Subcutaneous and intravenous delivery of diagnostic agents to the lymphatic system: applications in lymphoscintigraphy and indirect lymphography

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Abstract

Lymph node status is important in the staging of many malignancies. Although tissue characterization by histologic analysis of biopsy samples may improve staging, noninvasive staging is more acceptable to both patients and clinicians. Several imaging techniques may serve this goal. Modern noninvasive techniques such as computed tomography and magnetic resonance detect lymph node abnormality by nodal enlargement, but that does not always imply malignant involvement. On the other hand, many nodes are infiltrated or replaced by tumour without change in size. This becomes a serious diagnostic defect by these modalities. Consequently, attention has been focused to develop contrast agents and radiolabelled complexes for better cancer detection as well as characterization of individual tumours in lymph nodes. For delivery of such materials to regional lymph nodes one can take advantage from the distinct physiological function of the lymphatic capillaries. The thin-walled and fenestrated lymphatic microvessel is easily penetrated by particulate and macromolecular agents after injection into the extracellular space. Once inside the vessel, materials that are transported with the lymph either specifically target certain nodal elements (e.g. neoplastic cells) or become cleared by macrophages located in the lymph nodes. Indeed, interstitial delivery of diagnostic agents have been of benefit in determining regional spread of cancer and assessing lymphatic function either by lymphoscintigraphy or indirect lymphography. On the other hand, development of contrast materials that can reach lymph nodes after a single intravenous injection is highly desirable because of the large number of lymph nodes in the body and access being difficult to most of them. Today, a number of contrast agents exist that can reach a vast array of lymph nodes in the body, particularly those that are not readily accessible for histologic evaluation, after a single intravascular injection to help distinguish between normal and tumour-bearing nodes or reactive and metastatic nodes with magnetic resonance. In this article we critically examine advantages and limitations of both subcutaneous and intravenous routes of injection for the delivery of diagnostic agents to the lymphatic system.

Introduction

One of the most common disorders encountered in the lymphoreticular system is the development of primary neoplastic proliferation of various lymphocytic cell lines. Such neoplastic proliferations are usually divided into two broad groups: Hodgkin's lymphoma, which is characterized by neoplastic proliferation of large lymphoid cells of uncertain origin, and non-Hodgkin's lymphoma which are derived from neoplastic proliferation of lymphocytes or rarely histiocytic cells. These diseases usually present by involvement of a group of lymph nodes but then spread to involve multiple lymph node groups, spleen, and bone marrow. In addition to lymphomas, lymph nodes are commonly sites of metastatic deposits of melanoma and carcinomas of lung, colon, breast, and testis 1, 2, 3. Malignant involvement of a lymph node results in the enlargement of the affected node and may be considered to involve four stages. The initial stage is the deposition of a malignant cell within the lymph node and subsequent proliferation, resulting in the presence of a micrometastases while the affected lymph node remains of normal size and shape. Eventually, an involved lymph node will enlarge; some tumours result in discrete lymph node metastases while others extend into the perinodal tissue. Finally, the malignant spread of tumour to a lymph node results in a large amorphous tumour mass with infiltration of the tissue planes, where it is rather impossible to identify any residual nodal outline.

Lymph node status is therefore important in the staging of many malignancies. Hence, development of reliable techniques for the evaluation of the lymphatic function in cancer patients would be of great interest. An accurate method for detecting nodal metastases is lymphadenectomy followed with histologic evaluation [4]. However, this approach is tedious for the early detection of neoplastic involvement of lymph nodes that are not readily accessible for histologic analysis (e.g. pelvic, abdominal, and mediastinal nodes). Additionally, lymphadenectomy is associated with significant morbidity [4]. Alternatively, radiological tests can be performed for determination of tumour extent and bulk. Procedures such as chest radiographs and intravenous urography may demonstrate enlarged nodes or the effects of enlarged nodes on adjacent structures such as the bronchus or ureters [3]. For instance, the chest radiograph may be useful to detect the enlargement of mediastinal and hilar nodes. On the other hand, radiographs of the abdomen are less helpful, as only large masses can be confidently recognized and the nodal nature of these masses is difficult to establish. One form of visualization, the lymphoangiogram (direct lymphography), uses radioopaque contrast material injected into the lymphatic vessels to demonstrate the normal and disturbed lymph node architecture 3, 5. The criteria of metastatic involvement include abnormalities seen in either the lymphoangiogram (statis, displacement of normal channels, collateral flow, lymphaticovenous fistulae and peritoneal spill) and the lymphadenogram (spherical nodal filling defects over time, displacement of unopacified lymph node masses, opacification of nodes in unusual sites such as the internal iliac region, increase in size as follow up) phases. Lymphography, however, is technically difficult and time consuming and its accuracy varies from institution to institution depending on the skill of the radiologist. Additionally, it requires lymphatic cannulation and the availability of lymph node groups which drain suitable, peripheral sites with accessible lymphatic vessels. Other complications of lymphography include idiosyncratic reaction to various blue dyes that are injected subcutaneously for outlining lymphatics prior to cannulation (e.g. patent blue violet, methylene blue, isosulphan), pulmonary abnormalities, neurologic manifestations, and local wound complications [6].

Modern noninvasive techniques such as computed tomography (CT) and magnetic resonance (MR) detect lymph node abnormality by nodal enlargement, but that does not always imply malignant involvement 7, 8, 9, 10, 11, 12, 13, 14. For instance, benign lymph node enlargement may coexist with malignant disease as in hyperplasia. Infections, may also be responsible for local benign lymph node enlargement. On the other hand, many nodes are infiltrated or replaced by tumour without change in size; however, this becomes a serious diagnostic defect by these modalities. Furthermore, since CT looks only at two dimensions, a node enlarged and extending longitudinally may appear to be normal on a tomographic image [15]. The principle of MR is based on signal intensity characteristics (relaxation times, T1 and T2, and proton densities) of normal and neoplastic tissues [16]. Unfortunately, relaxation times and proton densities of normal and metastatic nodes overlap 16, 17. This makes MR rather unreliable in the distinction of normal and neoplastic lymph nodes.

To overcome some of the discussed deficiencies one can take advantage from the distinct physiological function of the lymphatic capillaries. The thin-walled and fenestrated lymphatic microvessel is easily penetrated by particulate and macromolecular agents after injection into the extracellular space 18, 19, 20. Once inside the vessel, materials that are transported with the lymph either specifically target certain nodal elements (e.g. neoplastic cells) or become cleared by macrophages located in the lymph nodes. Thus, interstitial administration of suitable radionuclide or contrast agents, rather than directly into the lymphatic vessel, may be of benefit in determining regional spread of cancer and assessing lymphatic function either by lymphoscintigraphy or indirect lymphography (with the aid of CT or MR). In this article we initially limit our discussion to advantages and limitations of the subcutaneous route of administration with respect to evaluation of lymphatic function by different modalities, mainly because of our interest and experience with this approach.

Intravascular delivery of radiological agents to lymph nodes is an alternative approach. Earlier, it was shown that intravenously injected tumour avid radiopharmaceutical such as gallium-67 citrate [21], monoclonal antibodies [22], and metalloporphyrins [23]can leak from blood capillaries into the interstitium and reach metastatic lymph nodes. For example, gallium-67 has been applied to patients with lymphoma but has proved less effective than CT in determining the extent of disease site by site within individual patients. Currently, the clinical role of gallium-67 citrate is best limited to the follow-up of patients with initial positive scans. Neglecting the technical difficulties of humanized monoclonal production and labelling, there exist many barriers and problems associated with intravenous administration of monoclonal antibodies (Section 2.2.1). However, a number of contrast agents (e.g. iron oxide nanocrystals) have now been engineered that can reach a vast array of lymph nodes in the body, particularly those that are not readily accessible for histopathological evaluation, after a single intravascular injection to help distinguish between normal and tumour-bearing nodes or reactive and metastatic nodes with MR 24, 25, 26, 27, 28, 29, 30, 31, 32. Some investigators 33, 34have even exploited the anaerobic glycolysis in neoplastic cells following intravenous administration of 18F-2-fluoro-2-deoxy-d-glucose (FDG) to detect nodal metastases by positron emission tomography (PET). We also evaluate these new approaches, particularly with regard to the underlying mechanisms, and discuss the results of recent clinical studies.

It is unlikely that the oral route could be successfully applied to lymphatic delivery of a wide range of particulate materials [35]and will not be discussed.

Section snippets

Lymphoscintigraphy

Lymphoscintigraphy is a safe, well tolerated, and reproducible technique utilizing radionuclides to image regional lymph node drainage systems, thus yielding functional and morphological information (Table 1). Since the first reported observation in 1953 by Sherman and Ter-Pogossian [36]of lymph node accumulation of interstitially injected radioactive colloidal gold, there has developed a substantial body of experimental and clinical papers concerning interstitial lymphoscintigraphy (see Ref.

Intravenous route of administration

Although recent advances in lymphoscintigraphy or interstitial lymphography are exciting these approaches suffer from certain disadvantages. For instance, lymphoscintigraphy lacks spatial resolution necessary for detection of tumour in unenlarged nodes. Furthermore, the state of disease and previous surgery could change the lymphatic flow and prevent visualization of lymph nodes by lymphoscintigraphy or indirect lymphography. Another problem with interstitial administration is that the delivery

Acknowledgements

We are grateful to Dr. J. Barentsz, Department of Radiology, University Hospital Nijmegen, The Netherlands for providing us with MR images.

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