Purpose: This study investigates the effect of constitutively raised interstitial fluid pressure on osteosarcoma physiology and chemosensitivity.
Experimental Design: We did pressure and blood flow ...assessments at the time of open biopsy in patients with the diagnosis of high-grade osteosarcoma
and correlated this to survival and chemotherapy-associated tumor necrosis. Osteosarcoma cell lines were then evaluated for
proliferative and therapeutic indices in a replicated high-pressure environment.
Results: Sixteen osteosarcomas in vivo were assessed and exhibited elevated interstitial fluid pressures (mean 35.2 ± SD, 18.6 mmHg). This was not associated with
significantly impeded blood flow as measured by a Doppler probe at a single site ( P < 0.12). Nonetheless, greater chemotherapy-associated necrosis and associated longer survival were seen in tumors with higher
interstitial fluid pressures ( P < 0.05).
In vitro , cells undergo significant physiologic changes under pressure. Osteosarcoma cell lines grown in a novel hydrostatically pressurized
system had variable cell line–specific growth proportional to the level of pressure. They were more proliferative as indicated
by cell cycle analysis with more cells in S phase after 48 hours of pressurization ( P < 0.01). There was a significant elevation in the cell cycle–related transcription factors E2F-1 ( P < 0.03) and E2F-4 ( P < 0.002). These changes were associated with increased chemosensitivity. Cells tested under pressure showed an increased
sensitivity to cisplatin ( P < 0.00006) and doxorubicin ( P < 0.03) reminiscent of the increased chemotherapy-associated necrosis seen in tumors with higher interstitial fluid pressure
in the clinical study.
Conclusions: The results of this study suggest that cells in the in vivo pressurized environment are at a higher state of regenerative activity than is demonstrable in conventional cell culture
systems. Variations in tumor interstitial fluid pressure have the potential to alter chemotherapeutic effects.
Small cell neuroendocrine carcinomas (SNECs) of the sinonasal tract are extremely uncommon tumors. We reviewed the clinicopathologic features of six cases of this neoplasm. There was no sex ...preponderance with three females and three males and a mean age at presentation of 51 years (range, 38 to 68). Two patients had disease limited to the nasal cavity, and in four the tumor involved the nasal cavity and maxillary or ethmoid sinuses. Involvement of the orbit was present in two patients. Surgery was the primary treatment. After a mean follow-up of 37 months, one patient died of local disease and liver metastases, four were alive with recurrent or metastatic disease, and one died of unrelated causes. The tumors were composed of sheets, nests, and trabeculae with extensive areas of necrosis and hemorrhage. The individual cells were small to intermediate in size and had scanty cytoplasm. The nuclei were oval or round and hyperchromatic with absent or inconspicuous nucleoli. Nuclear molding and crush artefact were present in five cases. All tumors had a high mitotic rate with frequent abnormal mitotic figures. All cases stained for Cam 5.2, neuron-specific enolase, and chromogranin. Five cases were positive for AE1: AE3, and four for synaptophysin. No case stained for S-100 protein, or neurofilaments. O-13 stained one case. No case contained EBV-RNA. SNECs of the nasal cavity and paranasal sinuses are aggressive tumors with pathological features similar to those of anaplastic small cell carcinomas of the lung. They exhibit morphological and immunophenotypic features different from olfactory neuroblastoma and should be distinguished from this tumor.
Our experience with 184 previously untreated patients who had adenoid cystic carcinoma of salivary gland origin is reviewed. Retrospective staging was possible in all but nine patients who had minor ...salivary gland primary tumors. Sixty-three percent of patients were diagnosed as having stage I or stage II disease (stage I, 64 patients; stage II, 47 patients), whereas 43 and 21 patients had stage III and IV tumors, respectively. Grading was as follows: cribriform pattern only (grade 1, 126 patients; 68%), mixed cribriform and solid features (grade 2, 48 patients; 26%), and solid only (grade 3, 10 patients; 5%). Treatment was predominantly surgical (174 patients), and relatively few patients received adjunctive, postoperative irradiation (27 patients). Cumulative 10-year survival was 75%, 43%, and 15% for stage I, stage II, and stage III and IV patients, respectively, and cause-specific survival at 10 years was as high as 94% in patients with stage I disease. Only the clinical stage had a significant impact on survival. Neither survival, regional metastases (16 patients; 11%), nor distant dissemination (64 patients; 43%) was predictable on the basis of tumor grade alone. The prognosis in patients with early stage lesions may be better than has been appreciated.
Bone morphogenetic proteins, which are capable of inducing mesenchymal tissue to form bone in mammals, have been implicated as important in normal skeletal development. The expression of bone ...morphogenetic proteins and their receptors were studied in 36 osteosarcoma specimens, six Ewing's sarcomas, 20 synovial sarcomas, and 20 chondrosarcomas by reverse transcriptase-polymerase chain reaction, and the findings were correlated with clinical data. Bone morphogenetic protein-2, and -4 messages were detected in most sarcoma samples. Bone morphogenetic protein-6 expression was detected in 22 of 32 osteosarcomas and seven of eight chondrosarcomas. Bone morphogenetic protein-7 and receptor IB were not detected in sarcoma samples but were detected in three osteosarcoma cell lines and one malignant fibrous histiocytoma cell line. Expression of bone morphogenetic protein receptor II was found in 25 of 36 osteosarcomas, eight of 20 chondrosarcomas, four of six Ewing's sarcomas, and 15 of 20 synovial sarcoma samples. Expression of bone morphogenetic protein type II receptor was found to correlate with metastasis in osteosarcomas, which suggests that the bone morphogenetic protein pathway may participate in tumor aggressiveness or progression. The expression of bone morphogenetic protein receptor II in metastatic synovial sarcoma and dedifferentiated chondrosarcoma lesions also supports this hypothesis. The current study showed that the ligands for bone morphogenetic protein receptors, bone morphogenetic proteins-2, -4, and -6 also are expressed in osteosarcoma and other sarcoma tissues, indicating a potential for autocrine or paracrine growth stimulation in these tumors.
Leiomyosarcoma of bone is a rare tumor in an unusual location. Previous analysis of this entity mostly involved small numbers of cases with limited follow-up. Thirty-three patients with ...leiomyosarcoma of bone between 1977 and 1996 were studied, and the histologic appearance and grade were correlated with subsequent treatment and clinical behavior. To be included in this study the tumor had to be intraosseous, with other primary sites of origin clinically excluded. Also, most of the sarcomatous tissue (> or =70%) had to be of intramedullary location with only limited extraosseous extension. The patient's age at diagnosis ranged from 13 to 77 years (average 44.4). The gender distribution was equal. The long bones were preferentially affected (64%), with the lower extremity, around the knee joint, predominantly involved. Five patients (15%) developed postradiation leiomyosarcomas. The histologic analysis showed that the osseous leiomyosarcomas are most commonly of the classic type, followed by the epithelioid, myxoid, and pleomorphic variants. Immunoreactivity for smooth muscle markers (smooth muscle actin, common muscle actin, desmin) was positive in all tumors, and ultrastructural confirmation was obtained in 21% of cases. All sarcomas were histologically graded, which accurately reflected the subsequent prognosis. Seventy-five percent of the lesions were high-grade and the rest low-grade. The histologic grade of the tumors correlated with both the recurrence as well as the metastatic rates and together with the clinicopathologic stage of disease represented the cornerstone on which prudent therapy should be based.
Primary mucosal melanomas are rare tumors. We compare melanomas arising in 2 histologically different mucosa, the stratified oral squamous mucosa and pseudostratified sinonasal respiratory mucosa, to ...investigate the clinicopathologic influence of native mucosal histology on the tumor.
Clinicopathologic features of 36 melanomas arising in the squamous mucosa of the oral cavity were compared with 59 melanomas arising in the sinonasal respiratory mucosa.
The median age of patients was 61 and 63 years for oral and sinonasal melanomas, respectively, with the squamous and respiratory mucosa covering the maxilla being most frequently involved (68.7% and 66%, respectively). The former had a remarkable male predilection (28 men, 8 women), while the latter affected both sexes equally (29 men, 30 women). The oral melanomas were more likely to be detected in the early in situ or microinvasive stage (4 cases vs none, P =.008) and were more frequently amelanotic (14 vs 12, P =.049) than sinonasal melanomas. The sinonasal melanomas were frequently thicker (median thickness, 9 vs 2.6 mm), polypoid (29 vs none), ulcerated (57 vs 20), and necrotic (57 vs 14) than oral melanoma (P <.001). Pseudopapillary architecture was more frequent in sinonasal melanomas (16 tumors vs none, P <.001), and desmoplastic melanomas were more frequent in the oral mucosa (6 vs 1, P =.005). Sinonasal melanoma showed vascular and deep tissue invasion more frequently than oral melanoma; however, no significant difference in disease-specific survival was noted (median survival, 2.8 years vs 3.0 years; 5-year survival, 37% vs 35%, respectively).
Sinonasal melanomas demonstrated aggressive morphologic features significantly more frequently than oral melanomas; however, prognosis remained similar in both groups.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Alterations of the p53 gene and of MDM2, a gene coding for a p53 binding protein, have been implicated in the pathogenesis of osteosarcoma (OS).
To determine the frequency of alterations of the ...p53/MDM2 pathway in OS and their possible correlation with clinicopathologic features, MDM2 copy number and p53 protein levels were determined in a series of 83 samples of OS by quantitative Southern blot analysis and immunohistochemistry, respectively.
Positivity for p53 was found in 26.5% and MDM2 amplification in 6.6% of the samples analyzed in a mutually exclusive fashion with one exception. Overall, alterations of the p53/MDM2 pathway occurred in 34% of cases; p53 accumulation was not associated with a higher proliferative rate. The mean age of patients with p53 positive OS (40 years) was older than that of the p53 negative group (28 years) (P < 0.04). Furthermore, three of the four cases of OS arising in Paget's disease showed p53 accumulation.
Alterations of the p53/MDM2 pathway are frequent in OS and usually represent mutually exclusive tumorigenic events. p53 does not appear to be a major determinant of proliferative rate in OS.
Aims
The diagnosis of polymorphous low‐grade adenocarcinoma (PLGA) of salivary glands remains difficult for general surgical pathologists. In an effort to understand the morphological heterogeneity ...of these neoplasms and facilitate their recognition we reviewed the architectural patterns, cell differentiation and immunohistochemical features of 17 cases of PLGA.
Methods and results
There were 11 females and six males with a mean age of 58 years. Twelve tumours were located in the palate, two in the posterior third of the tongue, and one each in the upper lip, buccal mucosa and retromolar triangle. Two patients presented with neck metastases. The mean tumour size was 20 mm (range 6–50 mm). The tumour cells were arranged in five architectural patterns: tubules and small duct‐like structures; cords and trabeculae; solid nests; cribriform areas and papillae. Twelve (71%) cases were composed of a combination of tubules and small duct‐like structures, cords and trabeculae, and solid nests. Cribriform areas with pseudoluminal spaces were seen in six (35%) cases. A focal papillary pattern was evident in three cases and constituted 40% of the tumour in one. Perineural invasion was seen in 13 cases (76%). All cases studied were positive for CAM5.2, 34BE12, vimentin and S100 protein and showed overexpression of bcl‐2 protein. Rb protein was present in 13 cases whereas p53 expression was absent in all cases. The average proliferation index (PI) was 7% (range 1–17%). Three patients developed local recurrences with cervical lymph node metastases but no patient died as result of tumour. No morphological features were found to be prognostic for the development of local recurrences or lymph nodes metastases.
Conclusions
PLGA is a distinctive neoplasm of salivary glands formed by luminal and nonluminal tumour cells with limited patterns of architectural differentiation. The relative proportion of these cells seems to play a significant role in the morphogenesis of these tumours. The overexpression of the bcl‐2 protein and the low PI suggest that inhibition of programmed cell death may be involved in the oncogenesis of PLGA.
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