Application progress of lymphography in oncology

Abstract

Lymphography is often used for the diagnosis of lymphatic metastasis in oncology. Determination of lymphatic metastasis is extremely important for accurate cancer staging, which may directly guide the clinical therapeutic scheme. In recent years, the technology of lymphography has developed rapidly on the basis of traditional lymphography, with the appearance of computed tomography (CT) lymphography, nuclear magnetic resonance (MR) lymphography, contrast-enhanced lymphosonography, and so on; the diagnostic accuracy has also been improved. The imaging principles and methods of these various technologies of lymphography are reviewed in this paper, and their applications and significance in oncology are also discussed in detail.

Keywords

lymphography / lymphatic metastasis / sentinel lymph node biopsy

Introduction

Nowadays, one of the difficulties in oncology is how to prevent the lymphatic metastasis of malignant tumors. Lymphography is often used in the diagnosis and therapy of lymphatic metastasis, helpful in the detection of the malignant lesion and evaluation of the extent of tumor progression, showing important guiding significances in determining therapeutic regimens, choosing surgical procedures and assessing long-term therapeutic effects. In recent years, the technology of lymphography has developed rapidly with the appearance of CT lymphography, MR lymphography, lymphoscintigraphy and contrast-enhanced lymphosonography, etc., on the basis of traditional lymphography. Here we review the application progress of lymphography in lymphatic metastasis.

Lymphatic metastasis

Normal anatomy and physiology of the lymphatic system

The lymphatic system consists of the lymphatic vessel, lymphatic organ and lymphatic tissue. The lymphatic vessel consists of a lymphocapillary vessel, lymphatic vessel, lymphatic trunk, and lymphatic duct. The lymphoid organs include the lymph node, tonsil, spleen and thymus. Lymphoid tissue is based on reticular connective tissues, with a large amount of lymphocytes, macrophages and plasma cells, etc. filling in the meshes. The normal lymph node is oval, with a transverse diameter < 1.5 cm, generally. The number and size of lymph nodes are different in various individuals, however, the number of lymph nodes are roughly the same in both sides of the body. A normal lymph node has a clear boundary which is often linked to a chain. The diameter of a normal lymphatic vessel is about 0.25-1.0 mm.

The lymphatic system, which originates from the cecum of lymphocapillary vessels, absorbs liquid and macromolecular materials exuded from blood vessels and ultimately transports these liquids and materials back to the blood vessels, so it plays a significant role in the process of regulating fluid balance and homeostasis. In addition, the lymphatic system is a very important defense barrier of the human body against inflammation and cancer. Dendritic cells in lymph nodes process and present exogenous antigens to stimulate immune responses. The lymph node is also a main locus for producing B lymphocytes, phagocytes and plasma cells. Lymphatic vessels, which have endemic vascular endothelial growth factor receptors, can form new lymphatic vessels through binding with the vascular endothelial growth factors C and D.

Tumor metastasis through the lymphatic system

Lymphatic metastasis is one of the main reasons leading to the failure of treatment and death of patients with malignant tumors. Accurate evaluation of lymphatic metastasis is closely related to the successful treatment and better prognosis of patients with malignant tumors. How to further enhance the diagnostic sensitivity and specificity towards lymphatic metastasis has been a long-term focus of imageology.

The sentinel node (SLN) is the first lymph node into which the primary tumor drains, making it the most likely of all the nodes in the draining basin to suffer from tumor invasion. If the SLN is negative, the likelihood of nodal metastases is very low, not requiring surgical excision; if the SLN is positive, treatment and prognosis are usually adjusted and the lymph nodes should be excised at an early stage with other adjuvant treatments. Surgical navigation is often performed clinically by location, excision and pathological examination of SLN, to judge the tumor stage and determine whether lymph node dissection should be considered. Multiple large-scale studies have shown that the accuracy rate of staging by lymphatic mapping and sentinel node lymphadenectomy ranges from 94% to 100%, confirming the validity of the SLN concept [1].

Traditional lymphography

Methods

Traditional lymphography (LG) is an approach for observing and studying the structures of the lymphatic system or lesions, by injecting a contrast agent directly or indirectly into lymphatic vessels and then carrying out x-ray photography. It is divided into indirect and direct visualization. The indirect method is done by injecting the contrast medium into the body cavity or soft tissues and allowing it to develop after absorption by lymphatic vessels. However, its application is limited because it is time-consuming, and the contrast agent cannot be fully absorbed by lymphatic vessels, and lymph nodes are only partially filled by contrast agents. The direct method, which is simple and reliable and has clear developing, involves injecting the contrast agent directly into specific lymphatic vessels, allowing the lymph nodes in the superior position to also be displayed. The direct visualization technology can be divided into surgical techniques and imaging examinations. Surgical techniques include: dye injection, display and identification of lymphatic vessels, lymphatic puncture and contrast agent infusion. Imaging examinations include x-ray, analysis and diagnosis.

The two methods commonly used at present are as follows: (1) Lymphangiography of the lower extremity: a blue dye is injected intradermally into the interdigital space in order to stain and localize the deep lymphatic vessels. An incision is then performed in the skin of the foot to locate lymphatic vessels large enough to allow cannulation. After successful cannulation, the organic iodide medium is injected, and then x-ray photographing is performed at the 12th and 24th hour after injection, respectively, to develop the lower limbs, pelvis, retroperitoneal lymphatic vessels and lymph nodes. It can be applied in the diagnosis of lymphatic metastasis in penile cancer, bladder cancer, prostate cancer, and so on. (2) Lymphangiography of spermatic cord: the contrast agent is properly injected into the lymphatic vessel of the spermatic cord by a thin needle. The first x-ray photography is performed after a 2 mL injection, and then the succeeding photographs are taken every 30 seconds, for a total of 7 photos. This method is mainly used in patients with testicular tumorectomy, for it can display the paraaortic lymph nodes in the first and second lumbar levels, which are the first stations of lymphatic metastasis in testicular cancer.

Imaging manifestations and resultant assessments

Abnormal manifestations of lymphatic vessels after lymphography: (1) thickening (diameter > 2 mm); (2) distortion; (3) bypass; (4) reduction or disappearance; (5) interruption. Abnormal manifestations of lymph nodes after lymphography: (1) size increasing (diameter > 1.5 cm); (2) filling defect (diameter of marginal defect > 5 mm, or the defect accounting for more than 1/3 of the lymph node); (3) destruction (obvious maldistribution, with an irregular, broken or wormhole-like shape); (4) decreasing or disappearing completely.

A filling defect can be used as a direct fluoroscopical sign, and others as indirect signs. According to the contrast of fluoroscopical signs with pathology, the standards of lymphography in the diagnosis of lymphatic metastasis include: one or more indirect signs of lymphatic vessels and lymph nodes simultaneously, or only the filling defect of the lymph node is considered as positive, otherwise it is negative [2].

Clinical significance

There have only been a few studies on LG in recent years; however, it was applied widely in the 1970s and 1980s, especially in malignant lesions in uterology and urology. Lymphography was performed for lymphatic metastasis in 295 patients with endometrial carcinoma and the results revealed that lymphography was positive in 8.9% of patients at Stage I, 28.6% at Stage II, 57.1% at Stage III, and 66.6% at Stage IV, with the coincidence rate with pathology reaching 86.3% [3]. In 1986, a retrospective study on 32 patients with urogenital tumors showed that the accuracy rate of LG was the highest, with a specificity of 83% in judging pelvic lymphatic metastasis [4]. Lang compared preoperative LG and retroperitoneal lymph node dissection in 30 cases of ovarian cancer, and found that the correlation between lymphography and histological examinations was 83.3% [2]. It was shown by Marks that LG was helpful for the accurate evaluation of testicular seminoma staging [5]. Multiple studies indicate that labeling deep lymph nodes by LG is not only helpful for lymph node dissection and staging of diseases, but also could promptly correct wrong clinical staging due to skipping of lymphatic metastasis.

Limitations

LG can display the internal structure of lymph nodes so as to identify small lesions within the normal-sized lymph nodes and differentiate benign reactive enlarged lymph nodes from malignant enlarged ones. However, LG has the following limitations. First of all, the scope of lymph nodes displayed by LG is limited strictly by lymphatic drainage approaches so that retroperitoneal lymphatic areas in the superior position cannot often be displayed fully; LG may yield false negative results because there are difficulties for plain films in displaying metastases smaller than 3-5 mm within the lymph node and when the lymph node is completely replaced by tumor; LG may also yield false positive results for reasons such as inflammation, fatty infiltration, and incomplete filling of the contrast agent, which may also lead to filling defects within lymph nodes. Secondly, LG is an invasive technology, which may lead to serious complications such as pulmonary embolism, pulmonary edema, and adult respiratory distress syndrome (ARDS).

CT lymphography

Routine CT

Routine CT with a high density resolution is simple and convenient, which can be used for evaluating the size, shape as well as location of lymph nodes, and can display extensively the retroperitoneal and abdominopelvic lymph nodes including those which are failed to be found by LG, such as the mesenteric,post crura diaphragmatis, and the peripancreatic, hepatic portal and para-aortic lymph nodes. The diagnostic criteria of lymphatic metastasis by CT are as follows: (1) lymphadenovarix, and the transverse diameter (TD) of isolated lymph nodes ≥ 15 mm in the iliolumbar area, ≥ 20 mm in the abdominal aortic area, or the TD of a number of lymph nodes ≥ 10 mm; (2) conglomerate lymph nodes; (3) suspicious lumps with displacement of surrounding organs and blood vessels; (4) cases with a clear fat interface and the retroperitoneal structure cannot be distinguished.

The clinical applications of cross-sectional imaging technology such as CT and MRI reduce the application of LG gradually, but there are limitations of routine CT: (1) The routine CT scan is mainly based on the size of the lymph node, with low resolution for the internal structure within the lymph node, so that it may yield false negative results in identifying metastatic lymph nodes with a normal size or a mildly enlarged size, especially those ranging between 5-10 mm; further, partly reactive lymph node hyperplasia may be misdiagnosed as positive by CT. (2) The slice thickness of the CT scan is 5 mm, however, the maximum diameter cannot be always displayed in each slice, so a few lymph nodes larger than 5 mm may be missed. (3) There is an absence of detailed dynamic information regarding internal blood flow-perfusion within lymph nodes.

CT lymphography

CT lymphography, a combination of CT and LG, can display filling defects with a diameter of 5-7 mm in lymph nodes, making up for deficiencies of CT and LG alone, and improving the coincidence rate of diagnosis. The CT manifestations of normal lymph nodes after lymphography are as follows: round or similar round high echogenic area, with a diameter of 7-15 mm, with an intra-nodular uniform echo and regular border, without filling defect, distributing in the normal region. CT manifestations of metastatic lymph nodes after lymphography are as follows: internal filling defect and maldistribution of contrast agent in addition to the routine CT manifestations of malignant lymph metastasis.

LG and routine CT were performed to diagnose lymphatic metastasis in 40 patients with cervical cancer and 37 patients with endometrial cancer, and the results showed similar accuracy rates with each method alone, and higher accuracy was obtained when both were combined [6]. However, the effectiveness of combined use is still controversial. One hundred and three patients with early cervical cancer were examined by LG, CT and CT combined with LG, respectively, and the results showed that there was no significant difference between the three groups [7]. With the application of contrast agents (such as iopamidol), functional CT lymphography has a potential in sentinel lymph node imaging and so on. At present, iopamidol enhanced CT imaging is one of the methods for detecting sentinel lymph nodes. Three dimensional CT scans were performed with iopamidol preoperatively in 17 breast cancer patients and the results showed that by CT lymphography, sentinel lymph nodes in all patients were detected, and the accurate anatomic location of SLNs and lymphatic drainage vessels could also be determined [8]. In addition, an endoscopic CT lymphography was performed after injection of iopamidol around tumors in patients with operable esophageal cancers, and the histopathologic examination revealed the high predictive value of CT lymphographic-guided SLN biopsy [9].

However, the shortcomings of CT lymphography include: (1) it cannot provide a real-time guide in the operative process and immediate information for surgeons. (2) Low-molecular-weight iopamidol would soon be washed out from the lymph nodes, so the scan time might be limited.

MR lymphography

Routine MRI

Like routine CT, routine MRI evaluates the status of lymph nodes also mainly based on some non-specific signs including the size, shape, etc., and can not provide any important information about internal structural changes of lymph nodes. Therefore, routine MRI has limited accuracy in judging between benign or malignant lymph nodes, especially detecting insidious lymphatic metastasis. However, by using MR lymphography, higher accuracy of qualitative diagnosis for lymph nodes can be obtained which can successfully display the structure of the lymphatic system and provide more important diagnostic information including the structural and morphological changes in the lymph node and lymphatic vessel.

Commonly used contrast agents

Positive contrast agents — extracellular contrast agents

Extracellular contrast agents are transported to lymph nodes through the supplying artery in vivo. Several studies have indicated that dynamic enhancement of lymph nodes following intravenous injection of extracellular contrast agents (gadolinium-based contrast agents on MRI, e.g., Gd-DTPA) could improve the identification accuracy of nodal metastases. Parameters derived from dynamic enhancement curves in patients with squamous cell carcinoma of the head and neck showed that malignant nodes presented decreased peak enhancement, decreased the slope of enhancement and slowed the washout profiles compared to normal nodes [10]. The enhancement indices and histopathology of excised nodes were compared by Murray et al in 47 women with primary breast cancer, and the results showed that all patients with lymphatic metastasis had at least one lymph node with an enhancement index > 21%, giving a sensitivity of 100% and a negative predictive value of 100%, however, the specificity was only 56% [11]. A total of 65 patients with invasive breast cancer were preoperatively evaluated by Kvistad et al., and the results showed that the dynamic contrast-enhanced MR imaging yielded an accuracy of 88%, a specificity of 90% and a sensitivity of 83% in the diagnosis of lymphatic metastasis [12].

Negative contrast agents — ultrasmall superparamagnetic iron oxide (USPIO)

Different from extracellular contrast agents, USPIO is transported into lymph nodes indirectly. After intravenous injection, iron oxide particles are firstly phagocytized by macrophages in circulation and then transported to lymph nodes, where they concentrate selectively in the reticuloendothelial system. Contrast agents may concentrate in lymph nodes with normal function, showing a shortened T2 time and low T2WI signal, whereas they develop a high signal in metastatic lymphatic nodes. Therefore, USPIO enhanced MR lymphography shows better sensitivity and specificity in the differential diagnosis of benign and malignant lymph nodes.

The sensitivity, specificity, and the positive and negative predictive value of USPIO-enhanced MRI in evaluating the status of lymph nodes are highly dependent on anatomical location and inspection techniques. Eighty one cases of head and neck carcinoma with suspected lymphatic node metastasis were assessed with USPIO-enhanced MRI, and the results showed a sensitivity of 88%, a specificity of 77%; however, the positive predictive value was only 50 % [13]. It was shown by Bellin in 30 cases of urinary tract and pelvic cancers that the sensitivity and specificity of USPIO-enhanced MRI in diagnosing lymph node metastases were 100% and 80%, respectively [14]. In a phase III safety and efficacy study of USPIO, 152 patients were evaluated, and the sensitivity, specificity, and accuracy of MR imaging for identifying lymph node invasion were 54%, 82%, and 68%, respectively, whereas all indices were improved to 85% if USPIO was used for enhancement [15].

However, this method has limitations. Because they lack normal function, the nontumorous lymph nodes such as obsolete, inflammatory and cicatricial lymph nodes, cannot uptake the contrast agent and present a high signal, thus it is difficult to discriminate them from real lymph node metastasis.

Lymphoscintigraphy

Characteristics

The mechanism of lymphoscintigraphy (LS) technology is such that the radiocolloids or high polymer materials in subcutaneous tissue or tissue space are absorbed into lymphatic capillaries and then drained into lymphatic nodes after being swallowed by phagocytes, thus enabling lymph nodes and lymph channels to be photographed by the scintillation camera. The normally used radiopharmaceuticals include ^99mT_c-antimony sulphide colloid, ^99mT_c-micro colloid, and ^99mT_c-sulfur colloid. According to the areas of interest, the isotope could be injected subcutaneously in the web space, within tumors or around tumors. Compared to traditional lymphography, LS can show large abnormalities in the lymphatic system and improve the imaging quality.

Clinical significance

Although LS was initially applied to the diagnosis of lymphedema, in recent years it has been applied more in the field of oncology and surgical evaluation of the sentinel lymph node. LS is often used with vital blue dyes so as to provide more intuitive, accurate information about draining lymphatic channels as well as SLNs. The commonly used blue agents include methylene blue, isosulfan blue, patent blue and fluorescein. The specific methods of operation are as follows: radionuclide marker is injected subcutaneously around the tumor 1-4 hours before surgery → a gamma detector is used to search for “hot” points → skin marking → vital stain is injected subcutaneously into the surrounding tissue of the tumor(s) → search for the stained nodus and “hot” nodus by operation. SLN is identified according to the location of intake of the radio-labelled sulfur colloid and blue agents. Lymph node biopsy will then be performed to evaluate the lymph node histopathology and the necessity for regional lymph node dissection.

Since being first utilized in patients with breast cancer and melanoma, the SLN was able to help avoid excessive lymph node dissection and contribute to the accurate staging of lymph nodes by gamma probe identification of the SLN during operation. ^99mT_c-sulfur colloid was used to localize sentinel nodes in 443 patients with breast cancer before axillary lymph node clearance, and the results showed that the SLN was detected in 91% patients, with a false positive rate of 11%, and diagnostic accuracy of 97 % when only the detected SLNs were considered [16]. LS was used by Vucetic in 201 melanoma patients before surgery, and the results showed that SLNs were found in 200 patients with a total of 372 sentinel nodes, while anomalous lymphatic drainage patterns were observed in 15% of all patients and 21% patients had tumor metastatic SLNs, all indicating that LS was of important value in the surgical treatment of melanoma [17]. In addition, LS technology could also be used in many other substantive tumors, including cancers in the urinary and reproductive system, cancers in the head and neck, gynecological and gastrointestinal malignancies.

Limitations

The main limitation of LS is the poor spatial resolution, which cannot provide specific anatomical information. Other disadvantages of this method include: (1) radioactive substances often take advantage of small particles such as human serum albumin, so colloidal albumin and filtered small particles of the sulfur colloid can be transferred through the lymphatic vessels and easily into the second-echelon nodes besides the SLNs; (2) SLNs are difficult to detect if they are located out of the view of the gamma camera, resulting in false negative results; (3) lymph nodes can not be distinguished by LS if they are located close to each other, especially if they are overlapped; (4) radioactive agents produce ionizing radiation exposure, and radioactive substance antigens may cause adverse effects on certain patients and operators.

Positron emission tomography (PET)

Characteristics

PET, belonging to metabolic imaging, has a high accuracy in judging lymphatic metastasis. The principle is that glucose marked by radioisotope accumulates in lesions and emits positrons that can be combined with positive electrons in the lesions to launch a strong radiation, by which the lesion site can be identified. The commonly used radioactive marker is ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG), which is relatively safe for inspection, with a small amount of radiation. Cancer cells have a greater need of glucose than normal ones so cancer tissue can be identified.

Clinical significance

PET has advantages in the early detection of metastatic lymph nodes. It can display the internal metastasis of lymph nodes with diameters less than 1 cm, which are usually misdiagnosed as normal by CT and MRI. FDG-PET can accurately detect metastasis into paraaortic lymph nodes while an abdominal CT shows negative results. It has been found that FDG-PET is helpful for lymph node staging, with a sensitivity and specificity of nearly 90% in many malignant diseases such as lymphoma, non-small cell lung cancer, squamous cell carcinoma in the head and neck, gynaecological cancer, breast cancer and so on. In addition, PET can be used to evaluate the prognosis of lymphoma. FDG-PET was compared to CT for prognosis prediction in patients with non-Hodgkin lymphoma (NHL), and the study indicated that the relapse rate was 100% for patients with a positive PET scan and only 17% for those with a negative PET scan, and PET was particularly more accurate than CT in remission assessment following treatment [18].

However, PET has some disadvantages, as follows: (1) it has a lower spatial resolution at only 5 mm; therefore, it is very difficult to detect micrometastases less than 5 mm by PET alone; also, PET can not show the accurate number of lymph nodes and their precise anatomical relationships when several metastatic lymph nodes are partly fused, yet the number of metastatic lymph nodes is closely related to the prognosis of diseases; (2) it is difficult for PET to distinguish metastasis from reactive lymph nodes, because reactive lymph nodes and the lesion regions of sarcoidosis, inflammation and granulomas all can absorb FDG and present with high glucose metabolism, so false positives may be obtained.

PET-CT

PET-CT, a combination of PET and CT, overcomes part of the above limitations of PET. It improves the spatial resolution of PET. For measuring tumor sizes, PET-CT can not only more precisely locate the lymph nodes, but also provide unique information about the activity of residual tumors [19]. Further, it was shown that PET-CT ruled out physiological and inflammatory FDG uptake, improving the specificity of mediastinal lymph node staging in patients with lung cancer [20]. In addition, it was reported that the combination of PET and CT would improve the accuracy of lung cancer staging [21].

Contrast-enhanced lymphosonography

Conventional ultrasound

Ultrasound has been used in lymph node imaging for a long time. It is an easy, low-cost and non-invasive technology, without ionizing radiation. The ultrasonic manifestations of metastatic lymph nodes are enlarged and hypoechoic round nodes with an irregular contour and redundant blood flow. However, the main limitation of conventional ultrasound is that it cannot detect the deep lymph nodes reliably. For occult metastatic lymph nodes of the neck, the sensitivity of conventional ultrasound is only 60% and only increases to 77% when combined with ultrasound-guided needle aspiration biopsy. In addition, conventional ultrasound also cannot differentiate whether the enlarged lymph nodes result from tumor invasion or reactive hyperplasia or chronic inflammation.

Contrast-enhanced lymphosonography

Contrast-enhanced lymphosonography can redeem the limitations of conventional ultrasound imaging. It may help to locate SLNs and diagnose regional lymphatic metastases. Compared with the lymphoscintigraphy of traditional SLN mapping, contrast-enhanced lymphosonography has the following potential advantages: (1) it is non-radioactive, without surgical radioactive contamination; (2) it is non-invasive and can display the movement of the contrast agent in real time, directly from the tumor to lymphatic channels, then to SLN; (3) the nearby lymph nodes can be observed, so as to judge the tumor invasion (metastatic lymph nodes are often manifested as external swellings and internal filling defects of the contrast agent).

Micro contrast agents were injected subcutaneously into the distal extremities of normal dogs to target the cervical and popliteal lymph nodes, and the results showed that the detection rate of SLNs was 85%, and each order of lymph node could be imaged and traced by contrast-enhanced lymphosonography [22]. After peri-tumoral injection of the contrast agent, contrast-enhanced lymphosonography was utilized to detect the lymphatic channels and sentinel lymph nodes and to assess the status of lymphatic metastasis in 17 cases of swine with melanomas [23]. The results showed that 28 SLNs were depicted by contrast-enhanced lymphosonography without false positives, while lymphoscintigraphy depicted 27 “hot spots” suspected as SLNs, with two false positives; the accuracy of SLN detection was 90% for contrast-enhanced lymphosonography and 81% for lymphoscintigraphy; contrast-enhanced lymphosonography correctly depicted metastases in 19 of 20 SLNs, and characterized five of the eight normal SLNs with an accuracy of 86% without a significant difference when compared to histological findings. In another study, contrast-enhanced lymphosonography was used to detect SLNs after subcutaneous, submucosal, or parenchymal injections of contrast agent Sonazoid (a tissue-specific ultrasound agent taken up by the reticuloendothelial system) in several animal models including pig, dog, rabbit and monkey [24]. The results showed that there was a close correlation between the results of lymphosonography and the blue dye in identifying the regional lymph vessel and SLNs, indicating that lymphosonography could be used to detect lymphatic drainage pathways and SLNs in a variety of animal models. In addition, contrast agent Sonazoid was injected into the margo lateralis linguae or mouth floor of swine to visualize SLNs compared with methylene blue, and the results indicated that it was feasible to perform contrast-enhanced ultrasound-guided sentinel lymph node biopsy of the head and neck [25].

In summary, the detection of metastatic lymph nodes and SLNs is still a challenging problem in oncology. Further studies are needed although the diagnostic accuracy has been improved with the rapid development of lymphography technology in recent years. Contrast-enhanced lymphosonography has potential advantages in this field. Albeit today, contrast-enhanced lymphosonography is situated in the stage of research and experimentation, we believe that in the near future, it will be gradually applied in the clinical detection of lymphatic metastasis and SLNs, and non-invasive diagnostic imaging will expand toward a new level.

References

[1] KelleyM C, HansenN, McMasterK M. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Am J Surg, 2004, 188(1): 49-61

[2] LangJ H, HuangR L, WuB Z. Lymphography in ovarian cancers. Zhonghua Fuchanke Zazhi, 1989, 24(1): 29-31 (in Chinese)

[3] MusumeciR, PaloG, ContiU, KendaR, MangioniC, BelloniC, MarziM, BandieramouteG. Are retroperitoneal lymph node metastasis a major problem in endometrial adenocarcinoma? Diagnostic and prognostic assessment with lymphography. Cancer, 1980, 46(8): 1887-1892

[4] WeinerS A, LeeJ K, KaoM S, MoonT E. The role of lymphangiography in vulvar carcinoma. Am J Obstet Gynecol, 1986, 154(5): 1073-1075

[5] MarksL B, ShipleyW U, WalkerT G, WaltmanA C. Role of lymphangiography in staging testicular seminoma. Urology, 1991, 38(3): 264-266

[6] MaranzanoE, LatiniP, CheccagliniF, BeneventiS, PanizzaB M, PerrucciE, BaffaS, RossiL, CaprinoG. Role of lymphangiography and abdomino-pelvic CT in uterine tumors. Radiol Med (Torino), 1990, 79(6): 599-602

[7] FernandoI N, MoskovicE, FryattI, GlaholmJ, BlakeP R. Is there still a role for lymphography in the management of early carcinoma of the cervix?Br J Radiol, 1994, 67: 1052-1056

[8] SugaK, YuanY, OkadaM, MatsunagaN, TangokuA, YmamotoS, OkaM. Breast sentinel lymph node mapping at CT lymphography with iopamidolβ: preliminary experience. Radiology, 2004, 230(2): 543-552

[9] SugaK, ShimizuK, KawakamiY, TangokuA, ZakiM, MatsunagaN, OkaM. Lymphatic drainage from esophagogastric tract: feasibility of endoscopic CT lymphography for direct visualization of pathways. Radiology, 2005, 237(3): 952-960

[10] FischbeinN J, NoworolskiS M, HenryR G, HenryR G, KaplanM J, DillonW P, NelsonS J. Assessment of metastatic cervical adenopathy using dynamic contrast-enhanced MR imaging. AJNR Am J Neuroradiol, 2003, 24(3): 301-311

[11] MurrayA D, StaffR T, RedpathT W, GilbertF J, Ah SeeK, BrookesJ A, MillerI D, PayneS. Dynamic contrast enhanced MRI of the axilla in women with breast cancer: comparison with pathology of excised nodes. Br J Radiol, 2002, 75(891): 220-228

[12] KvistadK A, RydlandJ, SmethurstH B, LundgrenS, FjosneH E, GribbestadI S, NilsenG. Axillary lymph node metastases in breast cancer: preoperative detection with dynamic contrast-enhanced MRI. Eur Radiol, 2000, 10(9): 1464-1471

[13] SigalR, VoglT, CasselmanJ, MoulinG, VeillonF, HermansR, DubrulleF, VialaJ, BosqJ, MackM, DepondtM, MattelaerC, PetitP, ChampsaurP, RiehmS, DadashitazehoziY, de JaegereT, MarchalG, ChevalierD, LemaitreL, KubiakC, HelmbergerR, HalimiR. Lymph node metastases from head and neck squamous cell carcinoma: MR imaging with ultrasmall superparamagnetic iron oxide particles (Sinerem MR)-results of a phase-III multicenter clinical trial. Eur Radiol, 2002, 12(5): 1104-1113

[14] BellinM F, RoyC, KinkelK,ThoumasD, ZaimS, VanelD, TuchmannC, RichardF, JacqinD, DellcourA, ChallierE, LebretT, CluzelP. Lymph node metastases: safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles-initial clinical experience. Radiology, 1998, 207(3): 799-808

[15] AnzaiY, PiccoliC W, OutwaterE K, StandfordW, BluemkeD A, NurenbergP, SainiS, MaravillaK R, FeldmanD E, SchmiedlU P, BrunbergJ A, FrancisI R, HarmsS E, SomP M, TempanyC M. Evaluation of neck and body metastases to nodes with ferumoxtran 10-enhanced MR imaging: phase III safety and efficacy study. Radiology, 2003, 228(3): 777-788

[16] KragD, WeaverD, AshikagaT, MoffatF, KlimbergV S, ShriverC, FeldmanS, KusminskyR, GaddM, KuhnJ, HarlowS, BeitschP. The sentinel node in breast cancer-a multicenter validation study. New Engl J Med, 1998, 339(14): 941-946

[17] VuceticB, RoganS A, BalenovicA, IvkicM, SitumM, HudorovicN, KusicZ. The role of preoperative lymphoscintigraphy in surgery planning for sentinel node biopsy in malignant melanoma. Wien Klin Wochenschr, 2006, 118(9-10): 286-293

[18] MikhaeelN G, TimothyA R, O’DohertyM J, HainS, HainS, MainseyM N. 18-FDG-PET as a prognostic indicator in the treatment of aggressive non-Hodgkin’s lymphoma-comparison with CT. Leuk Lymphoma, 2000, 39(5-6): 543-553

[19] SchneiderA, HertelH. Surgical and radiographic staging in patients with cervical cancer. Curr Opin Obstet Gynecol, 2004, 16(1): 11-18

[20] AquinoS L, AsmuthJ C, AlperN M, HalpernE F, FischmanA J. Improved radiologic staging of lung cancer with 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography and computed tomography registration. J Comput Assist Tomogr, 2003, 27(4): 479-484

[21] LardinoisD, WederW, HanyT F, KamelE M, KoromS, SeifertB, Von SchulthessG K, SternertH C. Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med, 2003, 348(25): 2500-2507

[22] WisterE R, FerraraK W, ShortR E, OttoboniT B, GabeJ D, PatelD. Sentinel node detection using contrast-enhanced power Doppler ultrasound lymphography. Invest Radiol, 2003, 38(6): 358-365

[23] GoldbergB B, MertonD A, LiuJ B,ThakurM, MurphyG F, NeedlemanL, TornesA, ForsbergF. Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic ultrasound. Radiology, 2004, 230(3): 727-734

[24] GoldbergB B, MertonD A, LiuJ B, MurphyG, ForsbergF. Contrast-enhanced sonographic imaging of lymphatic channels and sentinel lymph nodes. J Ultrasound Med, 2005, 24(7): 953-965

[25] CurryJ M, BloedonE, MalloyK M, CognettiD M, MertonD A, GoldbergB B, KeaneV M, RosenD, PribitkinE A. Ultrasound-guided contrast-enhanced sentinel node biopsy of the head and neck in a porcine model. Otolaryngol Head Neck Surg, 2007, 137(5): 735-741

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg