Malignant Cell Tumors Research Articles

The pathology of late recurrence of testicular germ cell tumors.

A total of 91 men had histologically documented late recurrences of testicular germ cell tumors characterized by a complete response to treatment with a subsequent disease-free interval of at least 2 years and no evidence of a second primary lesion. Ninety percent of the patients for whom information was available received chemotherapy shortly after their initial diagnosis of testicular germ cell tumors; most of the other patients were known to have stage I disease initially. Overall, 60% of patients had teratoma in their late recurrences, including 20 patients (22%) in whom teratoma was the only element. Thus, teratoma was the most common type of neoplasm in late recurrences. Excluding teratoma coexisting with other types of neoplasms, yolk sac tumor was the most frequent type of tumor in patients with late recurrence. It occurred in 47% of patients, either alone or with teratoma, another nonteratomatous germ cell tumor type, or a "nongerm cell malignant tumor." Unusual types of yolk sac tumor, including glandular, parietal, clear cell, and pleomorphic patterns, were seen frequently in late recurrences and often raised differential diagnostic problems with "nongerm cell" carcinomas. A smaller number of late recurrences consisted of other types of neoplasms. Twenty percent of patients with late recurrence had a nonteratomatous germ cell tumor other than yolk sac tumor, either alone, with yolk sac tumor, or with a "nongerm cell malignant tumor." Most of these nonteratomatous germ cell tumors other than yolk sac tumor were embryonal carcinoma, although rarely seminoma and choriocarcinoma were encountered. "Nongerm cell malignant tumors," including both sarcomas and carcinomas of various types, occurred in 23% of late-recurrence patients, either alone or with a nonteratomatous germ cell tumor. Late recurrences were seen in many different sites in these patients, including the retroperitoneum, abdomen, pelvis, liver, mediastinum, lung, bone (femur, vertebra, and rib), lymph nodes outside the retroperitoneum and mediastinum (supraclavicular, neck, and axillary regions), scrotum and inguinal regions, adrenal gland, chest wall, and buttocks. Follow-up data were available for 79 of the 91 patients studied. Duration of follow-up ranged from 2 months to 13 years after the patient's first late recurrences; the mean length of follow-up was 4.8 years. Patients whose late recurrences consisted of teratoma only had the most favorable outcomes, with 79% having no evidence of disease at last follow-up. Patients whose late recurrences consisted of pure "nongerm cell malignant tumor" or pure germ cell tumor (yolk sac tumor or other types) had a much worse prognosis: Only 36% to 37% were alive with no evidence of disease. Patients with two different types of nonteratomatous malignancies in their late recurrences had a dismal clinical course: Only 17% with both yolk sac tumor and other nonteratomatous germ cell tumor had no evidence of disease, whereas no patient with both nonteratomatous germ cell tumor and "nongerm cell malignant tumor" was disease free. Late recurrences consisting of teratoma alone often have a favorable outcome, but the prognosis in all other patients is poor. Furthermore, late recurrence is not likely to respond to chemotherapy and is best treated by surgical excision when possible.

Telomerase Repeat Amplification Protocol (TRAP): A New Molecular Marker for Parathyroid Carcinoma

Telomerase results to be active in human germ, stem cells, several malignant cell tumors and in immortalized cell lines. In order to investigate if molecular mechanisms other than Rb gene inactivation can be helpful to diagnose malignancy of parathyroid tumors, we decided to investigate the presence of active telomerase in homogenates from different pathological parathyroid tissues (hyperplastic, adenomatous, carcinomatous, and normal) and primary cell cultures. The TRAP assay was performed to detect this activity in histologically characterized normal, hyperplastic, adenomatous, and carcinomatous human parathyroid tissues, primary cell lines, and one metastatic tissue from parathyroid carcinoma. Only malignant parathyroid glands and the metastatic tissue were TRAP positive. Our findings suggest that telomerase expression could represent an important molecular mechanism underlying the acquisition and progression of an aggressive phenotype of epithelial parathyroid cells and it may help to predict their malignant potential. The TRAP assay is easy to perform and it could become an additional tool to be included in the harmamentarium for the molecular diagnosis of parathyroid carcinoma.

Fine-needle aspiration biopsy diagnosis of small round cell tumors of childhood: A comprehensive approach.

Fine-needle aspiration biopsy findings in small round cell malignant tumors of children are briefly reviewed. All of these tumors usually have characteristic cytomorphology which, when recognized, may lead to a definitive diagnosis. However, when these tumors are undifferentiated, morphologic criteria may not be sufficient for arriving at a correct diagnosis. A variety of ancillary studies including electron microscopy, immunohistochemistry and DNA ploidy, cytogenetics, and fluorescent in situ hybridization may provide valuable additional information for precise characterization of these neoplasms. Some of the ancillary studies may also be used for assigning these cases to prognostically significant subgroups. This information may also help in defining the most suitable chemotherapeutic regimens for these tumors. Since most of these special studies require only a small amount of cellular material, fine-needle aspiration biopsy is ideally suited for obtaining samples for these procedures. It is hoped that as cytogenetic and molecular techniques become available in many diagnostic laboratories, a comprehensive evaluation of aspiration biopsies from round cell malignant tumors, encompassing a precise pathologic diagnosis, determination of prognosis, and prediction of response to therapy, will be possible in a majority of cases. Diagn. Cytopathol. 1999;21:81-91.

Telomerase enzyme activation and human cell immortalization

Activity of telomerase, the enzyme that synthesizes the telomere ends of linear eukaryotic chromosomes, is repressed in most normal human somatic cells but induced in most human cancers. Normal human cells that lack telomerase activity progressively lose telomere sequences. In contrast, most immortalized cell lines and malignant human tumors appear to maintain constant telomere length via telomerase activity. Telomerase is composed of at least two subunits, an RNA subunit that templates telomere synthesis, and a catalytic protein subunit. The gene encoding the catalytic protein subunit of telomerase has recently been identified, first in yeast and ciliates and then in humans. This catalytic subunit belongs to the reverse transcriptase family. Studies of telomerase subunits further define a role for telomerase in the control of mammalian cell lifespan. The expression of the human telomerase catalytic subunit gene, hTERT, is induced in immortalized cells and primary tumors. When hTERT is ectopically expressed in hitherto telomerase-negative cells, telomerase enzyme activity appears, and an extended lifespan has been observed in some cells. In contrast, disruption of the mouse telomerase RNA subunit gene, mTERC, results in a delayed failure of cell proliferation. Telomerase activity therefore appears to be necessary for the prolonged survival of mammalian cells.

Malignant tumors of the eyelid: A Population-Based Study of Non-Basal Cell and Non-Squamous Cell Malignant Neoplasms. Margo CE, Mulla ZD. Arch Ophthalmol 116:195, 1998

Malignant tumors of the eyelid: A Population-Based Study of Non-Basal Cell and Non-Squamous Cell Malignant Neoplasms. Margo CE, Mulla ZD. Arch Ophthalmol 116:195, 1998

Telomerase Activity in Hodgkin's Disease

Telomere maintenance executed by the action of telomerase seems to be a prerequisite for immortalization. Telomerase is found in most cell lines and malignant tumors. A telomerase-independent mechanism for telomere maintenance in Hodgkin's disease has been proposed in the absence of detectable telomerase activity. In this study, telomerase activity was detected in 31 of 77 Hodgkin's disease samples and a strong correlation between eosinophilia and absence of detectable telomerase activity was found. Purified eosinophils and specifically eosinophil-derived neurotoxin and eosinophilic cationic protein, both ribonucleases, were found to degrade telomerase. Purified neutrophils also exhibited weak telomerase degradative activity. Reanalysis of previously telomerase-negative Hodgkin's disease samples with eosinophilia using ribonuclease inhibitors resulted in the detection of telomerase activity. Ribonuclease-containing cells in vivo thus have a considerable impact on the detectability of telomerase. In Hodgkin's disease samples without eosinophilia, 24 of 27 exhibited telomerase activity at decreased levels compared with non-Hodgkin's lymphomas and at increased levels compared with reactive nodes indicative of a telomerase positive tumor component in Hodgkin's disease. Telomerase positivity of the Hodgkin's and Reed-Sternberg cells in vivo was also supported by high levels of telomerase expression in Hodgkin's disease cell lines. Based on our data, Hodgkin's lymphomas are potential targets for antitelomerase therapy.

Telomerase Activity in Hodgkin's Disease

AbstractTelomere maintenance executed by the action of telomerase seems to be a prerequisite for immortalization. Telomerase is found in most cell lines and malignant tumors. A telomerase-independent mechanism for telomere maintenance in Hodgkin's disease has been proposed in the absence of detectable telomerase activity. In this study, telomerase activity was detected in 31 of 77 Hodgkin's disease samples and a strong correlation between eosinophilia and absence of detectable telomerase activity was found. Purified eosinophils and specifically eosinophil-derived neurotoxin and eosinophilic cationic protein, both ribonucleases, were found to degrade telomerase. Purified neutrophils also exhibited weak telomerase degradative activity. Reanalysis of previously telomerase-negative Hodgkin's disease samples with eosinophilia using ribonuclease inhibitors resulted in the detection of telomerase activity. Ribonuclease-containing cells in vivo thus have a considerable impact on the detectability of telomerase. In Hodgkin's disease samples without eosinophilia, 24 of 27 exhibited telomerase activity at decreased levels compared with non-Hodgkin's lymphomas and at increased levels compared with reactive nodes indicative of a telomerase positive tumor component in Hodgkin's disease. Telomerase positivity of the Hodgkin's and Reed-Sternberg cells in vivo was also supported by high levels of telomerase expression in Hodgkin's disease cell lines. Based on our data, Hodgkin's lymphomas are potential targets for antitelomerase therapy.

Expression of bcl-2 oncoprotein in benign and malignant spindle cell tumors of soft tissue, skin, serosal surfaces, and gastrointestinal tract.

An immunohistochemical study to determine the pattern of immunoreactivity for bcl-2 oncoprotein was performed in 380 spindle cell tumors of soft tissue, skin, serosal surfaces, and gastrointestinal tract. The cases studied included examples of benign, reactive spindle cell proliferations to benign and malignant spindle cell neoplasms, including nodular fasciitis (10), fibromatosis (5), dermatofibroma (10), dermatofibrosarcoma protuberans (18), Kaposi's sarcoma (15), spindle cell lipomatous tumors (24), benign and malignant smooth muscle tumors (35), neural/peripheral nerve sheath neoplasms (53), synovial sarcomas (70) solitary fibrous tumors of serosal surfaces and other sites (56), gastrointestinal stromal tumors (GIST) (47), and malignant undifferentiated fibroblastic spindle cell proliferations of soft tissue (37 cases). The results of bcl-2 staining was additionally correlated with CD34 immunoreactivity. Bcl-2 was uniformly negative in all cases of nodular fasciitis, fibromatosis, and dermatofibroma, as well as in benign and malignant smooth muscle proliferations. Strong positivity for bcl-2 was observed in all cases of spindle cell lipoma, dendritic fibromyxolipoma, Kaposi's sarcoma, solitary fibrous tumors, gastrointestinal stromal tumors, and in the spindle cell component of synovial sarcoma. With the exception of the last, there appeared to be a close correlation between the expression of bcl-2 and CD34 in these tumors. Strong bcl-2 positivity also was found, at least focally, in approximately one third of benign and malignant peripheral nerve sheath tumors, particularly in the better-differentiated (Antoni type A) areas. Sarcomas of fibroblastic type, including low-grade myxofibrosarcoma, malignant fibrous histiocytoma, and fibrosarcoma, showed variable expression of bcl-2 in the tumor cells. Our results appear to indicate that bcl-2 may have a wide distribution among benign and malignant spindle cell neoplasms. Strong expression of this marker in some of these conditions, particularly solitary fibrous tumor, gastrointestinal stromal tumors, and synovial sarcoma, may be of aid for differential diagnosis.

Malignant tumors of the eyelid: a population-based study of non-basal cell and non-squamous cell malignant neoplasms.

To determine the relative frequencies, average annual incidences, and patient characteristics of non-basal cell and non-squamous cell malignant neoplasms of the eyelid in a defined geographic population. A retrospective study using the Florida Cancer Data System to identify malignant tumors of the eyelid, except for basal cell and squamous cell carcinomas, from 1981 through 1994. Cases were limited to persons who resided within Florida. Incidence of histologically confirmed malignant eyelid tumors. Two hundred six primary malignant eyelid tumors were identified. The 3 most common, in order of frequency, were melanoma, sebaceous carcinoma, and lymphoma. The median age at diagnosis for all patients was 73 years. Only 3 of the 206 malignant neoplasms occurred in blacks. The annual incidence of eyelid melanoma and sebaceous carcinoma in whites older than 20 years was 0.6 and 0.5 per million, respectively. Kaposi sarcoma was the most common type of mesenchymal tumor. Eleven different histologic types of lymphoma were found in the eyelid. Only 2 of 27 lymphomas had T-cell lineage. Malignant tumors of the eyelid other than basal cell and squamous cell carcinoma are uncommon and usually occur in elderly white persons. Primary eyelid tumors of any type are rare in blacks. The risk of a non-basal cell and non-squamous cell malignant neoplasm of the eyelid in Florida is 6.4 times greater for whites than for blacks (95% confidence interval [CI], 2.1-20.2). A variety of B-cell lymphomas can be manifested as primary eyelid tumors.

有きょく細胞癌を合併したメルケル細胞癌の１例

We reported a case of merkel cell carcinoma (MCC) admixed with squamous cell carcinoma (SCC). The patient was a 82-year-old women who developed a red, domeshaped tumor, 18mm in diameter, on her left cheek. Histologically the tumor showed undifferentiated small cell malignant neoplasm that coexisted with SCC. Sweat gland differenciation was shown in a part of SCC. An immunohistochemical study showed that MCC was positive for neuron specific enolase and synaptophysin, SCC was positive for carcinoembryonic antigen and cytokeratin 20. An ultra-structual study showed dense core granules within the cytoplasm of MCC.

Inhibition of death receptor signals by cellular FLIP.

The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which can trigger apoptosis. However, Fas surface expression does not necessarily render cells susceptible to Fas ligand-induced death signals, indicating that inhibitors of the apoptosis-signalling pathway must exist. Here we report the characterization of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues. The short form, FLIPs, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis, whereas the long form, FLIP(L), contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue. FLIPs and FLIP(L) interact with the adaptor protein FADD and the protease FLICE, and potently inhibit apoptosis induced by all known human death receptors. FLIP(L) is expressed during the early stage of T-cell activation, but disappears when T cells become susceptible to Fas ligand-mediated apoptosis. High levels of FLIP(L) protein are also detectable in melanoma cell lines and malignant melanoma tumours. Thus FLIP may be implicated in tissue homeostasis as an important regulator of apoptosis.

Cell Cycle Regulatory Genes and Malignant Tumors

Cell Cycle Regulatory Genes and Malignant Tumors

Endometrial Carcinomas - Flow Cytometric DNA Content and S-phase Values

The purpose of the investigation was to determine the DNA content and S-phase value in a large material of fresh tumour tissue from endometrial carcinomas and to correlate these parameters to tumour type, grade of differentiation, depth of myometrial invasion and stage. The prospective study consisted of 290 unselected cases of endometrial carcinomas, FIGO stage I-IV where flow cytometry was performed on fresh tumour tissue blocks from hysterectomy specimens. 223 cases had more than 10% tumour tissue in tissue blocks taken adjacent to the blocks for flow cytometry. Non-diploidy was defined as 0.9 > or = DNA index > 1.10 and high S-phase value was defined as > 15%. Non-diploidy was found in 46% of the endometrioid adenocarcinoma and in 85% of the non-endometrioid carcinomas (clear cell adenocarcinoma, serous adenocarcinoma and malignant mixed mesodermal tumour) (p < 0.001). S-phase value was > 15% in 39% of the endometrioid adenocarcinoma and in 100% of the non-endometrioid carcinomas (p < 0.0001). In endometrioid adenocarcinoma there was a statistical significant relation between non-diploidy and grade of histological differentiation (p < 0.006), as well as with depth of myometrial invasion (p < 0.05). There was no relation between non-diploidy and the presence of squamous differentiation, whether benign or malignant or to FIGO stage. High S-phase values (> 15%) was related to the grade of differentiation (p < 0.002). No relation was demonstrated between S-phase > 15% and squamous differentiation, depth of myometrial invasion or FIGO stage. In conclusion, 50% of all the endometrial carcinomas were non-diploid and 43% had S-phase value > 15%. Ploidy correlated with histologic tumour types, grade of differentiation and depth on myometrial invasion while S-phase values only correlated with histologic tumour types and grade of differentiation.

Expression and interconversion of neuron-specific enolase in patient sera and extracts from small-cell lung cancer cells.

The isoforms of gamma-enolase were characterized in serum from patients with small-cell lung cancer (SCLC) and in extracts from SCLC cell lines and malignant melanoma tumor tissue. Large variations in the expression of the 3 gamma-isoforms of enolase were observed. These forms probably represent the homodimeric gamma gamma-enolase, the heterodimeric alpha gamma-enolase and the monomeric forms of gamma-enolase. Only the dimeric forms are enzymatically active. The predominant gamma-enolase in the cell lines is the heterodimeric alpha gamma-enolase. The SCLC cell lines can be divided into two groups: one with negligible gamma gamma-enolase expression and considerable amounts of the nonneuronal alpha alpha-enolase and a second group with a large fraction of gamma gamma-enolase concomitant with a low expression of alpha-enolase. Similar patterns are observed in tissue extracts from malignant melanoma. When changing buffer conditions by increasing the ionic strength and decreasing the Mg2+ concentration, interconversions between the isozymes occur. In contrast to the predominant alpha gamma-enolase in extracts from cell lines, the multiple forms of gamma-enolase in serum might be caused by a subunit exchange facilitated by the low Mg2+ concentration in plasma. However, there seems to be a stable equilibrium between the isoforms in undiluted patient serum. The induction of subunit exchange by perturbation in ionic strength and/or Mg2+ concentration indicates a need for caution when choosing diluents for use in assays for neuron-specific enolase.

Nonsquamous cell malignant neoplasms of the nasal cavities and paranasal sinuses.

Nonsquamous cell malignant tumors of the nasal cavity and paranasal sinuses are an uncommon and diverse group of neoplasms. Our goal was to define the relative frequency and distribution of these neoplasms, as well as treatment and outcome. This retrospective study analyzed 106 patients with nonsquamous cell malignant neoplasms of the nasal cavity and paranasal sinuses treated at our institution between 1966 and 1982. Pathology included: salivary type carcinoma (33 patients); sarcoma (25 patients); melanoma (18 patients); esthesioneuroblastoma (11 patients); lymphoma (11 patients); and anaplastic cancer (9 patients). Most tumors arose in the nasal cavity (50%), followed by the antrum (39%), ethmoid sinus (9%), and frontal sinus (2%). Fifty-four percent of all patients were treated with surgery alone. Determinate 5-year and 10-year cure rates were: esthesioneuroblastoma, 70% and 50%; lymphoma, 45% and 30%; anaplastic, 33% and 25%; salivary, 31% and 18%; sarcoma, 25% and 21%; and melanoma, 19% and 0%. Overall survival for patients with nonsquamous cell malignant neoplasms of the nasal cavity and paranasal sinuses is poor, particularly with follow-up extended to 10 years. Local recurrence is the major source of treatment failure. We were unable to demonstrate any survival advantage in the group of patients who received surgery and radiotherapy in combination.

Regulation of hyaluronan synthesis and the interaction of hyaluronan with cells

Hyaluronan is a high molecular weight polysaccharide ubiquitously found in the extracellular matrix. It acts as a lubricant in joints and tissues and provides stability and elasticity to the extracellular matrix. In addition, hyaluronan is directly or indirectly implicated in cell growth, angiogenesis, differentiation and malignant tumor invasion (for a review see Laurent and Fraser 1992, Sherman et al. 1994). This review focuses on the regulation of the biosynthesis of hyaluronan and the formation and structure of the pericellular coat around hyaluronan producing cells.

The clonal nature of mediastinal germ cell tumors and acute myelogenous leukemia: A case report and review of the literature

The clonal identity of a mediastinal germ cell malignant tumor and acute myelogenous leukemia is described in an 11-year-old boy in whom both tumors presented simultaneously. The relationship between these two histologically distinct malignancies is discussed in relation to this patient and 34 previously reported patients.

MISCELLANEOUS LESIONS OF BONE

There are several tumors and tumorlike entities of bone that do not easily fit into the specific classifications provided elsewhere in this issue. In this article, several seemingly unrelated entities are discussed, including cystic diseases of bone (simple bone cysts and aneurysmal bone cysts), Langerhans' cell histiocytosis, benign and malignant vascular tumors of bone, and adamantinoma of long bone and its relationship to osteofibrous dysplasia.

Small round blue cell malignant tumors of soft tissues and bone in adult patients

Small round blue cell malignant tumors of soft tissues and bone in adult patients

Nonpulmonary small cell carcinomas of extragenital origin metastatic to the ovary

Seven small cell carcinomas of extragenital and extrapulmonary origin that metastasized to the ovary are described. The tumors occurred in women who were 21-77 years of age (mean, 49 years) and were discovered at, or close to, the time of presentation. The primary sites were the intestine (three cases), thymus (two cases), and inguinal skin (one case), and in one case it was undetermined. The ovarian tumors, four of which were bilateral, ranged from 1.2 to 25 cm in diameter (mean, 11 cm). Microscopic examination showed typical features of small (oat) cell carcinoma in six cases; one neoplasm resembled a small cell carcinoma of intermediate cell type and contained rare glands. On immunohistochemical examination, six of six tumors stained for cytokeratin, five of five for neuron-specific enolase, two of six for chromogranin, and none of four for vimentin. The primary cutaneous tumor was a Merkel cell carcinoma. The patient with that case died at 8 months. Two patients with intestinal tumors died at 1 and 2 months, and one is free of disease at 4 years after receiving chemotherapy. Both patients with mediastinal tumors received chemotherapy; one died at 11 months and one had brain metastases at 5 months and was lost to follow-up. The final case is recent. The differential diagnoses in these cases include primary ovarian small cell carcinomas of hypercalcemic and pulmonary types and various other small cell malignant tumors metastatic to the ovary. Consideration of a variety of clinical and pathologic features should enable these important distinctions to be made.