Biomedical subjects
Publications and source records attributed to P Bitterman.
Verrucous carcinomas of the vulva are rare and have not been reported in women infected with the human immunodeficiency virus. We present such a case in a 32-year-old woman characterized by bladder involvement that failed therapy with 13-cis-retinoic acid and interferon-alpha and required anterior exenteration.
OBJECTIVES: Fascia lata allografts are commonly used in urogynecologic procedures. Functional failure of several grafts has occurred, and such failure has been recognized as a materials problem in 12 patients. STUDY DESIGN: Twelve patients with failure of an initial urogynecologic procedure performed with irradiated and freeze-dried donor fascia lata grafts underwent reoperation. Portions of the implanted fascia lata grafts could be retrieved in 7 cases. Graft specimens underwent histologic processing followed by hematoxylin and eosin staining. RESULTS: Histopathologic analyses of the retrieved material demonstrated several ongoing processes in the failed grafts. A few grafts showed areas of ideal remodeling. Most grafts, however, showed areas of disorganized remodeling and areas of graft degeneration. Evidence of immune reaction to the graft was observed in some cases. CONCLUSION: The high materials failure rate associated with the use of irradiated and freeze-dried donor fascia lata grafts suggests that such tissue should not be used for urogynecologic procedures.
Only 15% of primary malignant tumors are confined to the gland at the time of presentation. Fine-needle aspiration (FNA) is valuable in confirming the malignant nature of these unresectable lesions. Benign pancreatic lesions and metastatic neoplasms can also be evaluated by fine-needle aspiration. We undertook a retrospective study to evaluate the efficacy of FNA in assessing pancreatic masses. Three hundred and sixty-four radiologically guided FNAs of the pancreas performed between 1986-1996 were reviewed. Surgical material was also evaluated when available and compared to the FNA material. There were 223 men and 141 women. Their ages ranged from 23-90, with a mean of 64 yr. Two hundred and twelve patients (58%) had primary malignant tumors, 183 had adenocarcinomas, 15 had mucinous cystadenocarcinomas, 12 had neuroendocrine tumors, and 2 had pleomorphic giant-cell carcinomas. Ninety-one (43%) had available surgical material which showed adenocarcinoma. Ninety-one patients (25%) had benign aspirates, including 53 showing benign ductal epithelium, 23 showing pancreatitis/inflammation. 10 showing pseudocysts, and 7 showing serous cystadenomas. Surgical material was available in 24 (26%) of these patients. Two of these showed adenocarcinoma. Sixteen aspirates (4%) were suspicious for malignancy, 13 (81%) of which showed adenocarcinoma on follow-up biopsies. Twenty-two aspirates (6%) showed metastatic neoplasms. Twenty-three (6%) had unsatisfactory specimens. Ten (43%) of these had follow-up biopsies, 3 of which were malignant. FNA of primary benign and malignant pancreatic masses is highly sensitive (98%) and specific (100%). Eighty-one percent of the suspicious lesions showed adenocarcinoma on follow-up biopsy. FNA of metastatic neoplasms to the pancreas is also very accurate. This technique can be useful in avoiding unnecessary surgery.
Papillary endometrioid or villoglandular adenocarcinoma (VGA) is a relatively common type of endometrial adenocarcinoma, but studies describing its behavior have yielded conflicting results. Patients with a component of VGA were identified in a review of 819 women entered in a Gynecology Oncology Group Study (Protocol 33) of clinical stages I and II endometrial adenocarcinoma. Cases with coexisting foci of serous or clear cell carcinoma were excluded from further consideration. Of the 61 cases that formed the study sample, there were 24 with pure villoglandular differentiation and 37 who were admixed with typical endometrioid adenocarcinoma (EA). The general clinicopathologic features of patients with pure and mixed VGA are compared with 469 patients with pure EA. The VGAs were better differentiated (grade 1 or 2--97% of VGA versus 74% EA, p = 0.001). but they were not significantly different with respect to median age, depth of invasion, or frequency of nodal spread. Six of the 61 patients with VGA died of their tumor. The disease-specific survival rate at 3 years for VGA is 94% (95% confidence interval: 0.88-0.99) compared with 88% (95% CI: 0.86-0.91) for EA. Two of the patients who died had pure villoglandular tumors and four had mixed villoglandular and endometrioid carcinoma. In view of the frequent admixture of VGA and EA and their generally similar biological characteristics, with a prognosis similar to that of typical EA, we conclude that VGA should be considered a variant of EA.
Malignant mesothelioma causes profound morbidity and nearly universal mortality that is refractory to conventional treatment with aggressive surgery, radiotherapy, or chemotherapy. We report that pharmacologic concentrations of lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, induced apoptosis in human malignant mesothelioma cell lines. Mesothelioma cell viability was decreased in a dose-dependent manner by lovastatin (5 to 30 microM). These effects were not reversed by exogenous growth factors or cholesterol, but were reversed by addition of 100 microM mevalonate, confirming that lovastatin affected mesothelioma viability by inhibiting mevalonate synthesis. Lovastatin appeared to decrease mesothelioma viability by inducing apoptosis, as indicated by morphologic changes, histologic evidence of nuclear condensation and degeneration, and flow-cytometric analysis of DNA content. Lovastatin's effects on cell viability were partially reversed in the presence of farnesol, and treatment of mesothelioma cells with a specific farnesyl-protein transferase (FTP) inhibitor decreased cell viability and induced morphologic changes indistinguishable from those caused by lovastatin. In addition, lovastatin-treated cells showed translocation of ras guanosine triphosphate (GTP)-binding proteins from membrane to cytosolic fractions on Western blots, suggesting that lovastatin's effects on mesothelioma were mediated in part by disrupting acylation of GTP-binding proteins. Thus, lovastatin is a commercially available and clinically well-tolerated agent that reduces viability and induces apoptosis of mesothelioma cells, and may provide the basis for adjunctive treatments of patients with mesothelioma.
Colposcopy is standard for diagnosis of cervical cancer precursors, but the development of diathermy loop electrodes for excision of the cervical transformation zone offers a technique for validation. Loop excision of the transformation zone was performed for 47 consecutive women with dysplasia in colposcopically directed biopsies using 20 x 8-mm electrodes. Specimens were marked for orientation and serially sectioned. All pathology material was reviewed. Although 28% of women had disappearance of dysplasia at the biopsy site, only 9% had no dysplasia in the transformation zone. Half of the women with CIN 1 on directed biopsy had high-grade lesions found in loop excision specimens. Significant discrepancies may be found between the results of colposcopically directed biopsy and loop excision.
Interferon and retinoic acid are active agents for the treatment of cervical cancer, but their mechanisms of action are unclear. Results of [3H]thymidine uptake assays showed that exposure to pharmacologic concentrations of interferon-alpha (IFN-alpha) and all-trans-retinoic acid (RA) for 72 hr inhibited growth of the cervical cancer cell lines ME-180, 283, SiHa, C33-A, 621, CaSki, HeLa, and B132, CaSki and SiHa cells continuously exposed to IFN-alpha or RA or both for 9 days developed resistance to growth inhibition, and growth resumed at a rate comparable to control after removal of agents. Similar assays showed no significant difference in effects of RA and its cis isomer. Assays for lactate dehydrogenase release revealed no significant lysis of any cell line following exposure to IFN-alpha, RA, or their combination. In organotypic culture, cells grew in a pattern histologically similar to carcinoma in situ, and exposure to IFN-alpha and RA for 14 days yielded no change in this pattern. Immunohistochemical analysis showed no change in cytokeratin expression by cells in organotypic or monolayer culture. The major in vitro effect of IFN-alpha and RA on cervical cancer cell lines appears to be reversible inhibition of proliferation.
A case of clear cell eccrine hidradenocarcinoma of the vulva metastatic to regional lymph nodes with long survival after surgical resection is presented. Like the only other case reported to date, this suggests that surgical therapy alone may be adequate, even when metastasis is present.
Fibroblast migration and proliferation within the alveolar wall and airspace after lung injury can lead to the development of fibrosis. Fibroblast cell surface CD44 is an adhesion receptor for provisional matrix proteins and mediates fibroblast invasion into fibrin matrices. Here we show that incubation of cultured fibroblasts with an anti-CD44 monoclonal antibody induces fibroblast detachment from the substratum and morphological changes compatible with apoptosis. In addition, we show that anti-CD44 monoclonal antibody rapidly induces fibroblast apoptosis within fibrin matrices. The effect of anti-CD44 antibody on induction of fibroblast apoptosis occurred within 8 hours and was dose dependent. Anti-CD44 antibody also induced fibroblast apoptosis in suspension. Furthermore, fibroblasts plated on anti-CD44-antibody-coated surfaces initially attached and spread on the antibody; however, after an 8-hour incubation time, many of the cells developed characteristic morphological features of apoptosis. Collectively, these data indicate that apoptosis did not result solely due to detachment from the substratum. Our results identify a new function for fibroblast cell surface CD44 related to the control of cell viability. We suggest this function may be important in fibroblast population control and could potentially be exploited in designing anti-fibrotic therapies.
Endometrial intraepithelial carcinoma (EIC) is a recently described lesion characterized by replacement of endometrial surface epithelium or glands by malignant cells resembling high-grade invasive endometrial carcinoma. EIC has been identified in a high proportion of uteri containing serous carcinoma, but its association with other endometrial tumors is unknown. To determine the strength and specificity of the association of EIC with tumors displaying serous differentiation, the appearance of the endometrium in 38 uteri with serous carcinoma, 113 with endometrioid carcinoma, and 34 with malignant mixed mesodermal tumor (MMMT) were compared. EIC was present in 34 (98%) uteri with serous carcinoma compared with 7 (6%) uteri removed for endometrioid carcinoma (P = .0001). Hyperplasia without atypia was found in only 2 (5%) of 38 serous carcinomas compared with 38 (34%) of 113 endometrioid carcinomas. Similarly, atypical hyperplasia was not found in any uterus with serous carcinoma, but was present in 14 (12%) uteri with endometrioid carcinoma (P = .02). The endometrium was inactive or atrophic in 29 (76%) patients with serous carcinoma compared with 33 (29%) with endometrioid carcinoma (P = .0001). EIC was found in five (56%) of nine MMMTs with a serous epithelial component (serous-MMMT) compared with one (4%) of 25 MMMTs woth an endometrioid epithelial component (endometrioid-MMMT). As with endometrioid and serous carcinomas, hyperplasia with and without atypia was more common with endometrioid-MMMTs as compared with serous-MMMTs. Hyperplasia was found in 25 (100%) and atypical hyperplasia in 8 (32%) of 25 endometrioid-MMMTs, but in none of the nine serous-MMMTs. This study shows that EIC is frequently and specifically associated with uterine tumors displaying serous differentiation. The findings suggest that EIC represents a form of intraepithelial tumor growth characteristic of serous carcinoma and serous MMMT and that EIC is the likely precursor of these neoplasms. In addition, the findings provide further evidence supporting the view that MMMTs represent variants of carcinoma not sarcoma.
Malignant lymphomas comprise 1-4% of the malignant neoplasms of the gastrointestinal tract, but appendiceal lymphomas are exceedingly rare. Herein is presented a case of a well differentiated lymphocytic lymphoma of the appendix found incidentally at hernia repair. Forty-six cases of appendiceal lymphoma have been reported since 1898 with a mean patient age of 25.7 years. Thirty-one patients presented with right lower quadrant pain, and a mass was an incidental finding in five. Of the 46 cases, follow-up was possible in 28. There were four deaths within 30 days of the operation and five deaths within 1 year. Although extensive follow-up is limited, there have been only two reported deaths secondary to primary appendiceal lymphoma since 1945 and these two cases are discussed in detail. Based on this extensive review, appropriate recommendations are made.
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The abnormal localized deposition of lipofuscin-laden macrophages in the lamina propria of the fallopian tube (pseudoxanthomatous salpingiosis) is reported in two women. In both cases there was evidence of longstanding endometriosis; necrotic pseudoxanthomatous nodules of the ovary were present. Histochemical and ultrastructural analysis of the pigment confirmed that it is lipofuscin (ceroid). It is proposed that pseudoxanthomatous salpingiosis develops after an episode of acute salpingitis during which actively bleeding ovarian endometriosis leaks blood into the lumen of the fallopian tube.
Primary soft tissue sarcoma of the heart is encountered infrequently in clinical practice. Treatment is reported of an intracardiac malignant fibrous histiocytoma, consisting of maximal surgical resection followed by 5600 cGy of conventionally fractionated radiation therapy. Transesophageal echocardiograms done during follow-up were useful in assessing tumor control. Aspects of patient care are discussed in conjunction with a review of the available literature.
This study compares the clinicopathologic features of 13 pure uterine papillary serous carcinomas (UPSC) with 19 tumors consisting of UPSC admixed with other types of endometrial carcinoma and nine UPSC associated with endometrial polyps. The mean patient age, frequency of preoperative clinical understaging, postoperative pathologic stage, and survival of patients was similar for the three groups. Surprisingly, widespread metastasis, recurrence, and death occurred even in those cases where myometrial invasion amounted to less than 1 mm or where tumor was confined to an endometrial polyp. Poor prognosis appeared to be related to a propensity for vascular invasion and multifocal carcinogenesis. The latter was manifested by the presence of cytologically malignant cells closely resembling the invasive serous carcinoma in the surface endometrium adjacent to the tumor in 89% of cases and in multiple sites in the genital tract and abdomen. This lesion, designated "intraepithelial carcinoma," was present in the endocervix in nine (22%) of the 41 cases, in the fallopian tube in two cases (5%), on the surface of the ovary in four cases (10%), and on peritoneal surfaces or omentum in 10 cases (25%). In addition, we found that UPSC display considerable morphologic heterogeneity. Foci of clear-cell carcinoma were identified in 13 (32%) of the 41 tumors. In five (12%) neoplasms, the invasive component was composed primarily of glands; and in 22 (54%) tumors, thin as opposed to thick papillae predominated. Accordingly, UPSC may be broadly defined as a carcinoma that displays foci of well-differentiated papillae lined by cells that are markedly atypical cytologically. UPSC frequently contain areas of clear cells. Glands with papillary infoldings sometimes predominate in the invasive component. Because the behavior of endometrial neoplasms, in which at least 25% of the carcinoma exhibits a glandular or papillary architecture with serous differentiation, is similar, the term "uterine serous carcinoma" is an appropriate designation for these tumors, regardless of whether other patterns of differentiation are present or whether the tumor is associated with a polyp.
After acute lung injury, mesenchymal cells migrate into the alveolar airspace where they proliferate and deposit connective tissue macromolecules. Early in the disease process, inflammatory cell-derived trophic factors modulate these mesenchymal cell functions. However, in those patients who die, even as the inflammatory response abates, the fibroproliferative response continues, resulting in extensive intraalveolar fibrosis. We therefore hypothesized that lung mesenchymal cells obtained from individuals dying with acute alveolar fibrosis would manifest an enhanced proliferative capacity that was independent of persistent exogenous signals. To examine this hypothesis, the in vitro growth properties of mesenchymal cells prepared from patients dying with acute lung injury (n = 3) were analyzed in defined medium and compared with those of mesenchymal cells similarly prepared from patients dying with histologically normal lungs (n = 3). Isolates were characterized as mesenchymal cells by using morphological and immunohistochemical criteria. In accord with the hypothesis, mesenchymal cells isolated from lung-injured patients doubled within 3 d in the complete absence of exogenous peptide growth factors, reaching a saturation density of approximately 15 x 10(3) cells/cm2. As expected, lung mesenchymal cells from normal individuals failed to significantly increase in number. Consistent with this proliferative phenotype, the immediate early cell division cycle genes c-fos and c-jun were constitutively expressed in each cell strain prepared from injured lungs, but not in those from control lungs. The observed proliferative phenotype was stable through the fifth subcultivation of the cells. Despite these proliferative properties, three separate criteria indicated the mesenchymal cells from injured lungs were not transformed: normal karyotype; finite lifespan in vitro (9-10 subcultivations); and inability to disseminate in mice with severe combined immunodeficiency. These data support the hypothesis that mesenchymal cells manifest an enhanced proliferative state after acute lung injury.
A 63-yr-old female presented with uncontrollable uterine bleeding. Pathological evaluation revealed a uterine mesenchymal neoplasm which histologically represented a primary osteosarcoma. Immunohistochemistry was utilized to help support the diagnosis. The English literature regarding this rare uterine neoplasm is briefly reviewed.
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