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Lymphology 27 (1994) 111-113

EDITORIAL

CHROMOLYMPHOGRAPHY, LYMPH NODE SURGERY AND DETECTION OF LYMPH NODE METASTASES: CURRENT STATE AND FUTURE

The clinical value of chromolymphography radical retroperitoneal lymphadenectomy as needs to be updated as little activity in this performed commonly for uterine cervical area has been noted in recent years (see carcinoma, the value of chromolymphography Commentary by Chernomorsky, S). After the is limited. Here, fatty tissue is removed along introduction of computer tomography, the with embedded lymph nodes. These radical indications for chromolymphography, like dissections, although complete and accurate diagnostic conventional oil contrast lympho­ has poor selectivity. Paradoxically, only lymph graphy, for visualizing regional lymph nodes nodes which are not grossly involved are decreased rapidly. However, experience with removed. Thus, if metastatic lymph nodes are computer tomography and subsequently with palpable at the beginning of operation, the magnetic resonance imaging has shown that laparotomy is usually aborted and the patient lymph nodal metastases without marked treated by irradiation. Ironically, therefore, a lymphadenopathy can be missed by these large number of non-involved (healthy) lymph computed imaging methods. Although oil nodes (up to 80 per patient) are removed while contrast lymphography may delineate the potentially non-visualized small lymph nodes intranodal architecture and therefore the with metastases may remain in the body. likelihood of metastases with equivocal Because most women with uterine cancer that computerized scans, its cumbersomeness undergo surgery are already relegated to "low (involving a cut-down in lymphatic cannu­ staging", the histology of most lymph nodes lation) and side effects (e.g., oil embolism to removed show no metastasis. Moreover, when the lungs) makes its resurgence as a diagnostic patients are compared with and without tool problematic. Chromolymphography using lymphadenectomy, no difference in survival is chlorophyll and Lipiodol to color lymph nodes realized (8). never achieved popularity, having similar In most clinics, radical retroperitoneal drawbacks of conventional lymphography, the lymphadenectomy is deemed obligatory until impurity of the chlorophyll, and the fact that a reliable method for detecting lymph node tissues saturated with chlorophyll as opposed metastases (both microscopic and macro­ to black or blue dyes were difficult to delineate scopic) is found. Whether imaging by positron from surrounding structures. Accordingly, the emission tomography (PET scanning) can return of conventional lymphography with fulfill this expectation is as yet not known. chlorophyll and Lipiodol is unlikely no matter Until then, perhaps chromolymphography can how improved (purified) the chlorophyll substantially modify the role of retroperitoneal becomes. On the other hand, chromolympho­ lymphadenectomy (e.g., its extent and graphy is as good as endolymphatic therapy selectivity). If the extent of operative dissec­ and both are worthy of reconsideration. After tion and injury can be lessened and the

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY 112 complication rate can be reduced, preservation lymphadenectomy nowadays is mainly done of fatty tissue, which contains vegetative for diagnostic staging (although the removed nerves, is of signal importance for young men lymph nodes often contain metastases). In the undergoing radical retroperitoneallympha­ past, adjuvant treatment of breast cancer has denectomy to stage urologic cancer. With been restricted to patients with metastatic more selective dissection, the complications of axillary lymph nodes. Recent data suggest, retrograde ejaculation, impotence, and however, that even nodal-negative patients infertility can be avoided. may benefit from adjuvant chemo or hormo­ Chromolymphography can be performed nal therapy. In many centers, the rationale for before embarking on lymphadenectomy by performance of axillary lymphadenectomy for injecting guajazulen, a dark blue lipid soluble breast cancer has moved from "diagnostic" to dye, via a dorsal pedal lymphatic (2). After "prognostic". As with retroperitoneal nodal preliminary animal experiments, this dissection, however, axillary lymphadenec­ approach was used in 11 patients. Each tomy indiscriminantly removes adjacent fatty demonstrated dark blue retroperitoneal lymph tissue with the risk of subsequent peripheral nodes at the time of lymphadenectomy 1-3 lymphedema. This drawback of axillary days later. The disadvantage of this agent is lymphadenectomy raises the question as to the need to use a lipid solvent (analogous to how non-involved lymph nodes can be Lipiodol). This oil compresses lymph nodal preserved while metastatic lymph nodes are parenchyma and can initiate respiratory selectively excised. In this regard, chromo­ distress from oil embolism. lymphography has only limited value as To circumvent these drawbacks, aqueous lymph nodes with microscopic metastases blue dyes (patent blue V and isosulfan blue) typically stain normally because lymph flow encapsulated in liposomes were developed for remains intact. preoperative chromolymphography (3-5). Color staining of normal lymph nodes can Intraoperative lymph node visualization can be used, however, to resolve special issues. In alternatively be done using a carbon suspen­ the treatment of malignant melanoma of the sion with mean particle size of 150 nm (1). skin the question arises, whether tumor has After this latter suspension was injected into already seeded the regional lymph node basin. the gastric wall of 10 patients with gastric If the lymph nodes are uninvolved, then cancer undergoing gastrectomy with regional lymphadenectomy is not worthwhile. To nodal dissection, 76% of healthy lymph nodes examine regional nodal involvement, the blue and 69% of involved lymph nodes were found staining ("mapping") of lymph nodes draining blackened with carbon. In other words, only 3 the skin tumor site can be performed (6,7). If of 4 lymph nodes removed by this operation the lymph node nearest the site of the primary were actually stained black. The rest of the melanoma ("sentinel" node) is histologically lymph nodes had to be identified by the free oftumor, then more radicallympha­ "classical" all inclusive radical dissection thus denectomy is not done. The false-negative rate limiting the clinical value of this labeling is less than 1%. Because the blue dye (patent method. blue V or isosulfan blue) is administered in The problem of axillary lymphadenectomy aqueous solution, it diffuses out rapidly from in management of breast cancer differs the lymphatics. Accordingly, to obtain somewhat from retroperitoneallympha­ sufficient staining of lymph nodes, the dye denectomy for uterine cancer. Radical injections are repeated every 20 minutes. The retroperitoneal lymphadenectomy is procedure is therefore time-consuming, performed primarily for therapy (despite the although it is recommended that regional fact that the resected lymph nodes are often nodal dissection be performed promptly. More without metastases). In contrast, axillary experience with this technique is needed.

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Staining alone is not used to decide whether lymphadenectomy to treat metastatic regional lymph nodes should or should not be excised. lymph nodes. Thus, lymph nodes with metastases large enough to cause cessation of afferent lymph REFERENCES flow may not stain at all but can be identified at operation by its characteristics of large size 1. Hagiwara A, T Takahashi, K Sawai, et al.: and palpability. Lymph nodal vital staining with newer carbon particle suspensions compared with india ink: Lymphscintigraphy after intradermal Experimental and clinical observations. injection of radionuclides adjacent to a tumor Lymphology 25 (1992), 84-89. site shows promise in detecting small lymph 2. Harzmann, R, P Hirnle, M Geppert: node metastases. The error rate, however, is Retroperitoneal lymph nodal visualization still too high to reliably detect metastases with using 30% Guajazulen Blue (chromolympho­ graphy). Lymphology 22 (1989),147-149. this method. 3. Hirnle, P: Histological findings in rabbit lymph In experimental investigations using MR nodes after endolymphatic injection of images after endolymphatic administration of liposomes containing blue dye. J. Pharm. dextran-coated superparamagnetic iron oxide Pharmacol. 43 (1991), 217-218. particles (average size 47 nm), lymph node 4. Hirnle, P, R, Harzmann, JK Wright: Patent blue V encapsulation in liposomes: Potential metastases of VX2 rabbit tumor larger than 2 applicability to endolymphatic therapy and mm could be detected (9). Detection was based preoperative chromolymphography. on signal reduction of healthy lymph nodes Lymphology 21 (1988), 187-189. after injection of contrast medium. Stainable 5. Hirnle, P, R Schubert: Liposomes containing blue dye for preoperative lymph node staining: iron was not found within metastatic nodules. Distribution and stability in dogs after The authors recommend, however, that only endolymphatic injection. Int. J. Pharmaceutics tumor-free lymph nodes from highly tumorous 72 (1991), 259-269. lymph nodes can be consistently differentiated. 6. Morton, DL, DR-Wen, JH Wong, et al.: Besides PET scanning, the future in nodal Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch. marking for metastases probably belongs to Surg. 127 (1992), 392-399. antibodies directed against specific tumor cell 7. Morton, DL, DR-Wen, LJ Foshag, et al.: surface markers injected directly into the Intraoperative lymphatic mapping and lymphatic system. Liposomes as a lipoidal selective cervical lymphadenectomy for early­ carrier have already demonstrated their stage melanomas of the head and neck. J. Clin. Oncol. 11 (1993), 1751-1756. superior properties for this purpose. They can 8. Rauscher H, J Spurny: Ergebnisse der carry both specific antibody on their surface Wertheimschen Radikaloperation ohne und and a radionuclide (for gamma-camera mit obligatorischer Lymphonodektomie. detection) in their inner compartment. Geburtshilfe Frauenheilkd. 19 (1959), 651. Perhaps, these liposomes containing tumor­ 9. Taupitz M, S Wagner, B Hamm, et al.: MR lymphography using iron oxide particles. specific antibodies can also carry blue dye to Detection of lymph node metastases in the "map" the tumor drainage area thereby VX2 rabbit tumor model. Acta Radiol. 34 raising the accuracy of nodal involvement and (1993) 10-15. avoiding unnecessary radicallympha­ denectomy. Chromolymphography alone is likely to be useful only if most of the lymph nodes to be dissected are lymphographically accessible and some selective removal is Peter Hirnle, M.D., Ph.D. possible. In an analogous fashion, if such Dept of Gynecology & Obstetrics endolymphatic diagnosis is possible then University Hospital endolymphatic therapy with antitumor drugs Schleichstrasse 4 may someday substitute for curative radical 72076 Tiibingen, GERMANY

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