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Cellular origins of ultraviolet radiation-induced corneal tumours in the grey, short-tailed South American opossum (Monodelphis domestica).

Corneal tumours were induced in almost 100% of grey, short-tailed South American opossums (Monodelphis domestica) exposed three times weekly to ultraviolet radiation (UVR) for periods of a year or more. Five tumours, representing the morphological spectrum of UVR-induced corneal tumours (two fibrosarcomas, one malignant fibrous histiocytoma, one putative haemangiosarcoma, and one squamous cell carcinoma overlying a sarcoma), were assayed immunohistochemically for reactivity with antibodies against the intermediate filaments vimentin, smooth muscle actin (alpha isoform), muscle-specific actins (alpha and gamma isoforms), desmin and cytokeratin, and with antibodies against the vascular endothelial marker von Willebrand factor. The squamous cell carcinoma was cytokeratin-positive. Other tumours were cytokeratin-negative and vimentin-positive. Three tumours had scattered individual cells and groups of cells immunoreactive with antibodies against smooth muscle actin and muscle-specific actins; two tumours (a fibrosarcoma and the malignant fibrous histiocytoma) had small numbers of desmin-positive cells. The putative haemangiosarcoma contained two populations of neoplastic cells, von Willebrand factor-positive vascular endothelial cells and smooth muscle actin-positive spindle cells. It was concluded (1) that UVR-induced corneal tumours may be composed of cells derived from resident epithelial cells, immigrant vascular endothelial cells, or fibroblast-like cells of unknown origin, and (2) that such tumours may contain more than one neoplastic cell type.

Actins↗

Translocation t(12;22)(q13;q12.2-12.3) in a clear cell sarcoma of tendons and aponeuroses.

Cytogenetic analysis of a short-term culture from a clear cell sarcoma revealed a complex karyotype with the mainline of 49,XY,t(7;18)(p11.2;q21.3), +der(7)t(7;18)(p11.2;q21.3), +8, +der (8;17)(q10;q10),t(12;22)(q13;q12.2-12.3),add(13)(p13). An apparently identical translocation t(12;22) has been described recently in four clear cell sarcomas, indicating that this constitutes a primary cytogenetic change specific for this type of tumor. In our case, the breakpoint on chromosome 22 could be assigned to band 22q12.2 or 22q12.3. Together with the present case, trisomy or tetrasomy 8 has been found in six of nine clear cell sarcomas, suggesting that, as in Ewing's sarcoma and myxoid liposarcoma, trisomy/tetrasomy 8 represents a nonrandom secondary aberration. We conclude that the finding of the specific translocation t(12;22) may prove to be an important marker in the differential diagnosis of clear cell sarcoma from some other soft tissue sarcomas and malignant melanoma.

Adult↗

The value of electronmicroscopy and immunohistochemistry in the diagnosis of soft tissue sarcomas: a study of 200 cases.

Two hundred soft tissue sarcomas, accrued consecutively over a 4-year period, were examined by light and electronmicroscopy and by routine immunohistochemistry. The commonest tumour type was malignant fibrous histiocytoma. Fibrosarcoma, composed only of fibroblasts, was diagnosed in only one case; three others, composed also of myofibroblasts, could be regarded as fibrosarcomas or myofibrosarcomas. Immunohistochemistry was of most value in the diagnosis of rhabdomyosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumour of Schwann cell type and epithelioid sarcoma. Electronmicroscopy was of most use for the diagnosis of malignant peripheral nerve sheath tumour of perineurial cell type and marker-negative monophasic synovial sarcoma, and for confirming malignant fibrous histiocytoma. Fifteen of 19 marker-negative spindle cell tumours (79%) were diagnosable by electronmicroscopy. A combination of techniques resulted in a specific diagnosis in 193 cases (96.5%). The routine use of electronmicroscopy in sarcoma diagnosis can improve accuracy of diagnosis, establish the true frequency of marker-positivity for each ultrastructurally confirmed tumour type and minimise the number of unclassifiable cases.

Biomarkers, Tumor↗

Clinical experience with autobiotherapy of malignant tumor disease: a preliminary report.

It has been proposed that the elimination of excess scar tissue from the body is achieved by specialized killer cells, which are activated by vascular changes in the scar tissue. The malignant tumor is, according to this theory, considered to be a special type of excess scar tissue of fetal or near fetal age, the fetal blood supply of which prevents the activation of those specialized killer cells which were believed to eliminate excess scar tissue. Therefore, it is assumed that if the specialized killer cells of a malignant tumor patient are activated artificially, they would cause malignant tumor regression in vivo. This method of treatment is called autobiotherapy because it utilizes biological products from the patient to treat his own malignant tumor. Preliminary evidence is presented in support of autobiotherapy of malignant tumor disease.The peripheral leucocytes of 27 malignant tumor patients were activated separately by incubation in a serum-free medium containing the respective tumor cells or material. The effect of the injection of the activated leucocytes or their products, termed tumor leucocyte cultures (TLC), was studied in five patients with Kaposi sarcoma, five with carcinoma of the breast, four with carcinoma of the cervix, three with soft tissue sarcoma, two with carcinoma of the lung, two with carcinoma of the maxillary antrium, and a miscellaneous group of six patients. In 52 percent of cases, there was significant tumor regression. Tumor regression was most marked in patients with Kaposi sarcoma, carcinoma of the cervix, pharynx, and pancreas, one patient with a slow growing fibrosarcoma, one patient with a metastatic breast carcinoma, and also in one patient with myelogenous leukemia. However, not all the types of tumor studied responded satisfactorily to autobiotherapy. The reasons for the differences in response to autobiotherapy remain to be determined. Even so, the positive results obtained indicate that autobiotherapy is worthy of further research as an alternative in controlling malignant tumor disease.

Adult↗

Telomere lengths of translocation-associated and nontranslocation-associated sarcomas differ dramatically.

Sarcomas can be divided into those with specific translocations displaying monotonous cytomorphology, and those with complex karyotypes and marked cellular pleomorphism. Telomeres contain terminal DNA sequence repeats that maintain chromosomal stability. Telomeres shorten with cell division and may become dysfunctional leading to chromosomal instability. Using a fluorescence in situ hybridization/immunofluorescence method to assess telomere lengths in archival tissues we analyzed these two types of sarcomas using paraffin-embedded primary tumor specimens. Tissues from nine sarcomas with characteristic translocations (two synovial sarcomas, two alveolar rhabdomyosarcomas, two desmoplastic round cell tumors, and one each of infantile fibrosarcoma, myxoid liposarcoma, cellular congenital mesoblastic nephroma) and nine without (four malignant fibrous histiocytomas, two leiomyosarcomas, one pleomorphic rhabdomyosarcoma, one dedifferentiated chondrosarcoma, and one malignant peripheral nerve sheath tumor) were analyzed. In all (nine of nine) cases with specific translocations, which generally have few karyotypic abnormalities, telomere lengths were similar to or reduced compared to surrounding nonneoplastic tissues. In contrast, telomeres in cases lacking specific translocations, which generally contain complex karyotypes, were often found to be dramatically lengthened and heterogeneous. In addition to markedly elongated telomeres, seven of nine (78%) complex cases exhibited large brightly stained regions corresponding to a specific type of promyelocytic leukemia nuclear body found in immortalized cells that maintain telomeres in a telomerase-independent manner [alternative lengthening of telomeres (ALT) pathway]. This phenotype is unlike that of epithelial neoplasms that typically display complex karyotypes with abnormally short telomeres maintained by the enzyme telomerase. The discovery of heterogeneous telomere lengths and evidence of the ALT pathway in the majority of sarcomas with complex karyotypes supports the existence of a telomere maintenance pathway incapable of full karyotypic stabilization in pleomorphic sarcomas. These findings provide additional molecular-genetic evidence supporting the dichotomous grouping of sarcomas into those with characteristic signature translocations without extensive additional karyotypic abnormalities, and those without such signature translocations that typically display very complex karyotypes, and point to telomere dysfunction as a plausible contributor to the chromosomal aberrations found in complex sarcomas.

Cell Nucleus↗

Treatment effects in pediatric soft tissue and bone tumors: practical considerations for the pathologist.

Dramatic improvements in survival for children with cancer have led to increased numbers of posttreatment pathologic specimens, particularly in bone and soft tissue sarcomas. Current therapeutic protocols in North America require specific pathologic classification and stratify patients based on clinical, biologic, and pathologic features. For osteosarcoma, the pathologic response to therapy predicts prognosis and modifies the treatment regimen. Ongoing studies aim to assess the response to therapy and outcome in other types of soft tissue and bone tumors. The pathologic evaluation of pretreatment and posttreatment specimens is critical for therapeutic decisions and prognostic assessment. A standardized approach to posttherapy pathologic specimens, with attention to appropriate use of ancillary tests, and assessment of clinical and biologic significance of therapy-induced pathologic changes has significance for patient management and treatment protocols.

Bone Neoplasms↗

Subsequent cancer in patients with Ewing's sarcoma.

Among 31 long-term survivors of Ewing's sarcoma, two patients developed second primary cancers, compared to an expected number of 0.03 (relative risk = 72; 95% confidence limit = 8-259). One patient had renal medullary neuroblastoma, which is not known to be related to Ewing's tumor or its therapy. The second patient had a bone fibrosarcoma, arising at the primary tumor site, which was thought to be radiation-induced. The risk of radiation-induced bone sarcomas was lower, although not significantly so, than in a recently reported series of Ewing's tumor. These two reports suggest that patients with Ewing's sarcoma have a tendency to develop radiogenic sarcomas following primary megavoltage radiation therapy. The lowest radiation dose consistent with local tumor eradication should be employed to minimize the risk of subsequent radiogenic cancer.

Adolescent↗

Fine-needle aspiration of primary and recurrent benign fibrous histiocytoma: classic, aneurysmal, and myxoid variants.

There is a limited number of correlative cytopathological studies of fibrous histiocytoma (FHC). To better define cytopathological criteria of diagnosis, we have reviewed fine-needle aspirates (FNA) from 36 FHCs (32 classical, 1 myxoid, and 3 aneurysmal variants on corresponding histological sections). Original cytological diagnoses were benign in 33 (91.7%) cases (22 accurate) and false positive in 3 (8.3%) cases. All smears were surprisingly homogenous and composed of histiocytic cells with finely vacuolated cytoplasm in 27 (75%) cases, small regular spindle cells in 25 (69%) cases, and giant cells in 17 (47%) cases. Histiocytic cells were attached to vascular structures in 9 (25%) cases. Slight cytonuclear atypia was seen in five (14%) cases. Three (8.3%) cases showed numerous siderophages. In two (5.6%) cases, there were abundant inflammatory backgrounds and in one (3%) case there was a scant myxoid background. Storiform patterns, round cells, prominent atypia, necroses, or mitotic figures were not seen. FHC should be differentiated from other benign, low- and intermediate-grade spindle-cell neoplasms such as low-grade fibrosarcoma, dermatofibrosarcoma protuberans, nodular fasciitis, spindle-cell malignant melanoma, and monophasic synovial sarcoma. Some cases may be misinterpreted as malignant, especially in cases of recurrence or in patients with a cancer history.

Adolescent↗

Mouse tumors are heterogeneous in their susceptibility to syngeneic lymphokine-activated killer cells and delineate functional subsets in such effectors.

We have analyzed whether lymphokine-activated killer (LAK) cells, generated from C57BL/6J (B6) spleen cells at different times after recombinant interleukin-2 (rIL-2) culture, could be heterogeneous in their ability to lyse a variety of tumor targets. When tested 3 days after exposure to 250 U/ml rIL-2 (day-3 LAK cells) a significant lysis was detected with the natural-killer(NK)-sensitive YAC lymphoma, the NK-resistant P815 mastocytoma, three different syngeneic melanomas and a syngeneic fibrosarcoma (group 1 targets), whereas no lysis was observed with a reticulum cell sarcoma, two different lymphomas or concanavalin A blasts, all of B6 origin (group 2 targets). LAK cells cultured for 5 days, however, lysed group 2 targets and showed a parallel increase of cytotoxic activity against group 1 targets. At day 7, LAK activity declined on all targets examined. In cold-target inhibition studies, the lysis of group 1 tumor targets by day-3 or day-5 LAK cells could be inhibited only by group 1 and not by group 2 unlabelled tumor cells. All group 1 tumors could effectively compete each other. Conversely, the lysis of group 2 tumor targets by day-5 LAK cells was inhibited by both group 1 and group 2 targets. These data indicate the presence of separate LAK effectors that appear to arise with different time kinetics and have different recognition structures. In vitro antibody depletion at the effector level showed that day-3 LAK cells with cytotoxic activity against group 1 tumors were ASGM1+. Day-5 LAK cells included both ASGM1+ and Lyt2+ effectors and both populations, although to a different extent, contributed to the lysis of all targets. Our results indicate that LAK cells are functionally heterogeneous. This heterogeneity is defined by their susceptible target cells and cannot be ascribed to different (Lyt2+ versus ASGM1+) lineages.

Animals↗