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Treatment of metastatic carcinoid tumors and the carcinoid syndrome with recombinant interferon alpha.

Fourteen patients with metastatic carcinoid tumors were treated with recombinant interferon alpha-2b at a dosage of 3-4 x 10(6) IU s.c. daily or every second day. No objective tumor regression was observed. Six out of 8 patients with carcinoids of the ileum and the caecum showed stable disease lasting for a median of 25 months (range 4-57). In 3 out of 6 patients with carcinoids of rectum, lung and of unknown primary site, stable disease was observed lasting for 2-7 months. The remaining patients had progressive disease. Six out of 9 evaluable patients had a more than 50% reduction of urinary 24 h 5-hydroxyindoleacetic acid excretion lasting for a median of 4 months (range 2-11). Decrease of flushing was noticed in 3 out of 6 evaluable patients and decrease of diarrhea in 5 out of 9 evaluable patients. In 4 patients dose reduction was necessary due to confusion and fatigue.

Carcinoid Tumor↗

Gastrointestinal carcinoids and the malignant carcinoid syndrome.

The records of 59 patients with gastrointestinal carcinoid tumors at The New York Hospital from 1948 to 1978 were reviewed. Forty-seven instances were diagnosed surgically; 12 were identified on autopsy specimens. The average age at diagnosis was 55.8 years. No association with duodenal ulcer or carcinoma could be made. The appendix was the mose common site of origin, followed by the ileum, rectum and colon, respectively. Jejunoileal carcinoids were multiple in 37 per cent of the patients. Primary tumors of the colon had the highest malignant potential and only two patients had the malignant carcinoid syndrome. Radical excision of all primary tumors is advocated.

Adolescent↗

The neuroendocrine products of intestinal carcinoids. An immunoperoxidase study of 35 carcinoid tumors stained for serotonin and eight polypeptide hormones.

The intestinal carcinoid tumors of 26 patients were stained for the presence of serotonin, gastrin, somatostatin, motilin, secretin, glucagon, pancreatic polypeptide, ACTH, and neurotensin. Argentaffin and argyrophil stains were also performed in all cases. Thirty-five separate tumors (counting metastases and multiple primaries) from the 26 patients were studied. Serotonin was present in 30 of the 35 tumors. Nineteen tumors contained serotonin only. Fourteen tumors contained multiple neuroendocrine products. One tumor contained gastrin only. One tumor did not stain immunohistochemically, but was argyrophilic. Metastatic deposits were studied in nine patients. Some metastases produced the identical neuroendocrine products as the primary tumor, whereas others produced either additional or fewer hormones than the primary tumor. Moreover, different metastases from the same primary tumor were observed to produce different hormones. Argyrophilic cells were present in all cases and were much more numerous than cells staining by immunohistochemistry. Argyrophilic cells probably contain monoamines and polypeptide hormones in addition to those studied in this series. The argyrophil stain was the best general stain in this study for the demonstration of neuroendocrine cells. Argentaffin staining was negative in ten cases that were serotonin positive and two argentaffin positive cases were serotonin negative. The carcinoid syndrome, as clinically defined by the presence of flushing and diarrhea, was noted in five patients, all of whom had serotonin-containing small bowel carcinoids. Endocrine-related symptoms were not clinically appreciated in the remaining patients.

Adolescent↗

Intestinal infarction caused by carcinoid associated elastic vascular sclerosis: early presentation of a small ileal carcinoid tumour.

We describe a patient with extensive ischaemic necrosis of the ileum as a result of elastic vascular sclerosis (EVS). A 2 cm carcinoid tumour was located nearby with microscopic evidence of spread to regional lymph nodes. Severe intestinal ischaemia caused by carcinoid associated EVS may be the presenting feature of small carcinoid tumours resulting in their early diagnosis.

Aged↗

Tachykinins in carcinoid tumors: their use as a tumor marker and possible role in the carcinoid flush.

The plasma concentrations of various tachykinins were measured before and during flushing episodes in 16 patients with metastatic carcinoid tumors. The flushing attacks were induced by iv injection of pentagastrin or ingestion of food or alcohol. Tachykinins, such as neurokinin A (NKA) and neuropeptide K (NPK), increased 2-fold during flushing episodes in 12 patients, and the plasma concentrations of substance P increased to a varying extent in 3 patients. Chromatographic analysis of plasma samples taken before and during flushing episodes in 2 patients indicated the presence of individual spectra of tachykinins. In addition, the plasma concentration of tachykinin [TKLI(K12)], using an assay that detects NKA, NPK, kassinin, eledoisin, and NKB, but not substance P and physalaemin, and the urinary excretion of 5-hydroxyindole acetic acid (5-HIAA) were measured in 20 patients with midgut carcinoid tumors before and during treatment with human leucocyte interferon. The overall changes in the 2 tumor markers were concordant in 18 of the 20 patients. Thus, the Spearman correlation coefficient between the percent changes in urinary 5-hydroxyindole acid excretion and plasma TKLI(K12) was 0.54 (P less than 0.001). The patients who had a decrease in the tumor markers also had a decrease in flushing episodes and diarrhea. Plasma TKLI(K12) is a convenient tumor marker for the diagnosis and follow-up of patients with carcinoid tumors of midgut origin. The combined use of both tumor markers strengthens the diagnosis and may improve the evaluation of response during treatment.

Adult↗

Interferon-alpha 2b, with or without prior hepatic artery embolization: clinical response and survival in mid-gut carcinoid patients. The Norwegian carcinoid study.

BACKGROUND: Mid-gut carcinoid tumours often present with liver metastases, and survival has then been less than 2 years in earlier reports. We have evaluated the effects of interferon therapy on clinical response and survival, with or without hepatic artery embolization in these patients. METHODS: In a prospective study 30 female and 12 male patients, aged 23 to 75 years, with mid-gut carcinoid tumours and liver metastases underwent surgery with removal of as much as possible of their primary tumour. If technically feasible, embolization of hepatic arteries was performed in the absence of contraindications. Seventeen patients were embolized, and all patients received interferon-alpha 2b treatment for 1 year. Response factors were computer tomography (CT) measurement of the largest liver metastasis and the 24-h urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA). After 12 months patients with objective response or stable disease either continued or withdrew from interferon therapy. Survival was estimated when all patients had been observed for at least 36 months. RESULTS: Nine patients reduced the dose, and five withdrew from interferon treatment owing to side-effects the 1st year. Three patients died. Fifteen patients (39%) showed objective response 12 months after inclusion. Cumulative 5-year survival estimated from inclusion was 37.5% in all 42 patients but 71.4% in those who continued interferon therapy. The difference in survival between the interferon-treated and those who withdrew from interferon therapy at 12 months was significant when embolization was corrected for in a Cox model (p < 0.0125). The seemingly increased survival in embolized versus non-embolized patients did not reach statistical significance (p = 0.07). CONCLUSION: Interferon induced an objective response in mid-gut carcinoid patients as judged by the 24-h urinary 5-HIAA excretion. Patients receiving continuous interferon therapy showed improved response and survival compared with patients who stopped the treatment. Regardless of medical therapy, more survivors and more responders, as evaluated from CT measurements, were found among the embolized patients than among the non-embolized. Embolization could, however, not be shown to have a significant effect on survival.

Carcinoid Tumor↗

Signet-ring cell carcinoid: a primary hepatic carcinoid tumor with cytoplasmic inclusions comprising of aggregates of keratin.

A case of primary hepatic carcinoid tumor was recently encountered, which was argyrophil and showed positive reactions to serotonin, gastrin and pancreatic peptide in an immunohistochemical hormonal study. The tumor had unusual morphologic features. The neoplastic cells had a signet-ring cell appearance, similar to the signet-ring cells normally seen in mucin-producing adenocarcinoma. Ultrastructural and immunohistochemical studies revealed the formation of the signet-ring cells to have been caused by the presence of cytoplasmic inclusions consisting of cytokeratins. Further investigation, using eight monoclonal antibodies recognizing cytokeratins of different molecular weights, showed the accumulated cytokeratins to be of low and medium molecular weights. The morphologic observations in this unusual case of hepatic carcinoid tumor are described and reported cases with similar features, for which we propose the term "signet-ring cell carcinoid," are reviewed.

Adult↗

Carcinoid crisis after injection of 6-18F-fluorodihydroxyphenylalanine in a patient with metastatic carcinoid.

A carcinoid crisis is a severe complication of the carcinoid syndrome that can arise in patients with advanced metastatic neuroendocrine tumors. It can be initiated by stress, catecholamines, and tumor manipulation. In this article, we report a case in which an injection with the catecholamine tracer 6-18F-fluorodihydroxyphenylalanine, used for PET, induced a carcinoid crisis. Octreotide can be used for treatment and should be available. Tracer injection should be slow.

Dihydroxyphenylalanine↗

A study of cyproheptadine in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome.

Sixteen patients with metastatic neuroendocrine tumors and the malignant carcinoid syndrome were treated with cyproheptadine (Periactin, Merck, Sharp & Dohme, West Point, PA) at maximum tolerable doses that ranged from 12 to 48 mg daily. Usual side effects were mild sedation and dry mouth, but three patients found it impossible to sustain treatment due to nausea and vomiting. Most patients had significant relief of diarrhea, frequently associated with weight gain. Relief of flushing was uncommon. The therapeutic benefit produced by cyproheptadine would appear to be a peripheral effect because 5-hydroxyindoleacetic acid (5-HIAA) excretion in these patients was not reduced. Although there have been case reports of objective tumor regression with cyproheptadine therapy, this was not observed in any of these 16 patients. Cyproheptadine would appear to be a useful therapeutic tool for the management of diarrhea associated with the malignant carcinoid syndrome. An appropriate initial total daily dose is 0.4 mg/kg divided in three fractions with prompt modification to produce minimal and tolerable side effects.

Adult↗

Bronchial neuroendocrine (carcinoid) tumor causing unilateral left-sided carcinoid heart disease.

A female patient suffering from a bronchial neuroendocrine tumor with unilateral left-sided carcinoid heart disease is reported. Repeated x-ray films of the chest showed a slowly growing lung tumor in the left lower lobe. The patient refused any diagnostic or therapeutic procedure to define the type of the tumor. During the follow-up of 24 years she developed severe mitral and moderate to severe aortic insufficiency, both invasively quantified by thermodilution techniques. During surgery for double valve replacement the patient died from left ventricular heart failure. Necropsy revealed the typical pattern of a bronchial neuroendocrine tumor without metastases. Examination of the heart disclosed the characteristic deposits of fibrous tissue on the cusps of both the mitral and the aortic valves whereas the right heart showed no abnormalities. Review of the literature suggests the unilateral left-sided carcinoid heart disease to be a very rare finding, its pathogenesis remains to be elucidated.

Aged↗

Carcinoid crisis induced by receptor radionuclide therapy with 90Y-DOTATOC in a case of liver metastases from bronchial neuroendocrine tumor (atypical carcinoid).

SS receptors are overexpressed in many tumors, mainly of neuroendocrine origin, thus enabling the treatment with SS analogs. The clinical experience of receptor radionuclide therapy with the new analog [90Y-DOTA0-Tyr3 ]-octreotide [90Y-DOTATOC] has been developed over the last decade and is gaining a pivotal role in the therapeutic workout of these tumors. It is well known that some procedures performed in diagnostic and therapeutic management of endocrine tumors, such as agobiopsy and hepatic chemoembolization, can be associated with the occurrence of symptoms related to the release of vasoactive amines and/or hormonal peptides from tumor cell lysis. This is the first report of a severe carcinoid crisis developed after receptor radionuclide therapy with 90Y-DOTATOC administered in a patient affected by liver metastases from bronchial neuroendocrine tumor (atypical carcinoid). Despite protection with H1 receptor antagonists, octreotide and corticosteroids, few days after the therapy the patient complained of persistent flushing of the face and upper trunk, severe labial and periocular oedema, diarrhoea and loss of appetite. These symptoms increased and required new hospitalisation. The patient received iv infusion of octreotide associated with H1 and H2 receptor antagonists and corticosteroid therapy, which induced symptom remission within few days. The case here reported confirms that radionuclide therapy is highly effective in determining early rupture of metastatic tissue and also suggests that pre-medication should be implemented before the radiopeptide administration associated with a close monitoring of the patient in the following days.

Aged↗

Metastatic carcinoid tumors and the malignant carcinoid syndrome.

Patients with metastatic carcinoid tumors and the malignant carcinoid syndrome have benefited immensely from diagnostic and therapeutic advances during the past decade. Magnetic resonance imaging and whole body scintigraphy with radiolabelled analogues of somatostatin have improved our ability to diagnose, detect, stage and follow response to therapy. Surgical, medical, and radiation therapy may all contribute to the management of these patients. This disease is variable in its presenting symptoms and the biologic behavior of the tumor. The spectrum of clinical manifestations varies depending upon the type and quantity of polypeptide hormones or biogenic amines being produced. Although the tumors are usually indolent in their growth, the more dedifferentiated or anaplastic tumors can be quite aggressive. Thanks to new treatments that are very effective in the subgroup of anaplastic neuroendocrine carcinomas it is vital to recognize this subset. As research scientists and clinicians we must be aware of the natural history of the disease in order to optimize each patient's treatment. This highly selective review focuses on studies performed in collaboration with Dr. Charles Moertel along with other colleagues at the Mayo Clinic, have done in the past few years.

Carcinoid Tumor↗

Evaluation of combined cyclophosphamide and methotrexate therapy in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome.

Sixteen patients with metastatic carcinoid tumor and the malignant carcinoid syndrome were treated with combined cyclophosphamide and methotrexate therapy in a regimen previously described as highly effective. Toxicity was relatively mild and consisted primarily of leukopenia. One patient experienced some symptomatic benefit and minor reduction in hepatomegaly and 5-hydroxyindoleacetic acid excretion. None met our criteria for an objective response. Combined cyclophosphamide and methotrexate therapy does not appear to offer significant benefit for this disease.

Adult↗

[Carcinoid tumors, carcinoid syndromes and related tumors (104 cases)].

One hundred and four consecutive cases of carcinoid among 194 APUD-omas (cerebral and gynecological tumours expected) are presented. Localization is as follows: bronchopulmonary (21%), duodenum (5,5%), small intestine (19%), Meckel's diverticulum (5,5%), appendix (39%), colorectal (5,5%), other (4,5%). Average age at diagnosis is very different for each localization of carcinoid tumour, as is prognosis: in our material, 33% of cases had an infiltrative tumour, 17% had lymph nodes metastases and 16% hepatic metastases. All 15 patients with carcinoidosis died but their survival varied considerably in length (from a few weeks to 21 years after the beginning of carcinoidosis). In addition, 3 patients presented with the Zollinger-Ellison syndrome, 2 of them having an atypical or probable form of the MEN I syndrome.

Adult↗

Carcinoids, atypical carcinoids, and small-cell carcinomas of the lung: differential diagnosis of fine-needle aspiration biopsy specimens.

The acceptance of fine-needle aspiration biopsy in the diagnostic work-up of pulmonary masses has resulted in an increased number of neuroendocrine tumors of the lung first encountered as aspiration cytology specimens. The accurate cytologic identification of these neuroendocrine neoplasms is important in that they have relatively specific clinical and prognostic features in contrast to nonneuroendocrine neoplasms. We report on the cytologic features of 46 primary pulmonary neuroendocrine neoplasms initially encountered on fine-needle aspiration biopsies. The neoplasms are separated into three distinct cytologic groups, including the typical carcinoid (13 cases), the atypical carcinoid (3 cases), and small-cell carcinomas (30 cases). The clinical features of all cases--and histologic findings when they were available--are also considered. Finally, a detailed cytologic description of the three groups of neuroendocrine neoplasms is presented with emphasis on differential diagnosis including nonneuroendocrine pulmonary neoplasms.

Aged↗

Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid.

Neuroendocrine tumors of the lung embrace a spectrum from low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), and high-grade categories of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). We studied 200 neuroendocrine lung tumors to critically evaluate the Arrigoni histologic criteria for AC using statistical analysis to delimit more rigorously an intermediate survival for AC between TC and the high-grade tumors of LCNEC and SCLC. Histologic features that might predict prognosis were used for Kaplan-Meier and Cox proportional hazards survival analysis, and an optimal mitotic range for AC was calculated. The optimal mitotic range for AC was 2 to 10 mitoses per 2 mm2 of viable tumor (10 high-power fields). Based on this finding, we collapsed mitoses into three categories (< 2; 2-10; > or = 11) and performed Cox multivariate analysis for all 200 neuroendocrine tumors. Mitotic counts were the only independent predictor of prognosis. Based on this analysis, we propose that AC be defined as a tumor with neuroendocrine morphology, mitotic counts between 2-10 per 2 mm2 of viable tumor (10 high-power fields), or coagulative necrosis. Using these criteria, the 200 neuroendocrine tumors were classified as 51 TC, 62 AC, 37 LCNEC, and 50 SCLC. The 5- and 10-year survival was 87% and 87% for TC, 56% and 35% for AC, 27% and 9% for LCNEC, and 9% and 5% for SCLC, respectively. After stratification for stage, survival for AC was significantly worse than for TC (p < 0.001); for LCNEC and SCLC it was significantly worse than for AC; but the survival for LCNEC was no different than that for SCLC.

Carcinoid Tumor↗

Somatostatin, anaesthesia, and the carcinoid syndrome. Peri-operative administration of a somatostatin analogue to suppress carcinoid tumour activity.

A patient with carcinoid syndrome on long-term antiserotonin therapy with parachlorophenylalanine, experienced a flushing attack with hypotension during the prophylactic administration of aprotonin prior to the induction of anaesthesia. When she was subsequently prepared with a long-acting somatostatin analogue, octreotide (Sandostatin, Sandoz SMS 201-995), plasma levels of tumour-released hormones were reduced and anaesthesia for resection of hepatic metastases was uneventful. The advantages of an anaesthetic approach based on inhibition of carcinoid tumour activity, rather than antagonism of released hormones, are discussed.

Anesthesia, General↗