Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: histological review, genomic profile, and MDM2 and CDK4 status favour a single entity

Inflammatory malignant fibrous histiocytoma (inflammatory MFH) is a very rare tumour that occurs most often in the retroperitoneum. So far, it has been considered to be a special subtype of MFH. As it is now widely accepted that most retroperitoneal pleomorphic MFHs are dedifferentiated liposarcomas, the present study compared histological features, genomic profile (CGH analysis), and MDM2 and CDK4 status (immunohistochemistry, FISH, and quantitative PCR) in inflammatory MFHs from 12 patients and dedifferentiated liposarcomas that had an inflammatory MFH component from eight patients. Metaphase cytogenetic and FISH analyses were also performed on one inflammatory MFH. Histological review showed areas of well-differentiated liposarcoma in nine inflammatory MFHs. CGH analysis showed 12q13-15 amplification or gain in six of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas. Immunohistochemistry showed positivity of tumour cells for MDM2 in every tumour in both groups and for CDK4 in ten and seven inflammatory MFHs and dedifferentiated liposarcomas, respectively. Metaphase cytogenetic and FISH analysis performed on one inflammatory MFH showed the presence of a supernumerary large marker chromosome and ring chromosome with high-level amplification of both MDM2 and CDK4 genes. FISH analysis on paraffin wax-embedded sections showed amplifications of MDM2 and CDK4 in seven of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas. Quantitative PCR showed amplification of MDM2 in six and of CDK4 in seven of nine inflammatory MFHs. In conclusion, this study strongly suggests that most so-called inflammatory MFHs are dedifferentiated liposarcomas.     

Gastric large cell lymphoma expressing cytokeratin but no leukocyte common antigen. A diagnostic dilemma

A case of undifferentiated malignant tumor of the stomach is reported. The immunohistochemistry of biopsy specimens pointed to a diagnosis of carcinoma, the tumor cells being cytokeratin positive and leukocyte common antigen (LCA) negative. After resection, however, histopathologic results showed that the tumor was a large cell lymphoma with plasmablastic differentiation. A new immunohistologic study confirmed, on the one hand, the diagnosis of lymphoma with its monotypic character IgA kappa and, on the other, positivity with three different cytokeratins of the lymphoma cells and their negativity with LCA. The aberrant immunophenotyping of this lymphoma is exceptional and must not undermine the recognized usefulness of LCA and cytokeratin, which both are basic antibody markers of immunohistochemistry in undifferentiated malignant neoplasms.     

Antenatal solitary intestinal fibromatosis

Solitary intestinal fibromatosis (SIF) is rare. Only 16 cases have been described in the new-born and infancy. We describe a new case of SIF with an unusual presentation including abnormal antenatal echographic findings. SIF was diagnosed at 2 months age when the child developed an intestinal obstruction. Differential diagnosis and review of literature are discussed. This lesion has an excellent prognosis when it is completely excised.     

Management of soft tissue sarcomas (STS) in first isolated local recurrence: a retrospective study of 83 cases.

PURPOSE: To analyze the management and clinical outcome of patients treated for a first isolated local recurrence of soft tissue sarcomas (trunk or extremities) and to identify prognosis factors. METHODS AND MATERIAL: Between 1980 and 1999, 83 adult patients were included in the study. Mean age was 61 years. Mean tumor size was 6 cm. Most sarcomas were located in extremities (n=74), were deep (n=60), and proximal (n=53); 30 involved nerves or vessels. Histologic subtypes were mainly grade 2 (42%) or 3 (36%) histiocytofibrosarcomas (49%) and liposarcomas (20%). Surgical treatment of recurrences consisted in wide excision (29 cases), marginal resection (43 cases), 5 patients requiring amputation. Final results were R0 (n=33), R1 (n=47) or R2 (n=3) resection. Besides surgery, 6 patients received neo-adjuvant and 7 others adjuvant chemotherapy. Twenty three patients received post-operative external beam radiotherapy (EBRT) (mean dose 55 Gy) and 26 interstitial 192Ir low dose rate brachytherapy (BCT) (mean dose 45 Gy for BCT alone, 22 Gy when associated with EBRT), 19 patients being re-irradiated. RESULTS: Mean follow up was 13 years. Thirty-seven (45%) patients relapsed, 62% of whom presenting an isolated local recurrence. Nineteen patients developed distant metastases. Multivariate analysis showed only tumor depth (P=0.05) and re-resection for primary R1 resection (P=0.018) being independent prognosis factors for tumor control, radiotherapy (EBRT and/or BCT) being significant in univariate analysis (P=0.05). Overall survival rate was 73%, 54%, and 47% at, respectively, 3.5 and 10 years, and was 65%, 35% and 32% after a further local recurrence. Multivariate analysis showed trunk (P=0.0001) or inferior extremity locations (P=0.023), symptomatic (P=0.001), high grade (P=0.01), deep (P=0.01) tumors, and the occurrence of a further local failure (P=0.004) as unfavorable characteristics for overall survival. CONCLUSIONS: A first isolated local recurrence of STS increases mainly the risk of a subsequent local relapse. Quality of local treatment is decisive. When a conservative treatment is feasible, it should combine surgical resection and radiotherapy, BCT being the best suited in previously irradiated patients. Efforts have to be pursued to increase quality of the treatment of primary tumors, at best performed in centers that have expertise in this field.     

A quality control program for mutation detection in KIT and PDGFRA in gastrointestinal stromal tumours

Background

Although most gastrointestinal stromal tumours (GIST) carry oncogenic mutations in KIT exons 9, 11, 13 and 17, or in platelet-derived growth factor receptor alpha (PDGFRA) exons 12, 14 and 18, around 10% of GIST are free of these mutations. Genotyping and accurate detection of KIT/PDGFRA mutations in GIST are becoming increasingly useful for clinicians in the management of the disease.

Method

To evaluate and improve laboratory practice in GIST mutation detection, we developed a mutational screening quality control program. Eleven laboratories were enrolled in this program and 50 DNA samples were analysed, each of them by four different laboratories, giving 200 mutational reports.

Results

In total, eight mutations were not detected by at least one laboratory. One false positive result was reported in one sample. Thus, the mean global rate of error with clinical implication based on 200 reports was 4.5%. Concerning specific polymorphisms detection, the rate varied from 0 to 100%, depending on the laboratory. The way mutations were reported was very heterogeneous, and some errors were detected.

Conclusion

This study demonstrated that such a program was necessary for laboratories to improve the quality of the analysis, because an error rate of 4.5% may have clinical consequences for the patient.     

Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and follow-up analysis of 63 cases: a study from the French Federation of Cancer Centers Sarcoma Group

The clinicopathologic and immunohistochemical features of 63 pleomorphic liposarcomas are presented. There were 35 men and 28 women (median age 63 years; range 18-93 years). Tumor size ranged from 2 to 23 cm (median 10 cm). Tumor locations included lower extremity (36.5%), especially the thigh (28.5%), limb girdles (17.5%), upper extremity (16%), thoracoabdominal wall (9.5%), and internal trunk (20.5%). A total of 75% were deep seated and/or extracompartmental. Histologically, lesions show a varying combination of lipogenic and nonlipogenic areas characterized by malignant fibrous histiocytoma-like, round cell liposarcoma-like, and/or epithelioid/carcinoma-like features. A pericytic pattern was focally present in 15 (24%) tumors. Eighteen (29%) lesions were grade 2, and 45 (71%) were grade 3 sarcomas. Tumor necrosis was observed in 51 (81%) cases, vascular invasion in three, and mitotic counts ranged from 3 to 124 per 10 high power fields (median 25). Lipogenic areas were S-100 protein immunoreactive, at least focally, in 20 of 42 (48%) cases. Nonlipogenic areas showed focal reactivity for smooth muscle actin (24 of 49; 49%), desmin (9 of 48; 19%), CD34 (18 of 45; 40%), S-100 protein (5 of 49, 10%), CD68 (6 of 46, 13%), and epithelial membrane antigen (13 of 49, 26.5%). Epithelioid areas showed epithelial membrane antigen (4 of 11; 36%) but not cytokeratin (0 of 11) reactivity. Treatment procedures in 51 patients consisted of simple tumorectomy (16) and wide excision (33). Five and 31 patients received neoadjuvant and adjuvant chemotherapy and/or radiation therapy, respectively. Follow-up (48 patients, range 7-276 months; median 38 months) showed a 45% local recurrence rate and a 42.5% metastasis rate, metastases occurring mostly in lungs and pleura. Seventeen patients (35%) died of disease, of whom none was metastatic at diagnosis. Five-year overall, metastasis-free, and local recurrence-free survivals were 57%, 50%, and 48%, respectively. Patient age > or =60 years, truncal tumor location, deep situation, tumor size >5 cm, vascular invasion, and incomplete tumor excision were significant adverse prognostic factors. Tumor grade and histology did not affect patient outcome. In conclusion, pleomorphic liposarcoma is a rare, often deep-seated and limb-based aggressive and metastasizing neoplasm of late adulthood. It shows a wide range of morphologic appearances, but tumor grade and histology have no effect on patient outcome.     

The RB1 gene is the target of chromosome 13 deletions in malignant fibrous histiocytoma

Forty-four malignant fibrous histiocytomas (MFHs) were studied by comparative genomic hybridization. Among the observed imbalances, losses of the 13q14-q21 region were observed in almost all tumors (78%), suggesting that a gene localized in this region could act as a tumor suppressor gene and that its inactivation could be relevant for MFH oncogenesis and/or progression. We determined by CA repeat analyses a consensus region of deletion focusing on the RB1 region. The RB1 gene was then analyzed by protein truncation test, direct sequencing, fluorescence in situ hybridization, Southern blotting, and immunohistochemistry. RB1 mutations and/or homozygous deletions were found in 7 of the 34 tumors analyzed (20%). Among the 35 tumors with comparative genomic hybridization imbalances analyzed by immunohistochemistry, 30 (86%) did not exhibit significant nuclear labeling. The high correlation between chromosome 13 losses and absence of RB1 protein expression and the mutations detected strongly suggest that RB1 gene inactivation is a pivotal event in MFH oncogenesis. Moreover, the observation of a high incidence of MFH in patients previously treated for hereditary retinoblastoma fits well this hypothesis.     

Superior tibial epiphyseal osteochondroma with intra-articular development. Apropos of 2 cases in children

Two cases of intra-articular development of an osteochondroma in the proximal epiphysis of the tibia are reported. The first case, a 3 year old boy, resulted in blocking of the knee. After resection of the mass the diagnosis was confirmed by pathology. The second patient, an 8 year old boy, had no symptoms and surgery was not performed, although ablation was required of an associated astragalian osteochondroma of tibiotarsal intra-articular development. Relations between these epiphyseal osteochondromata and hemimelic epiphyseal dysplasia and metachondromatosis are discussed.