BRIEF COMMUNICATIONS

Somatostatin Receptor Expression in Primary Gastric Versus Nongastric Extranodal B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue Type

Markus Raderer, Julia Valencak, Franz Pfeffel, Johannes Drach, Thomas Pangerl, Amir Kurtaran, Michael Hejna, Friedrich Vorbeck, Andreas Chott, Irene Virgolini

Affiliations of authors: M. Raderer, J. Valencak, J. Drach, M. Hejna (Department of Internal Medicine I), F. Pfeffel (Department of Internal Medicine IV), T. Pangerl, A. Kurtaran, I. Virgolini (Department of Nuclear Medicine), F. Vorbeck (Department of Radiology), A. Chott (Department of Pathology), University of Vienna, Austria

Correspondence to: Markus Raderer, M.D., Department of Internal Medicine I, Division of Oncology, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria (e-mail: markus.raderer{at}akh-wien.ac.at).

Lymphoma of the mucosa-associated lymphoid tissue (MALT) type represents a distinct clinicopathologic entity (1,2). The majority of these lymphomas occur in the stomach, but they may also be found in the thyroid and salivary glands, lung, breast, and ocular adnexa where they tend to remain localized for a prolonged period of time (3). Before therapy is initiated for these lymphomas, there is widespread consensus about the importance of thorough staging, including otolaryngologic investigation, computerized tomography of the abdomen and thorax, gastroscopy, endosonography, colonoscopy, as well as enteroclysis and bone marrow biopsy (4), since stage influences prognosis and choice of therapeutic strategies (5,6). Although endosonography is highly sensitive for focal penetration and evaluation of regional lymph nodes (7), additional methods for imaging might still be needed to facilitate clinical decision making. Because of the finding that malignant lymphomas express somatostatin receptors (SSTRs), pilot studies have been performed using somatostatin analogues as therapeutic agents (8), and radiolabeled octreotide (OCT), a long-acting somatostatin analogue preferentially binding to SSTR subtypes 2 and 5, has been used for imaging of such tumors (9-11), allowing for estimation of the tumor burden after a single tracer injection.

We have performed a study to investigate the potential of commercially available 111In-DTPA-D-Phe1-OCT (OctreoScan®; Mallinckrodt Medical, Northampton, U.K.; referred to hereafter as 111In-OCT) for staging of patients with MALT-type lymphoma along with in vitro evaluations of SSTR expression in human samples of both gastric and extragastric origins.

Histologic diagnosis of low-grade lymphoma of the MALT type was performed according to the criteria outlined by Isaacson and co-workers (1,2). In addition, immunologic phenotyping on paraffin sections demonstrated light chain restriction in all cases, indicating monoclonal B-cell proliferation, and revealed the phenotype CD20+CD5-CD10-, which, in context with the microscopic appearance, is consistent with low-grade B-cell lymphoma of the MALT type (2). The diagnosis of high-grade lymphoma was based on the presence of large cells with a blastic appearance growing in sheets (often between glands), with or without a low-grade component, and was also confirmed by phenotyping. In patients with a predominance of a large-cell component, the presence of a low-grade component defined the MALT origin of the lymphoma, and also pure large-cell lymphomas without evidence of extragastric spread were included.

All patients underwent otolaryngologic investigation, gastroscopy with multiple biopsies, enteroclysis, colonoscopy, bone marrow biopsy, endosonography, and computed tomography scans of the thorax and abdomen. Staging was performed according to the criteria of Rohatiner et al. (4).

Included in this study were 29 consecutive patients (16 females and 13 males) aged 32-88 years with histologically verified lymphoma of the MALT type in clinical stage I (16 patients) and stage II (13 patients). Eighteen patients presented with primary gastric MALT-type lymphoma: Seven patients had gastric low-grade lymphoma, two had high-grade lymphoma with a low-grade component, and nine had a lymphoma of high-grade histology. Two patients with a lymphoma of high-grade histology had undergone gastrectomy for acute perforation but had lymph nodes involved in situ, while one additional patient presented with pulmonary relapse 6 years after gastrectomy because of a low-grade MALT-type lymphoma. Ten patients had primary extragastric manifestations of low-grade histology: Two had lymphoma of the conjunctiva, three had lymphoma of the lung, two had parotid lymphoma, and one patient each had lymphoma of the breast and the lacrimal gland. One patient with a history of Sjögren's syndrome and involvement by low-grade MALT-type lymphoma underwent cervical lymphadenectomy for diagnosis.

For imaging purposes, the commercially available OctreoScan® was used according to the manufacturer's description, and gamma camera imaging consisting of both planar imaging and single-photon emission tomography was performed according to published standard methods (12).

Informed consent according to institutional guidelines was obtained from all patients. The Ethical Board of the University of Vienna approved of the application of the tracer to humans.

We examined six tumor samples obtained at surgery for expression of messenger RNA (mRNA) of SSTR subtypes (SSTR1-SSTR5) by means of northern blotting according to previously published methods (13). We also investigated two cases of low-grade MALT-type lymphoma of extragastric origin (i.e., one pulmonary lymphoma and one cervical lymph node) from patients undergoing 111In-OCT scintigraphy. In addition, we evaluated four gastrectomy specimens (one low-grade lymphoma, one high-grade lymphoma with a low-grade component, and two high-grade lymphomas) including those of two patients imaged with 111In-OCT. Twenty-eight patients were considered evaluable, while one patient was excluded from the analysis because additional chronic lymphocytic leukemia was present. In patients with gastric MALT-type lymphoma, results were disappointing, since only one of 15 patients with the lymphoma in situ displayed uptake of the tracer at the endosonographically documented site of the primary tumor, which was seen only during the early phase of imaging but not after 24 hours and, thus, rated as nonspecific tracer accumulation. In addition, no lymph node involvement was imaged in patients with documented stage II disease. In all the 10 patients with primary extragastric manifestations, 111In-OCT scintigraphy resulted in the visualization of the neoplastic lesions present. Two patients underwent a second injection of the tracer after successful local irradiation, and no focal tracer uptake could be demonstrated. In the one patient who presented with pulmonary relapse after resection of a primary low-grade MALT-type lymphoma of the stomach, however, no tracer uptake in the pulmonary lesions could be demonstrated.

A different pattern of SSTR-subtype expression between gastric and extragastric MALT-type lymphomas was detected by northern blotting. Extragastric lymphomas expressed large amounts of mRNA for SSTR2, while gastric samples showed expression of mRNA for SSTR3 and also for SSTR4 but not for SSTR2 (Table 1).Go Our findings with regard to the mRNA level suggest a molecular difference between gastric and extragastric MALT-type lymphomas. While caution appears necessary because of the small sample size in both groups, these results are further supported by our scanning data: Primary extragastric MALT-type lymphomas could be readily visualized by 111In-OCT scintigraphy in all patients (Fig. 1,Go upper panels), which reflects the high level of expression of SSTR2 as seen in our samples in vitro. Especially noteworthy is the fact that one patient who presented with pulmonary relapse after initial resection of a gastric lymphoma showed no tracer uptake within the lung lesions. Thus, extragastric MALT-type lymphomas could be potential candidates for inclusion of 111In-OCT scanning into the diagnostic armamentarium and probably also for treatment with somatostatin analogues targeting SSTR2, since this receptor has been implicated in the growth control of malignant cells (14). In contrast, gastric samples did not express sufficient amounts of SSTR2 and, therefore, could not be imaged by means of 111In-OCT scanning (Fig. 1Go, lower panels). However, our findings suggest that 111In-OCT is a potential tool for discriminating between gastric and extragastric origins of the MALT-type lymphoma. Further investigations on gastric MALT-type lymphoma are needed to evaluate the function and density of SSTR3 and SSTR4 in this disease, as well as the potential application of somatostatin analogues targeting these SSTR subtypes for diagnosis and treatment.


View this table:
[in this window]
[in a new window]
 
Table 1. Northern blot analysis of relative messenger RNA expression of somatostatin receptor (SSTR) subtypes 1-5 as judged by laser densitometry*

 


View larger version (97K):
[in this window]
[in a new window]
 
Fig. 1. Imaging of MALT (i.e., mucosa-associated lymphoid tissue)-type lymphoma with 111In-DTPA-D-Phe1-OCT (OctreoScan®). Upper panelsLeft: low-grade MALT-type lymphoma of the lung (arrows) as visualized by coronal single-photon emission tomography reconstruction performed 24 hours after injection of 111In-DTPA-D-Phe1-OCT. Right: corresponding chest x-ray of the same patient, indicating the lymphoma in the left upper lobe. Lower panelsLeft: endosonography depicting high-grade gastric lymphoma (arrow) with diffuse involvement of all layers of the stomach wall. Right: corresponding 111In-DTPA-D-Phe1-OCT scan (planar acquisition 4 hours after injection), demonstrating physiologic tracer uptake within the liver and the spleen but no abnormalities within the epigastrium.

 

REFERENCES

1 Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer1983 ;52:1410-6.[Medline]

2 Isaacson PG, Norton AJ. Mucosa associated lymphoid tissue (MALT) and the MALT-lymphoma concept. In: Isaacson PG, Norton AJ, editors. Extranodal lymphomas. Edinburgh (U.K.), London (U.K.), Madrid (Spain), Melbourne (Australia), New York (NY), and Tokyo (Japan): Churchill-Livingstone; 1994. p. 5-14.

3 Thieblemont C, Bastion Y, Berger F, Rieux C, Salles G, Dumontet C, et al. Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol 1997;15:1624-30.[Abstract]

4 Rohatiner A, d'Amore F, Coiffier B, Crowther D, Gospodarowicz M, Isaacson P, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol 1994;5:397-400.[Abstract]

5 Bayerdorffer E, Neubauer A, Rudolph B, Thiede C, Lehn N, Eidt S, et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. MALT Lymphoma Study Group. Lancet 1995;345:1591-4.[Medline]

6 Taal BG, Burgers JM, van Heerde P, Hart AA, Somers R. The clinical spectrum and treatment of primary non-Hodgkin's lymphoma of the stomach. Ann Oncol 1993;4:839-46.[Abstract]

7 Pavlick AC, Gerdes H, Portlock CS. Endoscopic ultrasound in the evaluation of gastric small lymphocytic mucosa-associated lymphoid tumors. J Clin Oncol 1997;15: 1761-6.[Abstract]

8 Witzig TE, Letendre L, Gerstner J, Schroeder G, Mailliard JA, Colon-Otero G, et al. Evaluation of somatostatin analog in the treatment of lymphoproliferative disorders: results of a phase II North Central Cancer Treatment Group trial. J Clin Oncol 1995;13:2012-5.[Abstract]

9 van-den-Anker Lugdenburg PJ, Lowenberg B, Lamberts SW, Krenning EP. The relevance of somatostatin receptor expression in malignant lymphomas. Metabolism 1996;45:96-7.[Medline]

10 Leners N, Jamar F, Fiasse R, Ferrant A, Pauwels S. Indium-111-pentetreotide uptake in endocrine tumors and lymphoma. J Nucl Med 1996;37:916-22.[Abstract]

11 Goldsmith SJ, Macapinlac HA, O'Brien JP. Somatostatin-receptor imaging in lymphoma. Semin Nucl Med 1995;25:262-71.[Medline]

12 Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Koiij PP, Oei HY, et al. Somatostatin receptor scintigraphy with 111In-DTPA-D-Phe1- and 123I-Tyr3-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993;20:716-31.[Medline]

13 Raderer M, Pangerl T, Leimer M, Valencak J, Kurtaran A, Hamilton G, et al. Expression of human somatostatin receptor subtype 3 in pancreatic cancer in vitro and in vivo. J Natl Cancer Inst 1998;90:1666-8.[Free Full Text]

14 Buscail L, Esteve JP, Saint-Laurent N, Bertrand V, Reisine T, O'Carroll AM, et al. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR 5 through different mechanisms. Proc Natl Acad Sci U S A 1995;92:1580-4.[Abstract]

Manuscript received October 15, 1998; revised February 2, 1999; accepted February 16, 1999.


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 1999 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement