Proliferation of antigen MIB-1 in metastatic carcinoid tumours removed at liver transplantation: relevance to prognosis.

BACKGROUND: Metastatic carcinoid tumours are difficult to manage. In spite of a multidisciplinary approach, including orthotopic liver transplantation, the recurrence rate is high with a poor prognosis. Histopathology generally fails to provide prognostic information, hence it is essential to try to identify markers of prognosis in these tumours before considering orthotopic liver transplantation. The MIB-1 antibody, which detects cell proliferative activity, has been shown to be a useful prognostic marker for a variety of neoplasms. AIMS: To assess the value of MIB-1 immunostaining as a prognostic marker of the duration to recurrence and the survival of patients undergoing orthotopic liver transplantation for metastatic carcinoid/neuroendocrine tumours of the liver. METHODS: Fourteen patients were included in the study. Formalin-fixed, paraffin-embedded tissue sections of the tumours were stained with routine haematoxylin and eosin and chromogranin. The cell proliferative activity was assessed by MIB-1 antibody labelling using the immunoperoxidase method. Results were correlated with the time of tumour recurrence and the length of patients' survival after transplantation. RESULTS: No correlation was found between MIB-1 labelling index and age, gender, clinical and histological type of tumour (i.e. carcinoid, APUDOMA, secreting or non-secreting). The patients with higher MIB-1 indices ( 5%) showed a trend toward earlier recurrence and poorer survival than those with low MIB-1 indices ( 5%). The predictive value of a MIB-1 index of 2 indicating patient survival of 24 months was 83% (five out of six patients). CONCLUSIONS: The correlation between MIB-1 index and patients' survival suggests that a high proliferative rate, as assessed by MIB-1 immunostaining, may detect those tumours with more aggressive biological behaviour. Prospective studies on a larger number of patients will be needed to determine if, in any individual tumour, this method will provide an additional parameter for a rational approach to therapy.

Apudoma vesical / Bladder apudoma

Se presenta un caso de paraganglioma vesical, un tumor poco frecuente del sistema APUD

The role of 111In-octreotide scintigraphy in the detection of APUD tumours: our experience in eighteen patients.

111In-Octreotide scintigraphy has been recently proposed as a sensitive technique for the detection of neuroendocrine tumours, based on the high radiotracer affinity towards the somatostatin receptors expressed by the APUD-system cells. In the present study, a group of 18 patients with carcinoid tumours and gastrointestinal (GI) apudomas was investigated to assess the accuracy of Octreotide scintigraphy in localizing primitive, recurrent or metastatic lesions. Both planar and SPECT studies were obtained 4 hours after the i.v. injection of 111In-Octreotide (111 MBq); planar images were also carried out 24 hours later. In accordance with other authors, the sensitivity of the method was found to be very high (94%) in our group of patients; only in one case of nesidioblastosis was the scintigraphy negative. No differences in sensitivity were observed between the planar and SPECT studies, but the latter provided a better topographic localization of the neoplastic foci. It should be pointed out that in 7 cases (3 primitive, 1 recurrent and 3 metastatic lesions) scintigraphy correctly localized the tumour, when the other morphological techniques, such as echography, computed tomography or magnetic resonance, failed. On the basis of our data, we believe that Octreotide scintigraphy should be the first study performed in the evaluation of patients affected by APUD tumours.

Orthotopic liver transplantation in the treatment of metastatic neuroendocrine tumors of the liver.

The place of orthotopic liver transplantation (OLT) in the management of metastatic hepatic neuroendocrine tumors has not been adequately defined. The present report is concerned with patient survival, disease recurrence, and symptom relief in 11 such patients in a single center who, at the time of transplantation, had no extrahepatic tumor. All patients obtained complete symptom relief initially but tumor recurrence was observed in 6 of the 11 cases (5 carcinoid and 1 apudoma) at a median of 11 months (range 3.5-26). Five patients have died, 4 in the carcinoid group with recurrence and one from chronic rejection in the other apudoma group. Of the 6 patients currently alive one of 2 carcinoids and one of 4 other apudomas have tumor recurrence. Recurrent deposits were found predominantly in bone and in the transplanted liver. Actuarial survival post transplant was 82% and 57% at 1 and 5 years respectively. It is concluded that OLT is effective at controlling symptoms from secreting carcinoid deposits in the liver. Although the tumor will recur in most cases, this is not necessarily associated with early return of symptoms. Prolonged disease free survival is more likely in the non carcinoid apudoma group.

Metastatic proclivities and patterns among APUD cell neoplasms.

Neoplasms of APUD cell origin are quite variable in their metastatic behavior. Whereas pituitary and parathyroid tumors almost never metastasize, all oat cell lung cancers, malignant melanomas, trabecular carcinomas of the skin and medullary thyroid cancers are capable of dissemination. The metastatic proclivity of individual carcinoids, pancreatic and extrapancreatic islet cell tumors, and paragangliomas is much less predictable. In particular, there are no reliable histological markers of risk for lymphatic or hematogenous dissemination. The behavior of many carcinoids, islet cell carcinomas and paragangliomas is relatively indolent, even when metastatic disease is already present. However, unresectable distant metastases, especially liver involvement, connote a poor prognosis. Mortality is more often related to uncontrolled tumor growth and metastasis than to associated endocrinopathies. Curative or debulking surgical resection should be aggressively pursued as recent data show that worthwhile clinical disease-free survival can be realized in at least some patients.

Hepatic arterial chemoembolization in patients with liver metastases of endocrine tumors. A prospective phase II study in 24 patients.

BACKGROUND: Liver metastases of endocrine tumors are of major prognostic significance. The various therapeutic approaches have given disappointing results; however, locoregional treatment has allowed transient control of hepatic tumor growth. METHODS: Twenty-four patients with liver metastases of endocrine tumors (mainly carcinoid tumors [n = 18] and gastrinomas [n = 5]) were included in a Phase II study of hepatic arterial chemoembolization (CE). Metastases were bilateral in all patients and invaded more than 50% of the liver in 12. They were synchronous of the primary tumor in 62.5% of the patients. Seventeen patients had not responded to previous intravenous chemotherapy. CE courses were performed every 3 months using an emulsion of 10 ml of iodized oil and doxorubicin 50 mg/m2 injected into tumor vessels, followed by CE arterial occlusion with gelatin sponge particles. Seventy-one CE courses were performed in 23 patients; there was one technical failure. RESULTS: Among patients with carcinoid tumors, disappearance of diarrhea and/or flushing was observed in 8 of 11. Serotonin and/or its metabolite 5-hydroxyindoleacetic acid levels decreased by more than 50% in 57% of the patients. The size of liver metastases decreased by at least 50% in 6 of 18 patients, i.e., in 33% (range, 12-54%). Two had complete responses. The median duration of the responses was 14 months (range, 6-40). Among patients with noncarcinoid tumors, minor response or stabilization occurred in three of five patients. Major side effects were bleeding peptic ulcer (one patient) and oligoanuric renal failure (one patient). Abdominal pain, fever, and increases in hepatic enzyme levels were common and transient. CONCLUSIONS: These results suggest that CE is effective in patients with liver metastases of endocrine tumors, mainly in carcinoids. In the latter, CE allows control of the carcinoid syndrome and regression or stabilization of the liver tumors in 80% of patients.

Metastasizing neuroendocrine tumor of unknown origin found in cervical lymph nodes: a case report.

Neuroendocrine tumors are a diverse category of tumors that have been known to produce biologically active amines and ectopic hormones of various types. Numerous metastasizing primary lesions have been identified, however, the head and neck region is not a common site for them. Even less common than these are head and neck metastatic sites without an identifiable primary lesion. We report a case of a metastatic neuroendocrine tumor, where the primary site eluded detection despite an extensive battery of investigations.

Apudoma and subcorneal pustular dermatosis (Sneddon-Wilkinson disease).

The subcorneal pustular dermatosis (SPD) is a rare dermatosis. IgA monoclonal gammapathy is the most frequently associated disease with the SPD. We report a case of SPD in a patient with metastatic apudoma, an association not previously described. The rare nature of both diseases suggests that this association is not fortuitous.

Metastatic pancreatic polypeptide producing tumour presenting with diabetes mellitus.

A metastatic pancreatic polypeptide tumour is described which presented clinically with diabetes mellitus. This is the first case to present this way.

Chromogranin A, neuron-specific enolase and synaptophysin as neuroendocrine cell markers in the diagnosis of tumours of the gastro-entero-pancreatic system.

Neuroendocrine (NE) tumours of the gastro-entero-pancreatic tract were analysed immunohistochemically for the expression of chromogranin A, neuron-specific enolase and synaptophysin. In all cases at least one marker was present and in 17 out of 19 investigated neoplasms, at least one of the three markers could be demonstrated in more than 75% of the NE tumour cells. Monoclonal antibody chromogranin A stained a much higher proportion of NE cells in tumours with hormonal activity than in hormonally inactive ones. Immunostaining of the primary tumour as compared to its respective metastases was almost identical. Thus, chromogranin A, neuron-specific enolase and synaptophysin identify NE tumours and their metastases regardless of their localization and their state of hormonal activity. As 'panendocrine' markers of NE tumours they are of special diagnostic value in NE tumours that do not produce hormones and peptides.

Liver transplantation for primary and secondary hepatic apudomas.

Four patients underwent liver transplantation in the Cambridge/King's College Hospital programme for malignant primary and secondary apudomas, secreting various peptide hormones and uncontrollable by standard treatment techniques. After transplantation all patients had excellent symptomatic relief and specific peptide hormone levels fell to normal ranges. Two patients remain alive and well after 38 and 22 months, the latter with recurrence of slight tumour-related symptoms and elevation of the specific secretory product. The other two patients died from chronic graft rejection 7 and 8 months after transplantation.

A phase II trial of streptozotocin and adriamycin in advanced APUD tumors.

Thirty-three patients with advanced carcinoid tumors, islet cell carcinomas, or medullary carcinomas of the thyroid were entered into a phase II trial combining streptozotocin (STZ) and Adriamycin. Thirty-one patients are evaluable for response, and 29 are evaluable for survival. Six (19%) patients achieved objective partial responses (95% confidence limits: 5.4-33). The median duration of response for partial responders was 282 days. The median survival for responders and nonresponders was 16.2 months and 7.8 months, respectively, with an overall median survival of 10.9 months. At 10.9 months median follow-up, 4 (14%) of 29 patients are surviving. Toxicity was mild, except that nausea or vomiting occurred in 25 of 31 patients evaluable for toxicity. With this dose and schedule of administration, STZ and Adriamycin produce modest response rates with objective palliation of disease in patients with advanced amine precursor uptake and decarboxylation (APUD) tumors.

[Significance of neuron-specific enolase (NSE) in the diagnosis of bronchial carcinomas and neuroendocrine tumors]. / Bedeutung der neuronspezifischen Enolase (NSE) in der Diagnostik von Bronchialkarzinomen und neuroendokrinen Tumoren.

The diagnostic significance of neuron-specific enolase in serum was examined in 54 patients with bronchial carcinoma and in 28 with neuroendocrine tumors. Control groups were 42 patients with epithelial and 39 with nonepithelial malignant neoplasms as well as 40 patients with benign pulmonary diseases. The sensitivity of neuron-specific enolase in small-cell bronchial carcinoma was 60% and increased to 87.5% in advanced stages ("extensive disease"). On the other hand, non-specific enolase showed an increase in only 13.8% of patients with other than small-cell bronchial carcinoma. The proportion of false-positive enolase values in non-malignant pulmonary diseases was 5%. Some endocrinal tumors (e.g. tumors of the APUD cell system) showed pathological serum concentrations in 7.1% of the cases only. 37.5% of epithelial malignant neoplasms had enhanced levels, but only 5.1% in nonepithelial neoplasms. Small-cell bronchial carcinoma is most probably present in patients with bronchial carcinoma and neuron-specific enolase serum concentrations above 25 micrograms/l.

Monoamine and diamine oxidase activity in the diagnosis of carcinoid tumors.

This study determines if one could distinguish foregut from midgut carcinoid tumors by quantitative measurement of the monoamine oxidase (MAO) and diamine oxidase (DAO) activities in homogenates of tumors. The MAO activity of 16 foregut carcinoid tumors (1850 +/- 342 pmol/mg/minute) was significantly higher than the MAO activity of 11 midgut carcinoid tumors (407 +/- 43 pmol/mg/minute, P less than 0.01) with no overlap between the groups. Although all ten of the midgut carcinoids had measurable DAO activity (720 +/- 190 pmol/mg/minute), with the exception of one duodenal carcinoid tumor (33 pmol/mg/minute) the nine foregut carcinoid tumors evaluated did not have detectable DAO activity. The MAO activity of all of the foregut carcinoids was higher than that of 6 islet cell tumors, 28 paragangliomas, and 12 medullary carcinomas of the thyroid. Quantitative MAO and DAO activity may be useful in distinguishing foregut carcinoid tumors from other related tumors.

Inflammatory tumor response to monoclonal antibody infusion.

Two patients with melanoma and one with apudoma, all three with metastatic disease, received monoclonal antibody infusions with mAb R-24, specific for the disialoganglioside GD3. This marker was shown to be restricted to melanoma cells and a few other tumors of neural crest origin. Following treatment with mAb R-24 both melanoma patients showed inflammatory cutaneous responses around tumor nodules, i.e. blister formation or inflammatory perinodular halos. Local pain in bulky intestinal tumor sites occurred in all three patients about 3 hr after onset of antibody infusion. Adverse side-effects of antibody application were not observed with antibody doses up to 200 mg (single) and 440 mg total dose. The presented data indicate that mAb R-24 is active in vivo.

Neoplasia maligna indiferenciada de vulva: apudoma; descriçäo de um caso / Indifferentiated malign neoplasia of the vulva: apudoma; report of a case

Os autores estudam uma criança de três anos de idade com neoplasia indiferenciada na vulva com metástase cervical com provável extensäo pélvica. A microscopia ótica e eletrônica sugere ser o tumor do sistema APUD semelhante ao neuroblastoma

A metastatic endocrine-neurogenic tumor of the ampulla of Vater with multiple endocrine immunoreaction--malignant paraganglioma?

The present case report demonstrates the history of a 50-year-old man with a mixed endocrine-neurogenous tumor of the ampulla of Vater. The tumor was localized endoscopically after an attack of melena. There were no signs of endocrinopathy. A local resection with suturing of the pancreatic duct was performed. Morphologically, there were two different tissue types (neurogenous and carcinoid-like) with numerous cells and nerve fibers reacting immunohistochemically with somatostatin and neurotensin antisera: some immunoreactivity to PP-antibodies was observed. Still, after 20 months, the patient seems to have been cured by local resection.