(CANCER RESEARCH 50. 5969-5977. September 15. I990| Detection of Somatostatin Receptors in Surgical and Percutaneous Needle Biopsy Samples of Carcinoids and Islet Cell Carcinomas J. C. Reubi,1 L. K. Kvols, B. Waser, D. M. Nagorney, P. U. Heitz, J. W. Charboneau, C. C. Reading, and C. Moertel Sando: Research Institute Berne. P. O. Box 2173. CH 31)1)1Berne. Switzerland [J. C. R.. B. H'./: Departments of Oncology, //.. A'. A'., C. M./. Surgery /I). M. \J, and Radiology ¡J.H'. C. C. C. R./, Mayo Clinic, Rochester, Minnesota 5591)1;and Institute o)'Pathology, L'nirersity of'/.urich, Zurich, Switzerland ¡P.f '. H.J ABSTRACT Somatostatin (SS) receptor status was investigated in the tumor tissues from 62 patients with carcinoid tumors and 15 patients with islet cell carcinomas using receptor autoradiography techniques with two different iodinatcd Somatostatin analogues as radioligands, a |Leu*. IHrp '. Tyr"|somatostatin-28 and a Somatostatin octapeptidc, Tyr'-octreotide. The carcinoid tumors were either primaries (n = 32) or métastases(n = 43), sampled as surgical specimens or as small needle liver biopsies. Fifty-four of 62 carcinoid patients had SS receptor-positive tumors (87%). All 15 islet cell carcinoma patients had positive tumors (4 primaries, 11 métastases), i.e., 3 vipomas, 3 insulinomas, 2 glucagonomas, I gastri- noma, 2 polyfunctional tumors, and 4 nonfunctioning tumors. Saturation and competition experiments on tissue sections revealed saturable, high affinity binding sites pharmacologically specific for bioactive SS ana logues. In a majority of the tumors, the receptors were densely distributed and were always homogeneously found in the whole tumor. All except two tumors were labeled with both radioligands. Multiple liver métastases (n = 16) from three different patients were all shown to contain a comparable amount of receptors. SS receptors could be demonstrated even in very small tissue samples of liver métastases obtained by percu taneous liver biopsies (mean weight, 6.8 mg). The majority of the eight SS receptor-negative carcinoids were mainly bronchial carcinoids (n = 5), usually poorly differentiated. On the contrary. SS receptor-positive cases were never found to be anaplastic. All tumors except one from patients pretreated with octreotide (3 days to 3.8 years) were SS receptor positive. In the majority of carcinoids or islet cell carcinomas, the SS receptor status correlated with the in vivo biochemical response (hormone inhibition) to octreotide. These data demonstrate (a) the high prevalence of SS receptors in the primary tumors of both carcinoids and islet cell carcinomas, (b) their presence in métastasesas well. (<•) their continuous expression even during long term octreotide therapy. (</) the possibility of measuring SS receptors in percutaneous needle liver biopsies, and (e) the evidence of their functionality. This study therefore suggests that tumoral SS receptors may be the likely molecular basis for octreotide action and may be an important parameter for predicting the therapeutic efficacy of SS analogues ¡ncarcinoids and islet cell carcinomas. INTRODUCTION The variable symptom complexes associated with malignant carcinoid tumors and the peptide-producing metastatic islet cell carcinomas (1, 2) have posed therapeutic challenges to clini cians since they were first discussed in the medical literature more than three decades ago. These malignant diseases produce a constellation of clinical problems which create unique diffi culties in management for the surgical and medical oncologist (3). Recently, however, an analogue of the neuropeptide soma- tostatin, octreotide (Sandostatin, SMS 201-995), has been syn thesized and shown to be therapeutically beneficial in reducing most of the symptomatology in both islet cell carcinoma and carcinoid patients (4-9). Received 11/6/89: accepted 6/8/90. The cosls of publication of this article «eredefrayed ¡npart by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C". Section 1734 solely to indicate this fact. ' To whom requests for reprints should be addressed. The exact mechanism of action of the SS2 analogue in these tumors is not fully understood (10). We have recently shown in a small study that a high percentage of hormone-producing islet cell carcinomas such as vipomas, gastrinomas. insulino mas. or GRFomas do possess specific SS receptors (11-14). This suggests that SS analogues such as octreotide may have a direct effect on the tumor tissue itself, by regulation of the hormone secretion and/or by regulating tumor growth (10, 15, 16). However, because of the numerous actions of SS in the body (17), an indirect effect through a physiological SS target still remains conceivable (15. 16). At the present time, infor mation on SS receptor prevalence is completely lacking for carcinoids, which represent the largest group of tumors among the gastroenteropancreatic tumors. Carcinoid tumors arise most often in small intestine and metastasize early into the liver: less frequently they arise from other organs such as the lung, thymus, pancreas, or stomach (18). In all of these cases, episodic flushing and diarrhea are the most common initial symptoms, whereas biochemically an increase in serotonin (in the form of urinary 5-hydroxyindoleacetic acid) and sometimes substance P can be measured (2, 18). In the present study, we evaluated for the first time the SS receptor status of carcinoid tumors in a large number of cases. We tested additional islet cell carcinomas, including glucagon omas and nonfunctioning tumors, two types of tumors never tested for SS receptors before. Furthermore, we evaluated the feasibility of measuring SS receptors in nonsurgically removed tumors, i.e., in ultrasound-directed percutaneous needle biop sies for liver métastases,as an alternative to the SS receptor measurement in surgical samples. This method permits corre lation of SS receptor status and the ¡nvivoeffect of octreotide on hormone levels in these tumors. This may ultimately provide information about the functionality of these receptors and the possible predictive value of SS receptor measurements for fu ture octreotide therapy. MATERIALS AND METHODS Tumor samples from 62 carcinoid patients, including 32 primaries and 43 métastases,were investigated (Table 1). Sixty samples were obtained after surgical removal: in the remaining cases (n = 15) they were obtained through percutaneous needle biopsies of the liver métas tases. The islet cell carcinomas investigated included three vipomas. three insulinomas. two glucagonomas, one gastrinoma, as well as two poly- functional and four nonfunctioning tumors. Nine of these cases were liver biopsies. The biopsies were performed under local anesthesia. A Bard Biopty instrument with an 18-gauge Biopty-C'ut biopsy needle that had a sampling notch of 17 mm was used with ultrasound guidance (19,20). All tumor tissue from surgical and needle biopsy sampling was immediately fro/en and processed later for autoradiography. The cases in which needle biopsies of the liver were performed were subsequently- treated with octreotide therapy and had monitoring of hormone levels. In three cases of carcinoid, multiple liver métastases(nine. four, and 2The abbreviations used are: SS. Somatostatin: GRFoma. a carcinoma thai secretes growth hormone-releasing factor: ACTH, adrenocorticotropic hormone. 5969