Somatostatin-receptor imaging of neuroendocrine gastroenteropancreatic tumors

Somatostatin-Receptor Imaging of Neuroendocrine Gastroenteropancreatic Tumors HANS SCHERijBL,* MICHAEL Bb;DER,* UTE FETT,* BERND HAMM,§ HEINRICH SCHMIDT-GAYK,” KLAUS KOPPENHAGEN,* FRITZ-JAN DOP,’ ERNST-OTTO RIECKEN,* and BERTRAM WIEDENMANN* Departments of *Internal Medicine, *Nuclear Medicine, and 5Radiology, Steglitz Medical Center, Free University of Berlin, Berlin, Germany; “Institute of Clinical Chemistry, Heidelberg, Germany; and “Mallinckrodt Diagnostics, Petten, The Netherlands

&c&round: Gastroenteropancreatic neuroendocrine tumors are often difficult to localize. This study was conducted to examine the value of somatostatin-receptor scintigraphy for visualization of gastroenteropancreatic neuroendocrine tumors. Methods: Applying the recently developed indium-labeled somatostatin analogue “‘In-pentetreotide to 40 patients with gastroenteropancreatic neuroendocrine tumors, the diagnostic power of pentreotide-receptor scintigraphy was evaluated in comparison with conventional imaging techniques. Results: Expression of somatostatin receptors was observed in the majority of patients (11 of 17 in the foregut, 14 of 16 in the midgut, and 7 of 7 in metastatic neuroendocrine tumors with unknown primary). Comparative imaging by computerized tomography, magnetic resonance imaging, and transabdominal ultrasonography yielded false-negative results for somatostatin-receptor scintigraphy in 8 of 40 patients; however, in 16 patients, tumor tissue that had escaped conventional imaging techniques was detected by “‘In-pentetreotide scintigraphy. Conclusions: “‘In-pentetreotide scintigraphy is a practical, safe, and sensitive procedure for in vivo imaging of gastroenteropancreatic neuroendocrine tumors.

M

ost

crine

tumors

(NET)

ing sites for somatostatin. the control of specific somatostatin functional calization

(GEP)

gastroenteropancreatic

appears

to inhibit

NETS

neuroendo-

high-affinity

l-3 In addition hypersecretion

and nonfunctional of GEP

contain

the growth

tumors.8-‘2 has been shown

bind-

to its action in syndromes,c7 of both

Recently, by means

loof

the stable somatostatin analogue octreotide labeled with iodine 123.13-17 Because the use of ‘231-labeled octreotide has been technically cumbersome and the labeling procedure is sometimes even inefficient, a new labeling technique using indium 111 pentetreotide was developed. ‘*,19 We report on the efficacy of “‘In-pentetreotide scintigraphy in comparison with conventional imaging methods in 40 patients with GEP NETS.

Patients and Methods Patients Forty patients with immunohistologically proven GEP NETS were included in the study. The group consisted of 17 patients with foregut GEP NETS (10 men and 7 women; mean age, 53 years), 16 patients with midgut GEP NETS (8 men and 8 women; mean age, 58 years), and 7 patients with metastatic GEP NETS but unknown primary tumor site (3 men and 4 women; mean age, 48 years). Twenty-eight patients had undergone surgery for tumor size reduction of the primary tumor and/or metastases because curative surgical treatment was not feasible. At the time of this study, tumor metastases were found in the liver in 30 patients, in mesenteric lymph nodes in 9 patients, in paraaortic lymph nodes in 3 patients, in the mediastinum in 5 patients, and in the skeleton in 1 patient (Table 1). Previous or ongoing medical treatments entailed somatostatin therapy in 18 patients, the combination of somatostatin and interferon alfa in 7 patients, interferon alfa alone in 2 patients, chemotherapy (streptozotocin, 5fluorouraci1, and DL-folinic acid) in 3 patients, and omeprazole treatment in 3 patients with gastrinomas. In all patients, computerized tomographic (CT) scanning of the abdomen, magnetic resonance imaging (MRI) of the liver (except for 2 patients in whom it was not possible because of claustrophobia), transabdominal ultrasonography, and, in selected cases, intraoperative ultrasonography were performed. All patients gave informed consent to participate in the study, which was approved by the ethics committee of Steglitz Medical Center and by the Bundesamt ftir Strahlenschutz (Federal Agency for Radiation Protection), Salzgitter, Germany.

Methods Pentetreotide, a diethylenetriaminepentaacetic (DTPA)-bearing analogue of octreotide and “‘InCI,

acid were

Abbreviations used in this paper: CT, computerized tomography; DTPA, diethylenetriaminepentaacetic acid; GEP, gastroenteropancreatic; MRI, magnetic resonance imaging; NET, neuroendocrine tumor; SRS, somatostatin-receptor scintigraphy. 0 1993 by the American Gastroenteroioglcal Association 0016-5085/93/$3.00

1706

SCHERijBL ET AL.

GASTROENTEROLOGY Vol. 105, No. 6

Table 1. Characteristics

of Patients

With Gastroenteropancreatic Localization

NO. of

Mean

patients Localization pnmary

Sex

age (yr)

(range)

Neuroendocrine of

Functional

metastas&

(F/W

Tumors

characteristics

PWIOUS

tumor 1

Duodenum

4

45.7

33

IM

(9-64)

2 F/2

OP(I),SMS(l)

L(l) M

L(l).

Gastrlnoma

Med (I)

(1)

100

OP (2), SMS INF (I),

Pancreas

I2

57.4

16

Ileum

58.0

(37-77)

5 F/7

(30-77)

M

8 F/8

L (7)

M

L (14),

MLN (7), PLN

7

Unknown

47.9

(39-59)

4 F/3

M

lnsuknoma

(2)

OP (IO),

Gastrlnoma

(I)

(I),

Carcmold

(2), Med (2)

The mean

‘L. Ikver; MLN. operatlon:

cSRS-posWe.

age of the 40 patlents

mesentenc SMS. tumor

lymph

was 54.2

node(s);

somatostatm;

L (7)s MLN (2), PLN (1).

site(s) detected

erlands. Radiolabeling

lymph

OMP,

Diagnostics,

Med.

chromogranin

Petten, The Nethwas per-

The labeling efficacy was A were deterfor

Immunohistochemistry

was performed

A, synaptophysin,

with antibodies and neuron-specific

of

against eno-

lase (for review see reference 21 and references therein).

Planar images were recorded with a large-field view (Orbiter

7500;

Siemens,

many) equipped with a 360-KeV

Erlangen,

Ger-

parallel hole collimator.

In 21 patients, single photon emission

computer tomography

was performed

24 hours after injec-

tion. Images, both analogue and digital, were obtained hours and 24 hours after injection. radioactivity,

receptor

syndrome

and

bladder.

spleen,

4

In case of interfering

SMS

+ INF

(4). SMS

87.5

+ INF (2).

100

(I)

Chemo

matrix 64 X 64), a Sopha DS 7

camera (Sopha Medical, Frankfurt-am-Main, Germany) with a medium energy parallel hole general purpose collimator was used; images were reconstructed back projection and Chang correction

with filtered

in 6.7-mm slices. Dig-

ital (planar) images were analyzed quantitatively

by the re-

gion-of-interest method. Data were not corrected for transmission absorption and for self-attenuation. Liver uptake was calculated from anterior view, whereas uptakes of spleen and kidneys were calculated from posterior view.

Statistics

Results

uptake

radioligand

did not

cause

of the somatostatin

+ SEM,

spleen,

radioactivity

liver,

by liver,

by percentage

of

n = 40). The uptake was f 0.6%

at 24 hours

and 3.0% f 0.1% at 4 hours

at 24 hours

by the kidneys.

Based on the decay of radioactivity cordings

at 4 hours

biological

half-life

44.7

and 24 hours

for the liver, f

2.7 hours

abdominal

background,

11.0

to 18.2%

(SRS)

static

GEP

Expression

of

NET

of 16 patients

tissue

is shown

with

that

yielded

was observed (64.7%),

(87.5%),

origin

and trans-

false-negative

results

tumor

tissue in

conventional

imaging

by “‘In-pentetreotide scintigraphy

in comparison patients 1 patient

scin-

was particu-

with conventional with

nodes or liver metastases

bony

1 and Tametastases

the spine, the pelvis, and both femora. metastatic

skeletal

scan-

intra-abdominal

(see Figure

showed

in 14

and in

of unknown

However,

“‘In-pentetreotide in

1 and 2.

by CT, MRI,

had escaped

modalities

scintig-

NET

NET

NETS

imaging

was detected

larly sensitive

GEP

GEP

GEP

sonography

16 patients

involving

f

and meta-

in Tables

receptors

for SRS in 8 of 40 patients.

estingly,

(mean

of primary

with foregut

Comparative

lymph

dose

somatostatin-receptor

with midgut

7 of 7 patients

tigraphy.

for medias-

uptake at 24 hours ranged

of somatostatin

abdominal

0.7 hours for

0.4 hours

of the injected

in the localization

11 of 17 patients

(100%).

for the spleen,

16.9 f

0.7; n = 32).

sensitivity

raphy

the + 6.2

and 12.2 If: 0.4 hours for lung back-

(n = 40). The tumor

The

ning

f

the re-

it was 56.9

+ 3.5 hours

for the kidney,

tinal background, ground

99.2

between

after injection,

was evaluated;

ble 2). So far, only

of “‘In-pentetreotide

of

was calculated

at 4 hours and 2.9%

+ 0.1%

techniques

Apart from chromogranin A levels that are given as medians and ranges, data are represented as mean + SEM. Statistical significance was assessed by Wilcoxon’s rank sum test or the Mann-Whitney-Wilcoxon test.

in the circulation

in the kidneys,

at 24 hours by the spleen,

1.8 f

(360”

rapidly

The

3.7% + 0.6%

SEM,

applied. For single photon emission computer tomography

The

SMS

by the liver, 2.3% + 0.2% at 4 hours and 2.0% f 0.2%

injection. A mean dosage of 145.8 + 7.8 MBq (n = 40) was

any side effects.

(IO),

66.7

(2)

a vast distribution

applied dosage (mean

0.01%

Injection

+ INF

Chemo

SMS

OMP (I).

and kidneys

from

in 32 minutes,

OP (I), (I)

showed

images were recorded as late as 96 hours after

rotation

(2). SMS

(3), INF (I)

and accumulated

hours

All patients underwent anterior and posterior whole-body static scintigraphy.

SMS

OMP (I),

OP (14),

(4), Gastrinoma

and 2.2%

Scanning Procedure gamma camera

50

OMP (I)

chemotherapy

mined by a sandwich assay, using chemiluminescence tumor specimens

(l),

mediastmum.

Chemo,

with “‘In

98.0% +- 0.3%. Serum levels of chromogranin detection of immunoreactivity.”

IFN + SMS

scintigraphy.

of pentetreotide

formed as previously described.‘*

node(s);

omeprazole;

by somatostatln-receptor

developed by Mallinckrodt

(I),

years.

PLN, para-aortic

INF, interferon;

syndrome

(12) Carcinold

Med (2). Bone (I)

‘OP.

SRS-posltlve~ (% of patients)

(n)

of

Stomach

NOTE.

therap&’

(n)

(n)

involvement

Inter-

was first no-

SOMATOSTATIN-RECEPTOR

December

1993

Table

Sensitivity

2.

of Various

Detection

of Tumor

Imaging

Procedures

for

mL (range,

Sites Sensitivity

(%)

SRS

US”

CT

MRI

5 30 9 3 3 9 3 1

80.0 93.3 66.7 33.3 100

ND 73.3 55.6 0 33.3

100

11.1

100 100

ND 78.6’ 55.6 0 ND

33.3

22.2

Consistent

33.3

somatostatin suppression

33.3 100

100

NOTE. Forty patients with tumor characteristics as described in Table 1 were analyzed. ND, not done. “US, transabdominal ultrasonography. ‘In one patient, CT scanning was not perfoned because of noncompliance. ‘In two patients, MRI imaging was not possible because of claustrophobia. din three patients, the tumor was detectable only by endosonography. ?n two patients, the tumor was detectable only by endosonography. ‘The bonv metastases (spine, pelvis, and femora) were first detected by SRS, and the spine was consecutively confirmed by CT and MRI.

and MRI for the spine. mas

were

<5

metastases

in diameter

consecutively

confirmed

sonography creatic detected

measuring

by SRS. This

matostatin

receptors

2 patients

1 nonmetastatic)

only

detected

means.

by SRS and by

In contrast,

16 cm in diameter

Binding

suggests

on GEP

that the density NETS rather

tumor

means

to evaluate patients

with

(9 foregut,

2 midgut,

with and

nonfunctional 2 metastatic

GEP GEP

NETS with unknown primary) were somatostatin-receptor positive. Chromogranin A, known to be a valuable serum in NET

scintigraphy

and technically

disease,**-25 was evaluated

according

ana-

rosine-3-octreotide

with

sive and simple

labeling

has been developed

procedure

. Therefore, 1231 technique

procedure

using the radionu-

‘*-19., ‘*lIn binds without

ity of “‘In-pentetreotide

pentetreotide

easily and by more in a single-step

the necessity

Both the binding

of ty-

a less expen-

analogue

95% to DTPA-D-Phe-octreotide

rification.‘*

1231-oc-

by an expensive

labeling

elide “’ In and the somatostatin

for the in of their high

However,

was hampered

cumbersome

of further

and the biological

seem to be similar

puactiv-

to that of

‘231-octreotide. Because “‘In- P entetreotide accumulates less in the liver and the biliary system, there is less interfering

radioactivity of radioactivity

liver, gall bladder,

13 of the 19 patients

marker

treotide

pretation

Thus,

to its

somatostatin

has been used successfullv content.‘3-‘6

islet cell

In addition

of NET tissues by virtue

status,

NETS

with acromegaly,

carcinoids.6-10

receptor

with

to control

and may induce

vi;0

NETS.

GEP

syndromes

lorme octreotide localization

with

therapy

helps

value, the radioiodinated

nonfunctional

in

treatment

Thus,

analogues

in patients

somatostatin-receptor

even

of growth.

and metastatic

therapeutic

of NETS in vitro.2-3

who have NETS results in the secretion5-’ and, in selected

hypersecretion

regression

tumors,

for somatostatin

findings,*“*s

somatostatin

hormonal

labeling

a power-

in vitro

of patients of hormone

long-acting

a pan-

than tumor

(13 of 19).

in a great variety

with

cases, in the inhibition

than

of so-

NETS

sites with high affinity

have been shown

ultra-

was not

size seems to determine SRS sensitivity. As previously reported,’ the SRS provided ful

were

that were

intraoperatively

and histological

NET

gastrino-

of a gastrinoma

were

by CT

with

positive;

(1 metastatic,

Liver

mm

confirmed

patients

somatostatin-receptor

with insulinomas negative.

Three

GEP

Discussion

somatostatin ticed by SRS and was consecutively

high in

(32 of 40) and in 68.4% of patients

nonfunctional

1oob 80.0 55.6 0 33.3

0 ND

in the 7 recep-

A levels were abnormally

80% of all patients with

Localization of tumor Mediastinum Liver Pancreasd Duodenume ileum Mesenteric lymph nodes Para-aortic lymph nodes Skeleton’

were observed

330-56,300),

1707

tor-positive patients with metastatic GEP NETS of unknown primary. Consistent with previous reports,22-25 serum chromogranin

No. of patients

SCINTIGRAPHY

The present shows

that

simple, and localization. jection

in the biliary in GEP

and bile ducts

study

NETS

close to the

with

scintigraphy

GEP

bY “‘In-pentetreotide majority of patients

Tumor

NETS

is a safe,

sensitive method for whole-body No side effects to “‘In-pentetreotide

were seen in the patients.

inter-

is easier.‘,”

on 40 patients

“‘In-pentetreotide

system;

tumor in-

visualization

scintigraphy succeeded in the (80%); in particular, in 87.5% in

to somatostatin-receptor status in foregut, midgut, or metastatic GEP NET disease with unknown primary. The median levels of chromogranin A were 292 ng/ mL (range, 10-3450; n = 11) in receptor-positive vs.

midgut GEP NETS, in 64.7% in foregut GEP NETS, and 100% in metastatic GEP NETS of unknown primary. In 16 of the 40 patients (40%), “‘In-pentetreo-

145.5 ng/mL (range, 10-2550; n = 6) in receptornegative foregut NETS and 566.5 (range, 129135,000; n = 14) in receptor-positive vs. 201 (range, 94-308; n = 2) in receptor-negative midgut NETS. The highest values of chromogranin A, i.e., 3900 ng/

tide imaging showed tumor localizations not detected by ultrasonography, CT scanning, or MRI. “‘In-pentetreotide scanning was particularly superior in detecting intra-abdominal and bony metastases. Conversely, tumor masses shown by conventional scanning tech-

1708

SCHERijBL

ET AL.

GASTROENTEROLOGY

Vol. 105.

No. 6

Figure 1. Anterior scintigraphic views of the abdomen in patients with foregut (A-C) or midgut (D-f) NETS. Shown are gamma camera pictures 24 hours (A, C-F) or 4 hours (6) after injection of “‘In-pentetreotide. (A) Somatostatin receptor-positive primary tumor of the pancreas and liver metastasis. The somatostatin receptor-positive pancreatic head (arrow) had been missed by conventional ultrasonography, CT, and MRI. Note the radioactivity in the spleen (S) and colon (C). L, liver. (El) The primary localization of the gastrinoma in this patient was the duodenum (arrow). Additionally, multiple metastases in both the liver and mesenteric lymph nodes that had escaped detection by ultrasonography, CT, and MRI showed up in the “‘In-pentetreotide scan. K, kidney. (C) The gamma camera picture of the liver shows the tumor deposits of a gastrinoma that could also be localized by ultrasonography, CT, and MRI. (D) Only “‘In-pentetreotide scintigraphy identified the ileum as the primary tumor site (arrow) in this patient with metastatic GEP NET disease. The somatostatin receptor-positive metastasis in the right liver lobe could be similarly detected by ultrasonography, CT, and MRI. (E and F) Primary tumor and metastases in a patient with metastatic NET of the ileum. (E) Tumor manifestation in the ileum and para-aortic and mesenteric lymph nodes. The radioactivity in the gallbladder(G), though obvious in this picture at 24 hours, was absent as expected at 4 hours and 48 hours. (f) NET spreading to mediastinal and supraclavicular lymph nodes.

niques were missed by SRS in 8 patients. Because large tumors were missed by SRS in some cases, the low density of somatostatin receptors on these tumors appears to be the major factor for causing false-negative results rather than tumor size. This underlines the necessity to combine conventional and somatostatin-receptor imaging for an optimal staging in patients with GEP NETS. Chromogranin A is known to be a valuable tissue and serum marker for both functional and nonfunc-

tional NETs.“*~~ Thus, serum chromogranin A levels were pathologically elevated in the majority of patients (80%). A tendency for particularly high chromogranin A levels was observed in patients with somatostatinreceptor positive NETS of the midgut or unknown primary site; this indicates that chromogranin A may serve as a useful parameter for clinical response to somatostatin therapy in these tumor subgroups. We conclude that “‘In-pentetreotide imaging is a powerful technique to identify GEP NETS that ex-

December

press

somatostatin

statin-receptor sponsiveness harboring Because

functional of prolonged

NETS,

coupled while

receptors.

Additionally,

somato-

imaging may be useful in predicting reto somatostatin therapy of patients

and longer) GEP

SOMATOSTATIN-RECEPTOR

1993

or nonfunctional binding

of somatostatin-coupled radiotherapy

somatostatin therapeutic

with

analogue

principle

GEP

or “uptake”

NETS.

(96 hours

radioactivity a P-emitting

by

isotope-

may well be a worth-

to work

on.

References 1. Reubi JC, Hacki WH, LambertsSWJ. Hormone-producinggastrointestinal tumors contain a high density of somatostatin receptors. J Clin Endocrinol Metab 1987;65: 1127- 1 134. 2. Reubi JC, Krenning EP, Lamberts SWJ, Kvols L. Somatostatin receptors in malignant tissues. J Steroid Biochem Mol Biol 1990;37:1073-1077. 3. Reubi JC, Maurer R, von Werder K, Torhorst J, Klijn JGM, Lamberts SWJ. Somatostatin receptors in human endocrine tumors. Cancer Res 1987;47:55 l-558. 4. Gorden P, Comi RJ, Maton PN, Go VLW. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormonesecreting tumors of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Ann intern Med 1989; 1 10: 35-50. 5. Kvols LK, Moertel CG, O’Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 1986;3 15:663-666. 6. Lamberts SWJ, Krenning EP, Reubi JC. The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr Rev 199 1; 12:450-482. 7. Wood SM, Kraenzlin ME, Adrian TE, Bloom SR. Treatment of patients with pancreatic endocrine tumors using a new long-acting somatostatin analogue SMS 201-995: symptomatic and peptide responses. Gut 1985;26:438-444. 8. Schally AV. Oncological applications of somatostatin analogues. Cancer Res 1988;48:6977-6985 (Errata 1989;49: 16 18). 9. Taylor JE, Bogden AE, Moreau JP, Coy DH. In vitro and in vivo inhibition of human small cell lung carcinoma (NCI-H69) growth by a somatostatin analogue. Biochem Biophys Res Commun 1988; 153:8 l-86. 10. Weber C, Merriam L, Koschitzky T, Karp F, Benson M, Forde K, Logerfo P. Inhibition of growth of human breast carcinoma in vivo by somatostatin analog SMS 201-995: treatment of nude mouse xenografts. Surgery 1989; 106:4 16-422. 11. Evers BM, Townsend CM, Upp JR, Allen E, Hurlbut SC, Kim SW, Rajaraman S, Singh P, Reubi JC, Thompson JC. Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth. Gastroenterology 1991;101:303-311. 12. Wiedenmann B, Raeth U, Raedsch R, Becker F, Kommerell B. Tumor regression of an ileal carcinoid tumor under the treatment with the somatostatin analogue SMS 20 l-995. Klin Wochenschr 1988;66:75-77. 13. Lamberts SWJ, Bakker WH, Reubi JC, Krenning EP. Somatostatin-receptor imaging in the localization of endocrine tumors. N Engl J Med 1990;323: 1246- 1249. 14. Lamberts SWJ, Hofland LJ, van Koetsveld PM, Reubi JC, Bruining HA, Bakker WH, Krenning EP. Parallel in vivo and in vitro detection of functional somatostatin receptors in human endocrine pancreatic tumors: consequences with regard to diagnosis, localization, and therapy. J Clin Endocrinol Metab 1990;7 1:566-574.

SCINTIGRAPHY

1709

15. Reichlin S. Clinical application of somatostatin receptor imaging (editorial). J Clin Endocrinol Metab 1990;7 1:564-565. 16. Bakker WI-I, Krenning EP, Breeman WAP, Koper JW, Kooij PPM, Lameris JS, Reubi JC, Visser TJ, Lamberts SWJ. In vivo use of a radioiodinated somatostatin analogue: dynamics, metabolism and binding to somatostatin receptor positive tumours in man. J Nucl Med 1991;32:1184-1191. 17. Schurmann G, Raeth U, Bohme W, Wiedenmann B, Bihl H, Buhr H. In vivo localization of neuroendocrine tumors and their metastases with a radioiodinated analogue of somatostatin. In: Gall P, Berger K, Ungeheuer E, eds. Chirurgisches Forum 1992 f. experim. u. klinische forschung. Berlin: Springer-Verlag, 1992: l-4. 18. Bakker WH, Alberts R, Bruns C, Breeman WAP, Hofland LJ, Marbath P, Pless J, Koper JW, Lamberts SWJ. Visser TJ, Krenning EP. [“‘In-DTPA-o-PHE]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation. Life Sci 1991;49: 1583-1591. 19. Bakker WH, Krenning EP, Reubi JC, Breeman WAP, Koper JW, SeytonoHan B, de Long M, Kooj PPM, van Hagen TJ, Visser TJ, Lamberts SWJ. In vivo application of [“‘In-DTPA-o-PHE]‘-octreotide in somatostatin receptor-positive tumor-bearing animals. Life Sci 1991;49:1593-1601. 20. Bender H, Maier A, Wiedenmann B, O’Connor DT, Messner K, Schmidt-Gayk H. lmmunoluminometric assay of chromogranin A in serum with commercially available reagents. Clin Chem 21

22.

23.

24.

25.

26.

27.

28.

1992;38:2267-2272. Wiedenmann B, Huttner WB. Synaptophysin and chromogranins/secretogranins-widespread constituents of distinct types of neuroendocrine vesicles and new tools in tumor diagnosis. Virchows Arch B Cell Pathol 1989;58:9512 1. O’Connor DT, Deftos LJ. Secretion of chromogranin A by peptideproducing endocrine neoplasms. N Engl J Med 1986;3 14: 11451151. Gazdar AF, Helman LJ, Israel MA, Russell EK, Linnoila RI, Mulshine JL, Schuller HM, Park JG. Expression of neuroendocrine cell markers L-dopa decarboxylase, chromogranin A, and dense core granules in human tumors of endocrine and nonendocrine origin. Cancer Res 1988;48:4078-4082. Sobol RE, Memoli V, Deftos U. Hormone-negative, chromogranin A-positive endocrine tumors. N Engl J Med 1989;320: 444-447. Deftos U. Chromogranin A: its role in endocrine function and as an endocrine and neuroendocrine tumor marker. Endocr Rev 1991;12:181-187. Pate1 YC, Murthy KK, Escher EE, Banville D, Spiess J, Srikant CB. Mechanrsm of action of somatostatin: an overview of receptor function and studies of the molecular characterization and purification of somatostatin receptor proteins. Metabolism 1990;39: 63-69. Scherubl H, HeschelerJ, Schultz G, Kliemann D, Zink A, Ziegler R, Raue F. Inhibition ofCa?nduced calcitonin secretion bysomatostatin: roles of voltage-dependent Ca*+ channels and G-proteins. Cell Signal 1992;4:77-85. Zink A, Schertlbl H, Kliemann D, Hoflich M, Ziegler R, Raue F. Inhibitory effect of somatostatin on CAMP accumulation and calcitonin secretion in C-cells: involvement of pertussis toxin-sensitive G-proteins. Mol Cell Endocrinol 1992;86:2 13-2 19.

Received July 27, 1992. Accepted May 11, 1993. Address requests for reprints to: Bertram Wiedenmann, M.D., Abteilung Gastroenterologie, Unlversitatsklinikum Steglitz, Freie Universitat Berlin, Hlndenburgdamm 30, 1000 Berlin, Germany. The authors thank Dr. Harald Meinhold, Steglitz Medical Center, Freie Universitat Berlin, for his initial help with the radiolabeling of somatostatin.