea. Abdominal computed tomography (CT) revealed no intraabdominal abnormalities. A left paravertebral intramuscular, non-mineralized mass was found. Additional magnetic resonance imaging (MRI) was performed. The sagittal TIR sequence showed a hypo-intense nodule with a hyper-intense rim, and the T1-weighted images after gadolinium administration demonstrated a strong homogeneous enhancement pattern of the nodule. A tumorectomy was performed. The mass was well defined, lobulated and yellow, with gelatinous areas, and it measured 5.0 3.1 2.5 cm. Microscopically, the tumor was lobulated and surrounded by a thin, fibrous capsule. One nodule was located outside the capsule. The tumor cells were arranged in nests and cords. A major part consisted of smallto medium-sized, slightly eosinophilic, multi-vacuolated cells (Fig. 1a). Some cells presented with an oval-shaped nucleus, while others showed a centrally or peripherally located hyperchromatic, scalloped nucleus (lipoblast-like) (Fig. 1b). Nucleoli were inconspicuous. The cytoplasmic vacuoles contained lipid droplets, confirmed by a positive oil-red-O stain. Mature

Implications of Mutational Analysis for the Management of Patients With Gastrointestinal Stromal Tumors and the Application of Targeted Therapies

ABSTRACT The receptor tyrosine kinase inhibitors, imatinib and sunitinib, have significantly improved the prognosis for patients with advanced gastrointestinal stromal tumors (GISTs). Most GISTs exhibit mutations in the genes encoding the stem cell factor receptor (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Imatinib is more effective in patients with KIT exon 11 mutations compared with KIT exon 9 mutations and wild-type genotype, while sunitinib confers greater in vitro efficacy in patients with KIT exon 9 mutants and wild-type genotype than in KIT exon 11 mutants. This review examines the potential role of mutational analysis to optimize therapy with imatinib and sunitinib for GIST.