Prognostic information in soft tissue sarcoma using tumour size, vascular invasion and microscopic tumour necrosis-the SIN-system.

We have earlier devised a system for soft tissue sarcoma (STS), based on three negative prognostic features: large tumour size, vascular invasion, and microscopic tumour necrosis, the SIN-system. Tumours which exhibit 2 or 3 of these features are categorised as high-risk, the others as low-risk. We have now tested this system for reproducibility both as regards recognition of its components, and as regards prognostic strength in patients from another institution. We have also compared it with the American Joint Committee on Cancer (AJCC) system. 200 patients with STS were analysed, all had been treated by surgery, in 97 patients combined with radiotherapy. The median follow-up for the 117 survivors was 10 (1.5-27) years. Without knowledge of the clinical data, three groups of pathologists independently reviewed original slides from all of the tumours. Based on the factors, the tumours were classified as high-risk or low-risk. The prognostic strength was compared using the results obtained by the different observers. Concordance in recognition of vascular invasion, tumour necrosis, and overall grading was seen in 156 (78%), 154 (77%), and 167 (84%) of the 200 tumours, respectively. Based on the different observers' grading, the cumulative 5-year metastasis-free survival rate (MFSR) varied for patients with low-risk tumours between 0.85 and 0.80, and for patients with high-risk tumours between 0.48 and 0.43. The Kappa-value for grading between all three groups of observers was 0.77. The SIN-system gave more clinically useful prognostic information than the AJCC system. Useful prognostic information in STS can be obtained by using tumour size, vascular invasion and microscopic tumour necrosis. This system provides two distinct prognostic groups, and has a high reproducibility.

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders.

From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 microM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

Fine-needle aspiration features of pilomatrixoma.

BACKGROUND: Pilomatrixoma (PMX) is a benign skin neoplasm of hair matrix origin. The fine-needle aspiration (FNA) features of PMX frequently lead to a misdiagnosis of carcinoma. METHODS: Nine cases of PMX in which a preoperative FNA was performed were reviewed. The cytologic features were compared with the histologic appearance of corresponding surgical specimens as well as with cytologic features of tumors that arose in the differential diagnosis. RESULTS: Unequivocal benign diagnoses were rendered in three cases; the correct preoperative diagnosis of PMX was rendered in two of these cases and considered in an additional case. In four additional cases, carcinoma was diagnosed or could not be excluded. A noncommittal diagnosis of epithelial tumor, most likely of skin adnexal origin, was rendered in an additional single case. Retrospective review of the FNA smears in all nine instances disclosed cytologic features that corresponded well with the histologic components of PMX. Diagnostic cytologic features included cellular aspirates; clusters of small, primitive-appearing basaloid epithelial cells; a high nuclear-cytoplasmic ratio; evenly dispersed chromatin; prominent nucleoli; pink, fibrillary material enveloping clusters of basaloid cells; multinucleated giant cells; and sheets of ghost cells. CONCLUSIONS: The FNA cytologic diagnosis of PMX may be extremely difficult; its distinction from various primary cutaneous carcinomas is most problematic. Recognition of a unique constellation of cytologic features in FNA smears in the appropriate clinical context is most helpful in making this distinction.

Fine-needle aspiration characteristics of hibernoma.

BACKGROUND: Hibernoma is a rare, benign lipomatous tumor with features of brown fat. The preoperative diagnosis of hibernoma is difficult at times because its clinical, radiographic, and fine-needle aspiration (FNA) characteristics overlap with those of liposarcoma. METHODS: The preoperative FNA findings of eight surgically excised hibernomas from seven patients (three men and four women, ages 24-60 years) were reviewed. The cytologic features were compared with the histologic features of the corresponding surgical specimens as well as lipomatous tumors and other lesions that may cause confusion in the differential diagnosis. RESULTS: The FNA cytologic features of the hibernomas were found to correspond well with their histologic appearance. The FNA findings included small, round, brown fat-like cells with uniform, small cytoplasmic vacuoles and regular, small, round nuclei; delicate branching capillaries; and variable numbers of mature fat cells. CONCLUSIONS: The FNA cytologic features of hibernoma are characteristic and useful in the preoperative investigation of lipomatous tumors, particularly with regard to excluding a diagnosis of liposarcoma.

Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification.

PURPOSE: Malignant fibrous histiocytoma (MFH) has been regarded as the most common soft tissue sarcoma (STS) in adults. Yet its true nature and the validity of this diagnostic concept have increasingly been questioned. Available data suggest that most patients with MFH can be subclassified into specific STS types, but the clinical relevance of such categorization has been argued. In a retrospective study, we reclassified 100 tumors of the extremity and trunk wall primarily diagnosed as MFH and analyzed the outcome. PATIENTS AND METHODS: Patients were adults (median age, 70 years; range, 32 to 94 years). The median tumor size was 8 cm (range, 1 to 30 cm), and the thigh was the most common tumor location (n = 31). Median follow-up was 8 years (range, 3 to 16 years). The overall 5-year metastasis-free survival rate was 0.64. The tumors were reanalyzed histologically, immunohistochemically, and, where available, ultrastructurally, and were classified according to strict diagnostic criteria. Patients were staged according to the American Joint Committee on Cancer system, and prognoses were compared among different groups of the reclassified diagnoses, paying special attention to myogenic tumors. RESULTS: In 84 of 100 tumors, a specific line of differentiation was either proved or strongly suggested. The most common diagnoses were myxofibrosarcoma (n = 22) and leiomyosarcoma (n = 20). Overall, 30 tumors could be grouped as some form of myogenic sarcoma. These tumors had a worse prognosis, even within the same American Joint Committee on Cancer stage, and a shorter time to metastasis than nonmyogenic tumors. CONCLUSION: This retrospective study confirms that most so-called MFH can be subclassified by defined criteria; it provides evidence that such classification is clinically important. Specifically, pleomorphic STS showing myogenic differentiation are significantly more aggressive, a finding that allows planning future therapeutic trials.

Recurrent chromosome aberrations in fibrous dysplasia of the bone: a report of the CHAMP study group. CHromosomes And MorPhology.

The nosologic status of fibrous dysplasia (FD), a well-known and relatively common bone lesion, is controversial. Information collected by the CHromosomes And MorPhology (CHAMP) study group on published and unpublished cases of fibrous dysplasia shows the presence of clonal chromosome changes in at least a proportion of these lesions. The chromosome aberrations found in FD lesions have been quite variable and have included both structural and numerical changes. Two of the three cases investigated at the study group had trisomy 2 as the sole acquired anomaly. Combined with previously published data, +2 and rearrangements involving chromosome band 12p13 have each been detected in 3 of 8 cases with abnormal karyotype of 11 in which chromosomal analysis has been performed, suggesting that FD is a neoplastic lesion rather than a "dysplastic" process, as has been generally believed and as implied by its very name.

Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report from the CHAMP study group.

Aneurysmal bone cyst and giant cell tumor of bone are relatively rare bone tumors that sometimes coexist. We examined the karyotypes of 3 aneurysmal bone cysts, 12 giant cell tumors, and 3 combined lesions. All aneurysmal bone cysts showed involvement of chromosome segments 17p11-13 and/or 16q22. In addition, in 1 of the 3 giant cell tumors with secondary aneurysmal bone cyst, both chromosome bands were rearranged as well, albeit not in a balanced translocation. Seven out of 12 giant cell tumors were characterized by telomeric associations. One giant cell tumor showed a dup(16)(q13q22), suggesting the presence of a (minor) secondary aneurysmal bone cyst component, despite the absence of histological proof. Our results, combined with literature data further substantiate that segments 16q22 and 17p11-13 are nonrandomly involved in at least some aneurysmal bone cysts, irrespective of subtype (primary, secondary, intra/extraosseous, solid or classic). These findings strongly suggest that some aneurysmal bone cysts are true neoplasms. In addition, telomeric associations are the most frequent chromosomal aberrations in giant cell tumor of bone, the significance of which remains elusive. In combined giant cell tumor/aneurysmal bone cyst each component seems to retain its own karyotypic abnormality.

Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology.

Whether fibromatoses are neoplastic or reactive lesions has long been controversial and the relationship, if any, between the superficial and deep forms (desmoid tumors) are poorly understood. Clinical, pathologic, and cytogenetic data of 78 cases of fibromatosis were analyzed and correlated with each other. The results demonstrate that clonal chromosome aberrations are a common feature of this entity, being present in 46% of desmoid tumors, although less frequent in the superficial types (10%). In the deep-seated extra-abdominal fibromatoses, trisomies 8 and 20 and loss of 5q material were the only recurrent features. No correlation between +8 and local recurrence was found. Our findings provide additional evidence for the neoplastic nature of fibromatoses.

Cytogenetic evidence of clonality in cutaneous benign fibrous histiocytomas: a report of the CHAMP study group.

AIMS: Cutaneous benign fibrohistiocytic tumours are among the most common soft tissue lesions. Their biological nature, in particular whether they are neoplastic or reactive, has long been disputed. Some morphological subtypes can be confused with sarcoma. Since available karyotypic data in these lesions are scarce, this study was undertaken to determine whether their cytogenetic analysis might demonstrate clonality and might help in differential diagnosis. METHODS AND RESULTS: Thirteen karyotyped benign cutaneous fibrous histiocytomas (BFH) were morphologically reassessed and classified as ordinary BFH (eight cases), cellular BFH (four cases), and one ankle-type lesion. Five cases (38%) showed clonal cytogenetic changes, although the aberrations varied and did not correlate with histological subtypes. Karyotypic aberrations were more common in cellular BFH (3/4) than in the ordinary BFH (2/8). CONCLUSIONS: The demonstration of clonal chromosome abnormalities, in at least some cases, supports the neoplastic nature of cutaneous BFH. The karyotypic changes identified are different from those in dermatofibrosarcoma, with which cellular BFH is often confused histologically.

Comparative cytogenetic study of spindle cell and pleomorphic leiomyosarcomas of soft tissues: a report from the CHAMP Study Group.

Leiomyosarcomas (LMS) of soft tissues frequently show complex karyotypic changes, and no specific aberration has been identified. The aim of this study was to search for recurrent chromosome aberrations in soft tissue LMSs and to correlate these, if present, with morphological and clinical parameters. From a series of soft tissue sarcomas thoroughly reexamined cytogenetically and histopathologically, 45 LMSs were retrieved; 35 were classified microscopically as spindle cell, 3 as epithelioid, and 7 as pleomorphic. Clonal chromosome changes were present in 14, 3, and 3 cases, respectively. This series was combined with 11 previously published, karyotypically abnormal pleomorphic LMSs for cytogenetic-clinico-histopathological correlations. The breakpoints were widely scattered, with no predilection of any of the recurrent breakpoints and losses to any of the morphologic subtypes. Combining numerical and unbalanced structural changes, the most frequently lost segments were 3p21-p23 (11 cases), 8p21-pter, 13q12-q13, 13q32-qter (10 cases each), 1q42-qter, 2p15-pter, 18p11 (9 cases each), 1p36, 11q23-qter (8 cases each), and 10q23-qter (7 cases). The most frequent gain was 1q12-q31 (6 cases). There was a greater frequency of losses in 1p and 8p and a lower frequency of losses in 10q and 13q in tumors that had metastasized than in localized tumors. We conclude that LMSs with clonal abnormalities display highly complex karyotypic changes and extensive heterogeneity. No significant correlation exists between these changes and age and sex of the patients, or with depth of tumor, topography, microscopic subtype, or tumor grade. Losses in 1p36 and 8p21-pter may be associated with increased risk of metastases. Comparison of our findings in soft tissue LMS with those previously reported in LMS in other locations suggest that the karyotypic profile is more dependent on site of origin than on microscopic features.

Cytogenetic characterization of peripheral nerve sheath tumours: a report of the CHAMP study group.

The findings of characteristic, sometimes pathognomonic, chromosome aberrations in several types of soft tissue tumours have not only added to our understanding of the mechanisms behind the genesis of these tumours, but have also revealed the importance of cytogenetic analysis as a diagnostic tool. For many soft tissue tumours, including peripheral nerve sheath tumours, the number of analysed cases is, however, still very low, precluding evaluations of the clinical or biological significance of different chromosomal patterns. As part of an ongoing project aiming at identifying clinical-histopathological-cytogenetic correlations among soft tissue tumours, a series of 46 benign, the vast majority of which were located in the extremities, and 20 malignant peripheral nerve sheath tumours (BPNSTs and MPNSTs, respectively) that had been successfully analysed by chromosome banding techniques were evaluated with regard to clinical, morphological, and cytogenetic features. Clonal chromosome aberrations were found in 20 BPNSTs, with abnormal karyotypes being significantly more frequent among Schwannomas than among neurofibromas. Recurrent aberrations, all of which were confined to the Schwannoma subtypes, included loss of 22q material, loss of a sex chromosome, and trisomy 7. The results show that the cytogenetic features of Schwannomas are not dependent on the site of origin. The MPNSTs, all of which had clonal chromosome aberrations, displayed complex karyotypes with numerous structural and numerical changes, except in two cases showing +7 and -22, respectively, as the sole changes. None of the recurrent imbalances was restricted to either NF1-associated or sporadic MPNST, nor was any of the imbalances significantly associated with clinical outcome. The presence of a triploid or tetraploid clone was, however, associated with grade 3 tumours and a poor prognosis. The cytogenetic findings in peripheral nerve sheath tumours show that the karyotype is a good discriminator between BPNSTs and MPNSTs, and that the pattern of aberrations among the latter may add prognostic information.

Unique cytological features and chromosome aberrations in chondroid lipoma: a case report based on fine-needle aspiration cytology, histopathology, electron microscopy, chromosome banding, and molecular cytogenetics.

Chondroid lipoma is a rare, benign tumor that may mimic soft-tissue sarcoma clinically. Its histopathologic features may resemble hibernoma, myxoid liposarcoma, myxoid chondrosarcoma, and other lipomatous or chondroid neoplasms. In this study, a chondroid lipoma was analyzed by fine-needle aspiration cytology, histopathology, electron microscopy, chromosome banding, and metaphase fluorescence in situ hybridization. The results demonstrate that chondroid lipoma exhibits a characteristic pattern by fine-needle aspiration cytology, including a mixture of benign adipose tissue with lipoblastlike cells, and chondroblastlike cells with a fibrochondroid matrix. Cytogenetically, a three-way rearrangement between chromosomes 1, 2, and 5 was found, together with an 11;16 translocation with a breakpoint in 11q13, approximately 1 Mb proximal to the MEN1 region shown to be rearranged frequently in hibernoma. The presence of a karyotype of low complexity, but without any of the genetic aberrations characteristic for other types of soft-tissue tumors, indicate that chondroid lipoma develops along a unique pathogenetic pathway.

Diagnosis and tumor response in osteosarcoma and Ewing's sarcoma, according to treatment protocols SSG II, SSG VIII, ISG/SSG I, SSG IV and SSG IX.

114 patients with osteosarcoma in the extremities had been reported to the SSG II trial, 132 to the SSG VIII trial and, until October 1998, 99 to the ISG/SSG I trial. The SSG IV trial included 53 patients and the SSG IX trial 104 patients until October 1998. In the SSG II trial, 19% were good responders (grades III and IV) as compared to 51% in the SSG VIII trial. On reevaluation was the response changed in one forth of the cases in both the SSG II and SSG VIII trials. In 9 and 10 cases (8%), respectively, the reevaluation resulted in a change from "good responder" to "bad responder". In the ISG/SSG I trial, the preliminary results showed a good response in 22% of the cases. In the SSG IV trial, 44% were good responders (grades III and IV), as compared to 54% in the SSG IX trial.

Analysis of 35 cases of localized and diffuse tenosynovial giant cell tumor: a report from the Chromosomes and Morphology (CHAMP) study group.

The karyotypes of 44 specimens from 35 patients with localized (n = 19) or diffuse (n = 16) tenosynovial giant cell tumors were studied. The majority of cases in both categories (11 of 19 localized; 12 of 16 diffuse) displayed clonal chromosomal aberrations, with a complex karyotype in three cases and a simple chromosomal aberration in the others. No difference in the distribution of karyotypic abnormalities was found between the localized and diffuse form except for trisomies (usually of chromosomes 5 and/or 7), which were more frequent in the diffuse type. The short arm of chromosome 1 (1p11-13) was most frequently rearranged, with 7 of 11 localized and 7 of 12 diffuse lesions affected. These findings indicate that the localized and diffuse forms of tenosynovial giant cell tumor might represent two morphologic manifestations of the same entity. The high frequency of clonal chromosomal abnormalities, with a clustering of structural rearrangements to 1p11-13, suggests that this disease is most likely neoplastic in nature and paves the way to search for gene(s) that might be involved in its development.

Correlation between clinicopathological features and karyotype in spindle cell sarcomas. A report of 130 cases from the CHAMP study group.

Soft-tissue tumors have proved to be a fruitful area for the identification of reproducible cytogenetic aberrations, especially among pediatric round-cell sarcomas and lipomatous tumors. Thus far, however, data regarding sarcomas of monomorphic spindle cell type have been limited and somewhat disappointing, with the notable exception of synovial sarcoma. As part of an ongoing international collaborative study, 130 karyotyped spindle-cell sarcomas were reviewed and classified histologically, without knowledge of the clinical and karyotypic data, with the aim of identifying objective correlations between morphology, karyotype, and clinical parameters. Clonal chromosomal abnormalities were identified in 82 cases studied (63%), but only in the group of synovial sarcomas was there clear correlation between the cytogenetic findings, in the form of a consistent t(X;18)(p11;q11), and morphology. Among leiomyosarcomas (41 cases) and malignant peripheral nerve sheath tumors (MPNSTs; 27 cases) as well as in individual examples of rarer entities, there was a general tendency for karyotypic complexity associated with frequent loss or rearrangement of chromosome arms 1p, 10p, 11q, 12q, 17p, and 22q. Rearrangements of 17q (the region of the NF1 gene) were seen in 9/27 (33%) of MPNSTs. Among nine cases of solitary fibrous tumor (in which previous cytogenetic data are very limited) no consistent aberrations were identified. We conclude that, with the exception of synovial sarcoma, most spindle-cell sarcomas share with pleomorphic sarcomas the tendency for karyotypic complexity. There was no indication (in most of these lesions) that detectable cytogenetic aberrations could either facilitate their diagnosis or help to determine prognosis. There is a clear need to further study and understand the significance of multiple chromosomal abnormalities in this group of mesenchymal neoplasms with the particular goal of determining their role in the process of tumor development.

Inflammatory leiomyosarcoma may be characterized by specific near-haploid chromosome changes.

Identical near-haploid karyotypes with 28, X, +5, +18, +20, +21, +22 were found in two cases of inflammatory leiomyosarcoma, one of which had been reported previously as malignant fibrous histiocytoma. This abnormality may identify these tumours as a separate entity within this group of sarcomas.

Nonrandom pattern of telomeric associations in atypical lipomatous tumors with ring and giant marker chromosomes.

Atypical lipomatous tumors (ALTs) are cytogenetically characterized by supernumerary ring and giant marker chromosomes. Another common finding in ALT is that the tumor cells are cytogenetically heterogeneous with a variety of mostly nonclonal numerical and structural chromosome aberrations, including telomeric associations. In a series of 48 cytogenetically investigated ALTs, all chromosomal aberrations, clonal as well as nonclonal, were registered. Clonal ring chromosomes were present in 47 cases and giant markers in 11 cases. In 7 cases, 12 clonal telomeric associations were found and 37 cases showed nonclonal associations involving 344 identified telomeres. The telomere associations were nonrandomly distributed, with the telomeres of 11p, 20p, 20q, 9q, 15p, 19q, and 22q being most frequently (8.7-4.1% of all associations) involved; only Xp and Xq were never affected. The pattern of telomeric associations in ALT was compared with literature data on 47 giant cell tumors (880 telomeres), previously reported to show a nonrandom distribution of associations, and 36 sporadic cases of a variety of other human neoplasms (583 telomeres). The analysis indicated that the telomeres of 11p, 19q, and 20q are preferentially involved in associations in several tumor types. Among other structural aberrations in the ALT series, 221 nonclonal and 52 clonal breakpoints were identified, as well as 342 nonclonal and 14 clonal numerical aberrations. The combined data suggest that telomeric associations may predispose to acquired chromosome aberrations in neoplasia.