Pathogenesis of ascites tumor growth: angiogenesis, vascular remodeling, and stroma formation in the peritoneal lining.

In the accompanying papers, we demonstrated that two murine ascites tumors (MOT and TA3/St) induced peritoneal lining blood vessels to become hyperpermeable to plasma proteins, leading to extravasation of fibrinogen and its clotting to cross-linked fibrin in peritoneal lining tissues (peritoneal wall, mesentery, and diaphragm). In solid tumors, vascular hyperpermeability and fibrin deposition lead to the generation of vascularized connective tissue. In order to determine whether fibrin had similar consequences in ascites tumors, the vasculature and stroma of peritoneal lining tissues were analyzed at successive intervals after i.p. tumor cell injection. In both MOT and TA3/St ascites tumors, the size and number of peritoneal lining microvessels increased significantly by 5-8 days. Subsequently, peritoneal lining vessels increased in cross-sectional area by as much as 15-fold and peritoneal vascular frequency increased by up to 11-fold. Incorporation of [3H]thymidine by mesenteric blood vessels was negligible in control animals but came to involve 20 and 40% of endothelial cells lining mesenteric vessels in MOT and TA3/St ascites tumor-bearing mice, respectively. After an early dramatic increase in cross-sectional area, peritoneal lining microvessels subsequently underwent a novel form of remodeling to smaller average size as the result of transvascular bridging by endothelial cell cytoplasmic processes. Thus, both of the ascites tumors studied here induced angiogenesis and stroma similar to that elicited when these same tumors were grown in solid form. However, stroma developed more slowly in ascites than in solid tumors and was entirely confined to a compartment (peritoneal lining tissues) that was distinct from that (peritoneal cavity) containing the majority of tumor cells and ascites fluid. These findings are consistent with the hypothesis that vascular hyperpermeability, induced in both solid and ascites tumors by tumor cell-secreted vascular permeability factor, is a common early step in tumor angiogenesis, resulting in fibrinogen extravasation, fibrin deposition, and likely other alterations of the extracellular matrix that together stimulate new vessel and fibroblast ingrowth.

Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid accumulation.

Previous studies have shown that accumulation of tumor ascites fluid results in large part from increased permeability of peritoneal lining vessels (Nagy et al., Cancer Res., 49: 5449-5458, 1989; Nagy et al., Cancer Res., 53: 2631-2643, 1993). However, the specific microvessels rendered hyperpermeable have not been identified nor has the basis of peritoneal vascular hyperpermeability been established. To address these questions, TA3/St and MOT carcinomas, well-characterized transplantable murine tumors that grow in both solid and ascites form, were studied as model systems. Ascites tumor cells of either type were injected i.p. into syngeneic A/Jax and C3Heb/FeJ mice, and ascites fluid and plasma were collected at intervals thereafter up to 8 and 28 days, respectively. Beginning several days after tumor cell injection, small blood vessels located in tissues lining the peritoneal cavity (mesentery, peritoneal wall, and diaphragm) became hyperpermeable to several macromolecular tracers (125I-human serum albumin, FITC-dextran, colloidal carbon, and Monastral Blue B). Increased microvascular permeability correlated with the appearance in ascites fluid of vascular permeability factor (VPF), a tumor cell-secreted mediator that potently enhances vascular permeability to circulating macromolecules. VPF was measured in peritoneal fluid by both a functional bioassay and a sensitive immunofluorometric assay. The VPF concentration, total peritoneal VPF, ascites fluid volume, tumor cell number, and hyperpermeability of peritoneal lining microvessels were found to increase in parallel over time. The close correlation of peritoneal fluid VPF concentration with the development of hyperpermeable peritoneal microvessels in these two well-defined ascites tumors suggests that VPF secretion by tumor cells is responsible, in whole or in part, for initiating and maintaining the ascites pattern of tumor growth.

CT of pancreas transplantation.

Thirty-eight abdominal CT examinations obtained on 20 patients after pancreas transplantation were reviewed to determine the CT findings associated with pancreas transplantation and to assess the clinical utility of CT in this setting. Visualization of the transplanted pancreas was variable and was strongly influenced by adequacy of gastrointestinal opacification with contrast material. In four cases, linear high-density material was present within the graft, which, depending upon the surgical technique for handling exocrine secretions, represented either pancreaticojejunal stents or silicone within the pancreatic duct. Abdominal fluid collections were identified in 19 patients and were the most common complication identified by CT. Four of these collections were drained percutaneously. The major value of CT in pancreas transplantation is the identification and management of abdominal fluid collections in patients with abdominal pain and fever.

Cytologic diagnosis of primary serous lymphoma.

Lymphomas arising primarily in serosal surfaces have recently been described. Although these "body-cavity" lymphomas usually present as an effusion, the role of cytologic diagnosis has not been fully explored. The authors present seven cases of primary serous lymphoma. All were large cell lymphomas (5 B cell types, 2 T cell types). Three distinct clinical presentations were seen. Four patients had the rapid onset of pleural effusions without an associated mass in the setting of immunodeficiency (3 with AIDS, 1 with Castleman's disease). Cytologic examination of the effusion was positive in all cases for B-cell lymphoma. All four patients died of their disease in less than 6 months. Two other patients with AIDS and T-cell lymphomas both of which were associated with a serosal mass as well as an effusion. Although cytologic examination revealed numerous atypical lymphoid cells, clonality could not be demonstrated. One patient survived for more than 1 year, the other lymphoma was an incidental finding at autopsy. Finally, one B-cell lymphoma arose in a patient with chronic pleuritis. Pleural decortication was required to identify the neoplastic cells. The authors conclude that primary serosal lymphomas have characteristic clinical presentations, and that although cytologic and flow cytometric examination of effusions is necessary for the diagnosis of immunodeficiency associated B-cell lymphomas, tissue biopsy will likely be required in patients with immunodeficiency-associated T-cell lymphomas or lymphomas associated with chronic pleuritis.

Ventricular sepsis and abdominally related complications in children with cerebrospinal fluid shunts.

In a retrospective study of 300 children who underwent placement or revision of cerebrospinal fluid (CSF)-peritoneal shunts during a 10-year period, 15 (5%) developed shunt-related abdominal complications with ventricular sepsis and two developed acute perforated appendicitis. Abdominal complications and associated shunt infections suggested two potential modes of development: (1) descent of contaminated CSF from an infected shunt into the abdomen (CSF ascites--four patients, CSF pseudocysts--four patients, and shunt-induced abscess/peritonitis--five patients); and (2) ascent of bacteria into the shunt from an abdominal source (visceral perforation by the shunt catheter--two patients and acute perforated appendicitis--two patients). Three types of shunt systems were placed during the study period; five of the seven (71%) most serious septic complications were associated with the use of Raimondi spring-reinforced catheters. Bacteria isolated in this series were associated with differing modes of sepsis: those involving descent of bacteria into the abdomen from an infected shunt were predominantly gram-positive, cutaneous microorganisms, whereas those associated with ascent of bacteria from the abdomen into the shunt were mixed, gram-negative intestinal microorganisms. Appendicitis did not result in shunt infections. Aggressive treatment resulted in no operative or complication-related deaths. Removal of the shunt catheter from the abdomen and intravenous antibiotics were essential for eradication of sepsis; laparatomy was required only for cases with suspected peritonitis. In eight of the 17 (47%) patients, reestablishment of CSF-peritoneal shunts was performed after resolution of shunt-related complications. In recent years improved shunting materials and supportive care have reduced the incidence of the most serious of these complications.

Computed tomography and diagnostic peritoneal lavage in blunt abdominal trauma. Their combined role.

We reviewed medical records and films of all 196 trauma patients who underwent computed tomography (CT) between June 1982 and October 1986 to see whether CT achieved the level of accuracy attributed to it, whether diagnostic peritoneal lavage (DPL) performed in conjunction with CT was a useful diagnostic test for blunt abdominal trauma, and whether laparotomy was mandatory when pelvic fluid collections were seen by CT after blunt trauma. A total of 36 patients underwent DPL, 29 before and seven after CT. There were seven false-negative CTs that were clinically significant. Diagnostic peritoneal lavage was positive in three patients who had false-negative CTs. Although overall accuracy was excellent, CT was not reliable in detecting bowel injury. Diagnostic peritoneal lavage was helpful in detecting injuries missed by CT. Most stable patients with moderate or large intraperitoneal fluid collections on CT accompanying solid viscus injury were treated successfully without laparotomy.

Increased angiotensin II in ascites during severe ovarian hyperstimulation syndrome: role of early pregnancy and ovarian gonadotropin stimulation.

OBJECTIVE: To investigate the implications of the ovarian renin-angiotensin system (RAS) in the pathophysiology of the ovarian hyperstimulation syndrome (OHSS) in relation to gonadotropin stimulation and early pregnancy. DESIGN: A controlled clinical study comparing blood and simultaneously sampled peritoneal fluid (PF) from patients with severe OHSS and from controls without OHSS. SETTING: University Hospitals. PATIENT(S): Eleven patients with severe OHSS, 8 patients with ascites of other origin, 9 patients with a first-trimester pregnancy, and 15 patients stimulated with gonadotropins for IVF. MAIN OUTCOME MEASURE(S): Angiotensin II immunoreactivity was measured in blood and PF and analyzed by high-performance liquid chromatography (HPLC) in ascites from OHSS. RESULT(S): Angiotensin II immunoreactivity (pg/mL; mean +/- SE) was highest in the ascites from pregnant OHSS (1,669 +/- 418), reaching levels 5 times higher than in the plasma (331 +/- 61) and 100 times higher than in control ascites (17 +/- 6.7). Angiotensin II immunoreactivity was elevated in the PF during early pregnancy (211 +/- 68) and after gonadotropin stimulation (244 +/- 41) and was higher than in the plasma in both groups. Analysis by HPLC showed that the majority of Ang II immunoreactivity in the ascites of OHSS was because of true Ang II. CONCLUSION(S): Severe forms of OHSS, especially those associated with pregnancy, are consistently characterized by huge concentrations of Ang II immunoreactivity in the ascites, proved to be true Ang II by HPLC analysis. This may be due to the synergistic effects of exogenous and endogenous hCG on the ovarian RAS.

Interleukin-6 and its relationships to acute phase proteins in serous effusion differentiation.

The aim of the study was to assess the discriminative power of cytokine interleukin 6 (IL-6) between transudative and exudative pleural and peritoneal effusions, and to compare IL-6 with common acute phase proteins in serous effusion differentiation. One hundred and forty-five consecutive patients with pleural or peritoneal effusion underwent diagnostic parecentesis. Patients were categorized in three groups. Malignant effusion (group A) 56 patients, non-malignant effusion (group B) 46 patients and transudate (group C) 43 patients. Serum and effusion levels of IL-6, C-reactive protein (CRP), alpha2-macroglobuline (alpha2-MG), alpha1-antitrypsin (alpha1-AT) and alpha1-acid glycoprotein (alpha1-AG) were determined. Serum IL-6 levels were significantly higher in groups A and B in comparison to group C (p<0.001 and 0.001, respectively). In addition, serum IL-6 levels were higher in group A compared to group B (p<0.001), while the studied acute phase proteins were not significantly different. All the studied parameters were higher in the effusions of groups A and B compared to group C. At a cut-off value of 72.1 fmol/ml IL-6 had a sensitivity of 82.6-89.3%, specificity of 88.4-90.7% and positive predictive value of 90.7-94.6% among the three groups. Our results suggest that IL-6 at levels > or =72.1 fmol/ml, alpha1-AT at > or =170 mg/dl and alpha1-AG at > or =52.3 mg/ml give strong evidences for malignancy in exudates.

A new approach to the management of malignant ascites; a permanently implanted abdominal drain.

A new approach to the problem of intractable malignant ascites in preterminal abdominal carcinoma is presented. Seventeen patients treated with a new implantable silastic drain are described. Symptomatic relief was excellent in all patients for as long as the drain was patent. Complications included abdominal wall cellulitis in two instances and one case of peritonitis, but did not preclude continued drain function in 15 of the 17 cases. In eight of the 17 cases organisms were cultured from the ascitic fluid while the catheter was in situ. Drainage of ascitic fluid in this way appears to be a practical management for intractable malignant ascites.

Tumor markers in the diagnosis of malignant serous effusions.

To assess the possibility of increasing the detection rates of cytological examination in malignant effusions by the selection of specific tumor markers for a given type of tumor, we measured CEA, CA 19.9, CA 15.3, MCA, PSA, and AFP in malignant effusions from 89 patients with the following primary malignancies: colon, stomach, breast, liver, prostate, lung, and kidney. Cytological examination was positive in only 35 of 89 patients (40%), while the tumor markers were positive in 72 of 89 cases (80%). However, apart from small cell lung and kidney cancers, where the lack of a specific tumor marker resulted in no advantage, in the other types of tumors, the specific marker for each tumor identified correctly malignant effusions in 72 of 74 cases (97%). In fact, CEA was positive in 11 of 11 effusions induced by colorectal cancer; CA 19.9 in 28 of 30 gastric cancer effusions, while MCA and CA 15.3 were positive in breast cancer effusions (16/22 and 20/22). Finally, elevated AFP and PSA indicated hepatocellular and prostate cancer, respectively. In conclusion, in cancer patients with elevated effusion levels of specific tumor markers, the effusions could be considered of a malignant nature even without cytologically demonstrable tumor cells.

Assaying of tumor necrosis factor alpha, complement factors, and alpha-1-antitrypsin in the diagnosis of malignant serous effusions.

The objective of this study was to measure the concentrations of tumor necrosis factor-alpha (TNFalpha) in pleural and peritoneal effusions of different causes and to verify whether TNFalpha, alpha-1-antitrypsin (alpha1AT), and complement factors C3 and C4 can be used in the differential diagnosis of serous effusion. One hundred forty-five serous effusions of various origins were analyzed. TNFalpha, alpha1AT, and complement factors C3 and C4 concentrations were measured simultaneously in blood and serous effusion using commercially available methods. Serous effusions were classified as follows: 102 exudates and 43 transudates. All variables were found to have good diagnostic value in the differential diagnosis of serous effusion. In the stepwise discriminant analysis, four variables were selected, producing a significant discriminant function (p < 0.001). Their order of selection was alpha1AT effusion, C4 serum, TNFalpha-effusion, and C3 effusion. Combined use of these variables increased remarkably the diagnostic value (in diagnosing exudates versus transudates) giving sensitivity = 93.14%; specificity = 90.70%; positive predictive value = 95.96%; negative predictive value = 84.78%. Determination of TNFalpha, complement factors C3 and C4, and alpha1AT may be a significant parameter in the differential diagnosis of serous effusions, particularly in those patients with malignant disease. Moreover, the combination of them significantly increased their diagnostic power.

Fluid collections detected by ultrasound following uncomplicated colorectal surgery.

The aim of the study was to assess the incidence and site of intraperitoneal fluid collections following uncomplicated colorectal surgery and to identify factors relating to the presence of such collections. 38 patients (22 males) with a mean age of 67 years (range 38-85 years) undergoing uncomplicated colorectal procedures were studied prospectively. Patients underwent abdominal and pelvic ultrasound on Day 3 and Day 7 following surgery. The number, site and volume of collections were recorded. Ultrasound-detected fluid collections were present in 26% on Day 3 and 25% on Day 7 following laparotomy. The presence of a collection was not related to the amount of residual volume after peritoneal lavage with normal saline prior to operative closure, to intraoperative blood loss or to the presence of drains. The right upper quadrant was the commonest site of intraperitoneal collections. In the absence of additional clinical signs, the presence of such collections is not an indication for intervention.

Diagnostic aspiration of abdominal fluid in patients with acute abdomen.

Twenty-two patients with acute abdominal symptoms were studied by abdominal sonography and by sonographically guided aspiration of intraperitoneal fluid. The colour of the fluid was found to be diagnostically valuable: a green colour indicated gallbladder perforation, a yellow colour was found in a variety of infectious diseases, a red colour in haemorrhagic pancreatitis or haemorrhage. Aspirating fluid from the peritoneal cavity under ultrasound guidance in connection with any routine ultrasound examination is a valuable and easy method for studying patients with symptoms of acute abdomen.

Intracavitary beta-interferon for the management of pleural and/or abdominal effusions in patients with advanced cancer refractory to chemotherapy.

Twenty-three cancer patients with pleural and/or abdominal effusion refractory to chemotherapy were treated with intracavitary beta-interferon after drainage. The overall response rate at 30 days was 35% for the whole group of patients, 25% for those with pleural effusion, and 40% for those with ascites. In 15 patients the mean time to re-accumulation of fluid after drainage only was 8.7 days, while it approached 30.3 days after intracavitary beta-interferon. This difference was statistically significant (P less than 0.001). The treatment was well tolerated with only mild and transient pain in 3 cases.

Cytokines in the peritoneal fluid of patients with endometriosis.

OBJECTIVE: To determine which of the various cytokines interleukin-5 (IL-5), interleukin-6 (IL-6) and interleukin-1 (IL-1) are important in endometriosis. METHODS: Peritoneal fluid (PF) samples were taken from 55 women at the time of either laparotomy or laparoscopy, and were examined for the levels of IL-5, IL-6 and IL-1 using each cytokine specific sandwich enzyme-linked immunosorbent assay. Thirty-two patients had pelvic endometriosis, eight post-pelvic inflammatory disease, four advanced cancer, three adenomyosis, three benign ovarian tumor, and other diseases. Statistical analysis was performed with the Mann Whitney test, chi-square test or Fisher's test. RESULTS: Both IL-5 and IL-6 levels in PF specimens with endometriosis tended to be higher than normal, while the same specimens were mostly interleukin-1 beta (IL-1 beta) negative. Of great interest was the negative correlation between log (IL-5) and IL-6 (Fisher's test, P < 0.04). CONCLUSION: These findings support the concept that IL-5 and IL-6 but not IL-1 are associated with endometriosis.

Conservative management of bilateral massive edema of the ovary. A case report.

A case of bilateral massive ovarian edema with unilateral ovarian torsion is reported. Following surgical removal of the adnexa with the torsion, the edema of the opposite ovary resolved with oral contraceptive therapy. This has not been previously reported. This case is instructive because the nodular appearance and yellow color of the ovaries and the presence of yellow ascitic fluid could lead to an erroneous diagnosis of malignancy, resulting in performance of a more radical surgical procedure than is necessary. A review of the literature and the unusual nature of this lesion indicates the need for caution in diagnosis and management.

Goblet-cell carcinoid tumor in peritoneal fluid: a case report.

An unusual case of goblet-cell carcinoid in the peritoneal fluid of a 49-yr-old woman with a prior history of carcinoid tumor of the appendix is presented and discussed. Cytologic findings included clusters of uniform small cells containing nuclei with finely granular chromatin, small prominent nucleoli, and scant cytoplasm admixed with signet-ring cells. Peritoneal biopsies contained acini and small glands lined by malignant cells with features of a carcinoid tumor. Prominent signet-ring cells were interspersed within tumor nests. The signet-ring cells and small glandular lumens showed strong mucin positivity. Endocrine tumor cells were argyrophil- and argentaffin-positive. The histologic findings confirmed the diagnosis of goblet-cell carcinoid involving peritoneal fluid.

"Collagen balls" in peritoneal washings. Prevalence, morphology, origin and significance.

Peritoneal washings obtained at laparotomy from women undergoing surgery for neoplasms of the genital tract may contain "collagen balls," consisting of tissue fragments composed of collagen covered with mesothelial cells. Collagen balls were found in 19 (4.5%) of 418 peritoneal washings and were more prevalent in specimens labeled pelvic washings (17 of 294, or 5.8%) than in those labeled peritoneal washings (2 of 124, or 1.6%). In 15 of the 19 cases in which we found collagen balls, at least one ovary was available for microscopic examination. In 14 of the 15 cases minute nodular papillary stromal projections covered with mesothelium were found on the surface of the ovaries. We conclude that collagen balls, a nonspecific entity, most probably originate on the surface of the ovaries. Their significance lies in their being mistaken for mucin-distended cells exfoliated from a neoplasm or from detached fragments of a papillary ovarian neoplasm.

Extramedullary hematopoietic effusions.

OBJECTIVE: To investigate the frequency and diagnostic implications of extramedullary hematopoietic effusions. STUDY DESIGN: Smears of the effusions diagnosed cytologically as myeloid metaplasia or extramedullary hematopoiesis and their clinical records were reviewed and compared with the histologic diagnoses. RESULTS: There were 7 pleural and 1 peritoneal effusion from 5 patients out of 20,793 pericardial, peritoneal and pleural effusions studied during a period of 21 years. CONCLUSION: When compensatory responses can be ruled out, the diagnosis of extramedullary hematopoietic effusion points toward replacement of the bone marrow by a metastatic process. The first primary to consider in males is lung carcinoma.

Primary effusion lymphoma. A case report.

BACKGROUND: Primary effusion lymphoma (PEL) is a rare type of lymphoma that presents as an effusion, seldom with evidence of a solid neoplasm elsewhere; thus, cytology is the basic diagnostic method. It usually occurs in HIV-positive males with a history of Kaposi's sarcoma (KS), and DNA sequences of human herpesvirus 8 (HHV-8) are detected by molecular analysis. The distinct morphologic, immunophenotypic, molecular and clinical characteristics render this neoplasm a new pathologic entity. CASE: A 57-year-old, HIV-positive man presented to the hospital with ascites and absence of neoplasm on radiologic investigation. Cytologic evaluation of the ascitic fluid revealed the presence of highly atypical, pleomorphic lymphoid cells. Immunocytochemistry of the lymphoma cells was positive for CD45 (leukocyte common antigen), CD30 and epithelial membrane antigen antigens and negative for panB, panT and cytokeratin antigens. DNA sequences of HHV-8 were identified by polymerase chain reaction (PCR), and DNA ploidy analysis showed aneuploidy. The patient died 5 months after the diagnosis. CONCLUSION: Conventional and ThinPrep (Cytyc Corp., Boxborough, Massachusetts, U.S.A.) cytology, in combination with immunocytochemistry and PCR for HHV-8 DNA sequences, can lead to an accurate diagnosis of PEL. DNA ploidy analysis confirms the aggressive nature of this neoplasm.