Regional Lymphadenectomy for Adrenocortical Carcinoma
To the Editor:
W e read with interest the article from Reibetanz et al”1 titled, “Impact of Lymphadenectomy on the Oncologic Out- come of Patients With Adrenocortical Car- cinoma.” Adrenocortical carcinoma (ACC) is an extremely rare disease, and limited progress in improving overall survival from ACC has been made in the past 30 years.2 There has been a recent surge in interest in ACC with new clinical trials; however, operative resection remains the most criti- cal treatment modality. The German ACC study group has extensive experience treat- ing patients with ACC and maintains a ro- bust database. In the study by Reibetanz et al, the authors evaluate the performance of lymph node removal and its associated out- comes. Patients having multiple organs re- sected as part of their operation were found to have more lymph nodes in the specimen. With multivariate analysis adjusting for age, ENSAT (European Network for the Study of Adrenal Tumors) tumor stage, multivisceral resection, adjuvant treatment, and lymph node status on preoperative imaging, they reported risk reduction in both risk of recurrence and disease-related death in those patients having more lymph nodes dissected (>5). The au- thors suggest that because 26% of those pa- tients undergoing removal of at least 1 lymph node had positive findings, it is possible that in those patients not having removal of any lymph nodes, up to a quarter would have resid- ual tumor left in the lymphatics adjacent to the tumor, leading to higher rates of local re- currence. The authors propose fields of lymph node dissection for right- and left-sided ACCs in Figure 5.
The role of lymph node sampling or formal regional lymph node dissection in the treatment of ACC remains unknown. Al- though removal of tumor contained within lymphatic channels or lymph nodes can both decrease local recurrence in the tumor bed or decrease regional recurrence if tumor is in the nearby lymph node basins, knowledge of lymphatic invasion may be most impor- tant as a marker of tumor biology. Its impact upon overall survival may provide informa- tion that informs potentially more intensive
Disclosure: The authors declare no conflicts of interest. Copyright @ 2013 by Lippincott Williams & Wilkins ISSN: 0003-4932/13/25704-e0013
DOI: 10.1097/SLA.0b013e3182891ee5
use of chemotherapy and external beam radi- ation therapy. At the University of Michigan, it is customary for our pathologist to com- ment upon lymphatic and vascular invasion within the tumor and immediately adjacent to the tumor capsule in addition to evalua- tion of larger vasculature, lymphatic vessels, and lymph nodes resected as part of the sur- rounding soft tissue. Did the authors compare outcomes based on knowledge of intra- or peritumoral lymphatic invasion versus lymph node involvement alone? Did evidence of microvascular invasion and/or large vessel invasion lead to similar findings of risk of recurrence when compared with lymph node involvement? Would this provide equally rele- vant outcome data? Did those with high-grade tumors have a higher incidence of lymphatic invasion?
Tumor recurrence in the study could be further specified. Was this local recurrence in the tumor bed or regional recurrence along the aorta or vena cava, intraperitoneal, intra- hepatic, pulmonary, or at other distant sites? Making a distinction between local tumor bed recurrence and other sites of recurrence would be more informative for us in assessing the role of lymphadenectomy along with the in- fluence of microvascular and lymphatic in- vasion within the tumor. Now that several studies, including one from the University of Michigan3 and one from the German ACC study group,4 have shown that local recur- rence is decreased with the use of external beam radiation therapy, will routine use of ex- ternal beam radiation therapy negate the effect of decreased recurrence after regional lym- phadenectomy as defined by the authors, as it is customary for our radiation oncologists at the University of Michigan to cover draining lymphatic basins in the radiation field?
We would suggest a more precise def- inition of regional lymphadenectomy. The number of lymph nodes removed has been promoted for some tumor types (colon cancer, for example) to reflect the oncologic qual- ity of the operation and pathology assess- ment; however, for adrenal cancer, we believe that this information should be enhanced by recording from where these lymph nodes were obtained. This requires detailed operative re- ports, marking of specimens, and cooperation from pathologists to accurately report this in- formation. In this series, lymphadenectomy has been defined retrospectively by the num- ber of nodes removed and documented on pathology, rather than any attempt to clear a lymph node basin of soft tissue. Lymphatic vessels derive from 6 sacs at the points of junction of certain embryonic veins, includ- ing a retroperitoneal sac in the root of the mesentery near the adrenal glands. Lymphatic vessels emanate from the lymph sacs, and the lymph sacs are divided by connective tis-
sue bands and transformed into lymph glands. Surgeons experienced in resections for ACC who resect the tumor en bloc with all sur- rounding retroperitoneal fat know how few lymph nodes, sometimes none, are found in the specimen even when they are attempting to obtain lymph nodes for staging purposes. It is simply an area with few lymph nodes. Some of this may be dependent on the reviewing pathologist. With regard to right adrenalec- tomy and Figure 5, postoperative imaging re- veals that the dissection in most cases is car- ried out entirely posterior to the vena cava and many times to the left side of the vena cava, as much of the adrenal gland lies posterior to the vena cava. So, some soft tissue between the vena cava and aorta is removed as well, yet many times no lymph nodes are reported in the surgical specimen. The number of lymph nodes reported is also dependent on how care- fully the pathologist examines the submitted specimen.
As the results show, an increased num- ber of lymph nodes become apparent when adjacent organs were resected. Likely, these are not lymph nodes within the demarcated areas in Figure 5. More likely, these are lymph nodes posterior to the renal hilum or anterior to the aorta near the superior mesenteric artery (SMA) or celiac axis. It is possible that lym- phadenectomy for staging purposes should target the area near the SMA (at the base of the mesentery) for drainage from the adrenal gland in addition to the customarily removed tissue immediately adjacent to the adrenal gland in the fat-filled upper retroperitoneum, which harbors few if any lymph nodes. A fair number of lymph nodes can be found between the vessels of the renal hilum and may be a source of in-transit tumor as the adrenal vein and lymphatics course toward the left re- nal vein and many smaller venous tributaries that increase in ACC course toward the re- nal vessels on both sides. Because the ipsi- lateral kidney is one of the most frequently removed adjacent organs, it seems likely that “lymphadenectomy” in this series often re- flects removal of the renal hilum and its con- tained nodes during en bloc nephrectomy. The SMA and renal hila are not included in Fig- ure 5. In the case of distal pancreatectomy and splenectomy, there are a fair number of lymph nodes adjacent to these organs and in the gas- trosplenic ligament. If the transverse colon or splenic flexure is involved with tumor and resected en bloc, multiple lymph nodes are present in the colonic mesentery.
We also question whether the absolute number or fraction of positive lymph nodes makes a difference in outcome rather than considering only the total number of lymph nodes removed? In the group undergoing adrenalectomy alone, did the surgeon report an attempt to separate tumor from an adjacent
organ, thereby rubbing tumor cells off into the surrounding tissues when an en bloc resection should have been performed (this commonly occurs when surgeons inappropriately attempt to spare the kidney, liver, distal pan- creas, or spleen), and did this contribute to the difference in outcomes? These data may not be known if the surgeon does not accurately describe the conduct of the operation. As a final question, many patients both undergo resection for local tumor recurrence and undergo more than a single adjuvant or pallia- tive therapy. Statistically, how did the authors account for the likely increased length of sur- vival in patients who underwent re-resection?
Although the study of Reibetanz et al brings to the forefront an important issue that has not been well described because of the rarity of the disease, we believe that their outstanding database likely contains informa- tion to clarify these important questions. Lo-
cal recurrence may be impacted by removal of regional lymph nodes but may be miti- gated by XRT. Improved survival as reported in this study should be interpreted carefully. Broadening the area of dissection for regional lymphadenectomy should be considered to in- clude nodal basins based on vascular supply. It is our opinion that Figure 5 in the referenced article will provide few if any lymph nodes for examination in many cases. Dictated op- erative notes should indicate precise areas of dissection with regard to lymphadenectomy.
Barbra S. Miller, MD Division of Endocrine Surgery Section of General Surgery Department of Surgery University of Michigan Health System Ann Arbor, MI barbram@umich.edu
Gerard M. Doherty, MD Department of Surgery Boston University Boston, MA
REFERENCES
1. Reibetanz J, Jurowich C, Erdoga I, et al. Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma. Ann Surg. 2012;255:363-369.
2. Bilimoria KY, Shen WT, Elaraj D, et al. Adreno- cortical carcinoma in the United States: treat- ment utilization and prognostic factors. Cancer. 2008;113:3130-3136.
3. Sabolch A, Feng M, Griffith K, et al. Adjuvant and definitive radiotherapy for adrenocortical car- cinoma [published online ahead of print August 1, 2010]. Int J Radiat Oncol Biol Phys. 2011;80:1477- 1484.
4. Fassnacht M, Hahner S, Polat B, et al. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma [published online ahead of print August 8, 2006]. J Clin En- docrinol Metab. 2006;91:4501-4504.