Lymphatic mapping helps to defineresection margins formidgut carcinoidsYi-Zarn Wang, DDS, MD, Saju Joseph, MD, Erika Lindholm, BSE, John Lyons, MD,J. Philip Boudreaux, MD, and Eugene A. Woltering, MD, New Orleans, LA

Background. The extensive mesenteric lymphadenopathy associated with midgut carcinoids often causeslymphatic obstruction and leads to the development of alternative lymphatic drainage pathways. Wehypothesized that altered lymphatic drainage makes traditional determination of resection marginsinadequate.Methods. One hundred and seventy patients underwent cytoreductive surgery for neuroendocrine tumorsfrom November 2006 to August 2008. Forty-nine patients underwent intra-operative lymphatic mappingwith lymphazurin dye as a single agent. Twenty-seven patients had midgut primaries. We reviewedoperative findings and pathology to evaluate the safety and efficacy of lymphatic mapping for midgutcarcinoids. Lymphatic mapping defined resection margins were compared to traditional surgicalmargins.Results. There were no adverse events associated with the 49 lymphatic mapping procedures. Twenty-five(92%) patients had ileal and 2 had jejunal primaries. Lymphatic mapping changed traditionalresection margins in 88% of patients. We preserved the ileocecal valve in 6 of 15 (40%) of patients withterminal ileal primaries.Conclusion. Lymphatic mapping seems to be a safe, time efficient, and effective way to determineadequate resection margins for midgut carcinoids. We advocate using lymphatic mapping for patientswith midgut carcinoids to identify adequate resection margins and assist in preservation of the ileocecalvalve in patients with terminal ileal primary carcinoids. (Surgery 2009;146:993-7.)

From the Louisiana State University Health Sciences Center, Department of Surgery, Section of SurgicalOncology and Endocrine Surgery, New Orleans, LA

MIDGUT CARCINOID is an uncommon malignancywith reported incidences of only 1--2 per 100,000populations per year.1 It has been estimated theaverage surgeon only sees 2--3 carcinoid patientsbefore their retirements. The presenting symp-toms of midgut carcinoid are usually extremelyvague, especially in the early stages of the diseaseand the diagnosis of most patients with midgutcarcinoid is often delayed for years. As a result,midgut carcinoid patients almost always presentat an advanced stage. Common intra-operativefindings in a midgut carcinoid patient includepartial bowel obstruction resulting from thedesmoplastic retraction of the bowel down towardthe boggy mesenteric lymphadenopathy. This

Accepted for publication September 17, 2009.

Reprint requests: Yi-Zarn Wang, DDS, MD, 200 West Esplanade,Suite 200, Kenner, LA 70065. E-mail: ywang@lsuhsc.edu.

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lymphadenopathy often encases the major mesen-teric vessels and this encasement can lead to mes-entery ischemia and intestinal angina. Frequently,multiple ‘‘primaries’’ are found within a short seg-ment of the small bowel. The cause of these multi-ple primaries remains unexplained. There are notreatment options other than surgery for the pri-mary tumor in the small bowel and its associatedlymphadenopathy. Many authors advocate aggres-sive cytoreduction procedures to remove the pri-mary tumor and its associated nodal disease, evenin patients with liver metastasis.2-4 The surgicalprinciples that guide these major cytoreductionprocedures mandate careful attention to theadequacy of surgical margins, the resection of thelymphatic drainage bed of the tumor, and preser-vation of the blood supply to the bowel margins.

Traditionally, the presence of a terminal ilealcarcinoid mandates a formal right hemicolectomyor at least a resection of the terminal ileum and ashort segment of the cecum. Preservation of thesmall bowel length and the ileocecal valve inpatients suffering from carcinoid syndrome is

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extremely crucial because it minimizes diarrheaand reduces the incidence of short gut syndrome.In contrast, inadequate resection of the smallbowel and its associated mesentery might lead topromulgation of lymphatic tumor emboli andincrease local recurrences at or near the bowelresection margins and the adjacent mesentery.

Lymphatic mapping and sentinel lymph nodebiopsy have become the standard of care intreating patients with breast cancer and mela-noma.5-7 The utility of sentinel lymph node proce-dures in gastrointestinal malignancy has beenlimited.8,9 No data exist on the use lymphatic map-ping in small bowel tumors. To date, there havebeen no reports on use of lymphatic mapping todirect the resection of small bowel carcinoids.

We first implemented lymphatic mapping insmall bowel carcinoid patients in late 2006. Ourinitial goal was to evaluate the movement ofmethylene blue dye, injected around the primarytumor, to determine if this technique would helpus to understand the limits of lymphatic drainagealong the length of the bowel wall. We neverintended to perform a sentinel lymph node pro-cedure using this technique because the presenceof massive lymphadenopathy in these patientsmade the use of sentinel node detection of thedraining lymph nodes superfluous. Our lymphaticmapping revealed a group of reproducible find-ings that included boggy mesenteric nodal disease,extensive longitudinal subserosal lymphatic drain-age within the small bowel, and the existence ofclusters of multiple ‘‘primary’’ tumors in thosepatients who had the most extensive lymphaticobstruction at the root of the mesentery. In thesepatients, the obstruction of the lymphatics at theroot of the mesentery seemed to drive the tumor-bearing lymph in a longitudinal fashion along thebowel wall. This drainage progressed until anunobstructed lymphatic channel was encountered.At that point, the lymphatic drainage turned in aradial fashion and dove into the mesentery. Wehypothesized that boggy lymphadenopathy withinthe mesentery blocks the normal radial drainage oflymph into the mesenteric lymphatic channels. Asa consequence, the lymphatics detour the block-age of the lymphatic channels within the smallbowel until it reaches a point where the interme-senteric lymphatic channels remains patent. At thispoint, the lymph again drains radially. Our hypoth-esis easily explains why patients with massive lym-phadenopathy may have multiple ‘‘primaries’’ andwhy recurrent carcinoids, treated by traditionalresection techniques, are almost always located ator adjacent to the previous resection margins. We

also observed that intra-operative lymphatic map-ping accurately demonstrate the altered lymphaticdrainage of midgut carcinoids and help the sur-geon to more accurately define the resectionmargins. We believe that in patients with terminalileal carcinoids, in whom the lymphatic drainagedives into the small bowel mesentery before itslongitudinal progress reaches the ileocecal valve,would be candidates for valve preservation ratherthan radical resection.

In this report, we summarize our intra-operativefindings obtained from lymphatic mapping inmidgut carcinoid patients and propose a methodby which surgeons can better define the resectionmargins in bowel-based neuroendocrine tumors.

METHODS

Patients undergoing cytoreductive surgery wereexplored using standard incisions. Adhesions weretaken down using a combination of sharp andblunt dissection and the overall tumor burden ofthe patient was evaluated by 2 experienced seniorsurgeons. Care was taken to avoid dissection anddisruption of the lymphatics of the small bowelbefore lymphazurin blue injection.

Patients underwent injection of 1--5 cm3 of 1%lymphazurin blue dye (Covidien, Norwalk, CT) ina circumferential pattern into the subserosa(Fig 1). In patients with multiple small bowel tu-mors, the most proximal, the most distal, and thelargest tumors were injected. The dye was allowedto migrate for 10--15 minutes while surgeons wereperforming cholecystectomy, ultrasound examina-tion of the liver or mobilization of liver for radio-frequency ablation, or resection of liver. Thelongitudinal and radial progression of the dyewas then assessed (Figs 2--4). The cessation of

Fig 1. Injection of lymphazurin blue into the primarytumor.

proximal dye migration (the point that longitudi-nal movement of dye ceased and the drainage ofthe dye began to migrate toward the root of themesentery in a radial fashion) was used to definethe resection margins (Fig 5).

In some cases with terminal ileal primary tu-mors, the dye was seen to transverse the ileocecalvalve, whereas in other cases (40%) the dye drain-age pattern moved radially toward the root of theileal mesentery before it reached the ileocecalvalue (Fig 2). In these cases, the line of resectionwas chosen to preserve the ileocecal valve.

RESULTS

One hundred and seventy patients underwentcytoreductive surgery for neuroendocrine tumorsfrom November 2006 to August 2008. Forty-ninepatients underwent intraoperative lymphatic map-ping using lymphazurin dye as a single mappingagent. Twenty-seven patients had midgut prima-ries. Twenty-five (92%) patients had ileal and 2(8%) had jejunal primaries. Among them, 15patients had tumors located near the ileocecal

Fig 2. Terminal ileal carcinoid with radial lymphaticdrainage proximal to the ileocecal valve.

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valve that would traditionally require an ileocec-tomy or a right hemicolectomy. All attempts atmapping were successful.

Patients with boggy nodal metastasis often hadmultiple primary tumors and long segments oflongitudinal subserosal dye movement (Fig 5).Conversely, unobstructed mesenteries were alwaysassociated with single primary tumor and muchshorter longitudinal dye drainage pattern (Fig 6).

Lymphatic mapping changed the resection mar-gins in 88% of the patients and we were able topreserve the ileocecal valve in 6 of 15 (40%)patients with terminal ileal primaries. There wereno adverse events or anaphylactic reactions associ-ated with the 49 lymphatic mapping procedureswith lymphazurin blue dye.

DISCUSSION

Lymphazurin blue or methylene blue is com-monly used in conjunction with 99mTc colloid todetect and ultimately to histologically evaluate sen-tinel lymph nodes. In this large series of cases,

Fig 3. Terminal ileal carcinoid with lymphatic drainagethat crosses the ileocecal valve.

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lymphazurin blue was not used to detect sentinellymph nodes but rather used to map subserosallymphatic channels that might carry cancer cells.This report represents the first use of thislymphatic mapping technique to identify adequatemargins for surgical resection of midgut carcinoidtumors and to spare the ileocecal valve when con-ditions permit.

The unexpected intra-operative findings ofelongated longitudinal alternative subserosal lym-phatic drainage patterns seen in midgut carcinoidpatients with multiple small primaries and itsassociated boggy mesenteric lymphadenopathyhave not been previously reported. It seems thatthe obstructed mesenteric lymphatics drive thelymph drainage of the tumor along the bowel’ssubserosal lymphatics in a longitudinal direction.As this lymph travels along the length of the bowel,it finally reaches an unobstructed lymphatic andthen turns radially toward the root of the mesen-tery (Fig 2). Conceivably during this lymphaticdetour, microtumor emboli in the lymphatics canthen become ‘‘drop’’ metastasis, as often seen inpatients with melanoma. This explains the consis-tent association between extensive nodal diseaseat the mesenteric root and the occurrence of

Fig 4. Multiple ‘‘drop lesions’’ and fibrotic mesenterywith longitudinal lymphatic drainage.

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multiple, often small, tumors along the length ofthe small bowel. It also may answer the questionwhy recurrent carcinoid is always located at ornear to the previous resection margin. Logically,the subserosal lymphatics, mapped out by theblue dye, might represent the true resection mar-gin for midgut carcinoids. Another advantage ofusing lymphazurin blue lymphatic mapping is todelineate the limits of distal lymphatic drainagefor terminal ileal carcinoids, allowing the operat-ing team to determine whether the ileocecal valvecan be preserved.

We have shown that this technique is safe, timeeffective, and well tolerated. Whether or not theimplementation of lymphatic mapping for midgutcarcinoid resection leads to a decrease in localrecurrence, lesser incidence of postoperative diar-rhea, fewer short gut symptoms, better quality oflife, and eventually improvement in long-termsurvival will only become clearer with long-term

Fig 5. Longitudinal lymphatic drainage >18 cm proxi-mal to the primary tumor.

Fig 6. Normal radial drainage of midgut carcinoid.

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follow-up studies and a comparison of the long-term outcomes among the patients treated withand without mapping. The new developed radio-labeled methylene blue dye might be useful formapping hindgut tumors or any carcinoid wherethe visualization of the lymphatic drainage mightbe insufficient to determine the resection mar-gins.10,11 Detection of the radioactive signal mayadd to the utility of this technique in those cases.

REFERENCES

1. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoidtumors. Cancer 1997;79:813-29.

2. Soreide JA, van Heerden JA, Thompson GB, Schleck C,Ilstrup DM, Churchward M. Gastrointestinal carcinoid tu-mors: long-term prognosis for surgically treated patients.World J Surg 2000;24:1431-6.

3. Hellman P, Lundstrom T, Ohrvall U, Eriksson B, SkogseidB, Oberg K, et al. Effect of surgery on the outcome of mid-gut carcinoid disease with lymph node and liver metastases.World J Surg 2002;26:991-7.

4. Sutton R, Doran HE, Williams EM, Vora J, Vinjamuri S,Evans J, et al. Surgery for midgut carcinoid. Endocr RelatCancer 2003;10:469-81.

5. Krag D, Weaver D, Ashikaga T, Moffat F, Klimberg VS,Shriver C, et al. The sentinel node in breast cancer: a mul-ticenter validation study. N Engl J Med 1998;339:941-6.

6. Krag DN, Harlow S, Weaver D, Askikaga T. Radiolabeledsentinel node biopsy: a collaborative trial with the NationalCancer Institute. World J Surg 2001;25:823-8.

7. Kelley MC, Hansen N, McMasters KM. Lymphatic mappingand sentinel lymphadenectomy for breast cancer. Am J Surg2004;188:49-61.

8. Cahill RA. What’s wrong with sentinel node mapping incolon cancer. World J Gastroenterol 2007;13:6291-4.

9. Bell SW, Mourra N, Flejou JF, Parc R, Tiret E. Ex vivo senti-nel lymph node mapping in colorectal cancer. Dis ColonRectum 2005;48:74-9.

10. Stafford SJ, Wright JL, Schwimer J, Anthony CT, Cundiff JD,Thomson JL, et al. Development of 125I-methylene blue forsentinel node lymph biopsy. J Surg Onc 2006;94:293-7.

11. Cundiff JD, Wang YZ, Espenan G, Maloney T, Camp A, Laz-arus L, et al. A phase I/II trial of 125I methylene blue forone-stage sentinel lymph node biopsy. Ann Surg 2007;245:290-6.

DISCUSSION

Dr Janice L. Pasieka (Calgary, Alberta, Canada): Thankyou very much for bringing a novel technique to us. Ithink, as you alluded to, these are very challenging pa-tients and the more aggressive we can be surgically thebetter these patients will do. My question is on a techni-cal aspect. When you have the multiple tumors, which tu-mor do you inject to do the lymphatic mapping? How doyou decide which tumor to inject?

Dr Yi-Zarn Wang (New Orleans, LA): When we have apatient with multiple tumors, we try to define whichmost likely represents the primary tumor. We inject the

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blue dye around that one. In cases with multiple tumors,we inject the most proximal one and the most distal oneto ensure that we have the widest drainage patternpossible.

Dr Scott Wilhelm (Cleveland, OH): I have 2 ques-tions for you. One, what was the primary presentationin most of your patients who had the midgut carcinoids?Did these people present with small bowel obstructionsor were these incidental findings in patients with ab-dominal pain? Did these patients have pain, get a com-puted tomography (CT) scan and the mesenteric masswas an incidental finding? Second, you alluded to thefact that you are hoping that this technique may de-crease chances for local recurrence. Do you have anyfollow-up on any of these patients that you have doneso far, even if it’s early, in terms of any recurrencedata or not?

Dr Yi-Zarn Wang (New Orleans, LA): Let me answerthe second question first. We don’t have any long-termfollow-up yet; but hopefully, I will be able to show youwhat we have found in a year or 2. In terms of the patientpopulation, we have become a referral center and thusmost of the patients are diagnosed somewhere else andsent to us. Most commonly these patients present withabdominal pain and are found to have a mesentericmass during their radiologic workup.

Dr Richard A. Hodin (Boston, MA): Can you give ussome insight into how often this lymphatic mappingmay have made you excise more versus less bowel? The-oretically it could work in either direction.

Dr Yi-Zarn Wang (New Orleans, LA): In general, thistechnique leads to resection of slightly more bowel. Usu-ally when you do the small bowel resection you chooseyour resection margins based on gross examination ofthe specimen. With the lymphatic mapping techniqueguiding the resection, most of the time the traditionalmargin was inadequate.

Dr Richard A. Hodin (Boston, MA): In your discus-sion, were you referring to taking out lymph nodesand leaving the blood vessels in cases where there wasmesenteric encasement?

Dr Yi-Zarn Wang (New Orleans, LA): Yes. We spend alot of time carefully dissecting the node from the vessels.When we finish, hopefully we leave the vessels with nosurrounding tissue.

Dr Emus Camden (New Orleans, LA): I’m interestedin your experience with the frozen sections of your mar-gins. Do you need to check these margins with frozensections?

Dr Yi-Zarn Wang (New Orleans, LA): We hardly everuse a frozen section to determine the adequacy of ourmargins. We tried it a couple times in the past, becausewe were worried about these margins. All of these werenegative so we stopped doing frozen sections and on re-view we have had no positive permanent bowel resectionmargins.

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