Review
1039
Updating the management of patients with rectal neuroendocrine tumors
Authors
Louis de Mestier1, Hedia Brixi1, Rodica Gincul2, Thierry Ponchon2, Guillaume Cadiot1
Institutions
1
submitted 30. January 2013 accepted after revision 11. July 2013
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1344794 Published online: 25.10.2013 Endoscopy 2013; 45: 1039– 1046 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Guillaume Cadiot, MD, PhD Department of Hepatogastroenterology and Digestive Oncology Robert-Debré University Hospital Avenue du Général Koenig 51092 Reims Cedex France Fax: +33-3-26784061 [email protected]
Department of Hepatogastroenterology and Digestive Oncology, University Hospital Robert-Debré, Reims, France Department of Hepatogastroenterology, Hospital Edouard Herriot, Lyon, France
Rectal neuroendocrine tumors (NETs) account for approximately one-third of all digestive NETs, with an increasing incidence and good overall prognosis. Although recent guidelines have been published, endoscopic techniques have expanded substantially and the most recent reports should be taken into account for clinical practice. The ob-
jectives of this report were to review the latest advances on prognosis, pre-interventional explorations, treatment– with particular focus on endoscopy – and surveillance of well-differentiated rectal NETs, excluding poorly differentiated and metastatic tumors.
Introduction
accounting for 2 % – 5 % [1, 2, 7]. Avenel et al. reported that 73 % of 50 rectal carcinoid cases were asymptomatic and were diagnosed during screening colonoscopies [3]. All tumors were < 20 mm in diameter (mean size 8.9 mm) and 96 % were at a localized stage. Rectal NETs are generally solitary, set in the wall, often polypoid, and small submucosal nodules. Because the diagnosis is mostly suspected during endoscopy, local excision is commonly performed without biopsy, and therefore diagnosis is usually confirmed after endoscopic resection. Alternatively, tumors are biopsied and marked for future removal. The European Neuroendocrine Tumors Society (ENETS) recently published consensus guidelines for the management of patients with colorectal neuroendocrine neoplasms [7]. However, several reports on endoscopic techniques have been published since the guidelines were issued and should therefore be taken into account for practical NET management. This review highlights the prognostic factors of rectal NETs (excluding poorly differentiated and metastatic tumors, the prognoses of which are similar to that of adenocarcinomas [12]) and the latest advances in their management. In particular, the latest insights in preinterventional procedures, resection techniques, long-term results, additional investigations, and salvage therapies are described and discussed.
!
Rectal neuroendocrine tumors (NETs) account for approximately one-third of all digestive NETs, and are almost as frequent as ileal NETs [1 – 8]. In the most recent surveillance, epidemiology, and end results (SEER) analysis, the rectum was the second most common location of digestive NETs (34.6 %) after the small intestine (36.5 %) [2]. The most informative data may come from a prospective cohort including almost all cases of Austrian digestive NETs over 1 year [9]. The rectum was the fourth location (n = 40, 15.4 %) of all digestive NETs. A total of 26 (65 %), 9, and 5 tumors were classified as benign, uncertain, and malignant (1 well and 4 poorly differentiated) tumors, respectively [9]. Asian series showed higher frequencies of rectal NETs (approximately 50 %), which might be a reflection of more frequent screening and ethnic factors [10, 11]. However, the real incidence may be underestimated, as all benign rectal carcinoids are not systematically reported in registers. According to SEER data, the rise of the incidence of rectal NETs has been one of the highest among all NETs over the past few decades [1, 2]. This rise may be linked to the expansion of colorectal cancer screening, improved detection through recent endoscopic developments, and better clinical awareness. A consequence of this enhanced detection is that rectal carcinoids are now predominantly detected at an early stage. Regional and metastatic spreading are uncommon at the time of diagnosis, each
de Mestier Louis et al. Management of rectal NETs … Endoscopy 2013; 45: 1039–1046
Downloaded by: University of Arizona Library. Copyrighted material.
2
Review
Table 1 Main factors predicting metastases in patients with rectal neuroendocrine tumors.
Predictive factor [ref]
Odds ratio
95 % confidence interval
Tumor size > 14 mm [16]
57.5
23.3 – 1002.6
vival was 100 % [16]. Although muscularis invasion was not evaluated in this study, it appeared to be a significant prognostic fac" Table 1). tor in another study [20] (●
Mitotic index ≥ 2 /10 HPF [16]
56.2
2.4 – 1295.8
Pre-interventional explorations
Lymphovascular invasion [16]
65.1
1.1 – 3846.7
!
Muscularis layer invasion [20]
37.9
5.0 – 290
ENETS and recent expert reviews have defined the recommended pre-interventional explorations [7, 13, 16]. The approach de" Fig. 1). pends on how the diagnosis is made (● When biopsies are taken before excision, pre-interventional endoscopic ultrasonography (EUS) should be performed systematically to evaluate the precise tumor size, depth (especially invasion of the muscularis layer), and lymph node invasion [6, 7, 13, 23 – 25]. The accuracy of EUS determination of the invasion depth is high (91 % – 100 %) [16, 24, 26]. Pelvic magnetic resonance imaging (MRI) (otherwise, computed tomography [CT] scan) is recommended for tumors ≥ 10 mm in diameter [7]. Octreotide scintigraphy should be performed for well-differentiated tumors ≥ 20 mm in diameter (ENETS/WHO T2/T3/T4) [7]. When the tumor is first resected endoscopically and the diagnosis is confirmed retrospectively, the explorations required depend on the predictive risk of local/distant recurrence. No additional testing is recommended for rectal NETs < 10 mm with low risk predictive factors (ENETS/WHO T1a) [7, 13]. In cases of high risk factors predictive of metastases, EUS should be performed to search for residual tumor and suspicious lymph nodes. MRI should be considered in this setting and is recommended when the tumor has not been removed completely [7, 16]. Finally, colonoscopy is recommended for all patients with rectal NETs, in order to exclude concomitant colonic cancer and possible synchronous colorectal NET.
HPF, high-power field.
Prognostic factors !
Disease stage is the main prognostic factor of rectal NETs [1, 7, 8]. The 5-year overall survival rates are 94 % – 100 %, 54 % – 74 %, and 15 % – 37 % for patients with localized (ENETS/World Health Organization (WHO) stages I/II/IIIa), nodal-positive (ENETS/WHO stage IIIb), and metastatic (ENETS/WHO stage IV) rectal NETs, respectively [1, 13]. Reported risk factors for metastases are tumor size, depression in or ulceration of the lesion, muscularis invasion, histoprognostic grade (proliferation and mitotic index), and lymphovascular invasion [4, 7, 12 – 21]. The risk of metastases has been reported to be 0 % – 10 %, 4 % – 30 %, and 57 % – 80 % for tumors < 10 mm, 10 – 19 mm, and ≥ 20 mm in diameter, respectively [15, 22]. However, previous studies differ too much to enable pooled analysis of all prognostic factors and the determination of meaningful relative risks. In the largest prognostic study on rectal NETs (n = 347) [16], independent factors predictive of metastasis retained by multivariate analysis were size > 14 mm, mitotic rate ≥ 2 /10 high-power fields (HPF), and lymphovascular invasion " Table 1). In the absence of the other factors predictive of me(● tastases, the optimal cut-off size to predict the metastatic risk was 14 mm (receiver operating characteristics curve, 100 % sensitivity and 92 % specificity). Ulceration and central depression were not retained as significant predictors of metastases in the analysis. Patients without any factors predictive of metastases had no lymph node or distant metastasis and their 3-year overall sur-
Rectal NET
Primary resection
Primary biopsy
Histologically confirmed diagnosis
Histologically confirmed diagnosis EUS
Size 20/10 HPF should always be subjected to regional and distant follow-up, as for other aggressive digestive NETs.
de Mestier Louis et al. Management of rectal NETs … Endoscopy 2013; 45: 1039–1046
Fig. 3 Endoscopic submucosal dissection of a residual rectal neuroendocrine tumor after primary polypectomy. a Electrocautery dots (ICC200, ERBE, Tübingen, Germany) using a dual knife (Olympus, Tokyo, Japan), indicating the minimal internal circumference of the lesion to assure an adequate safety margin. b First circumferential incision along the outer perimeter of the marking dots, after saline injection. c Directly visualized dissection along the submucosal plane, using the dual knife. d Endoscopic appearance after dissection.
Downloaded by: University of Arizona Library. Copyrighted material.
1044
Conclusions !
Although rectal NETs are still rare tumors, their incidence has increased during the past few decades. This rise is linked to the increasing number of colonoscopies, which have mostly enabled their diagnoses at an early stage. Risk factors for future relapse and/or metastases are becoming better characterized: tumor size ≥ 10 mm (and probably ≥ 15 mm in the absence of other risk factors), mitotic index ≥ 2/10 HPF, and muscularis propria and/or lymphovascular invasion. EUS is the most accurate technique for pre-therapeutic determination of the invasion depth. Endoscopic resection is recommended for low risk rectal carcinoids, and ESMR-L and ESD are techniques that are better adapted than standard polypectomy. Surgical excision should be performed for high risk tumors. In the case of incomplete resection margins following local excision, transanal resection (e. g. TEM) or radical surgery has to be considered, except for tumors with low predictive risk of metastases. Other than small well-differentiated rectal NETs, these tumors have substantial risk of relapse and/or spreading, and must be followed for at least 5 years. However, the long-term evolution of rectal NETs remains to be specified in order to determine the relevance of their current management strategies. Competing interests: None
Acknowledgment !
The authors thank Mrs. Janet Jacobson for technical assistance in the preparation of the manuscript.
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49 Kajiyama T, Hajiro K, Sakai M et al. Endoscopic resection of gastrointestinal submucosal lesions: a comparison between strip biopsy and aspiration lumpectomy. Gastrointest Endosc 1996; 44: 404 – 410 50 Anthony LB, Strosberg JR, Klimstra DS et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (NETs): well-differentiated NETs of the distal colon and rectum. Pancreas 2010; 39: 767 – 774 51 Shida T, Aminaka M, Shirai Y et al. Endoscopic submucosal dissection with a ligation device for the treatment of rectal carcinoid tumor. Endoscopy 2012; 44 Suppl 2: E4 – E5 52 Jeong WK, Park JW, Choi HS et al. Transanal endoscopic microsurgery for rectal tumors: experience at Korea’s National Cancer Center. Surg Endosc 2009; 23: 2575 – 2579 53 Kinoshita T, Kanehira E, Omura K et al. Transanal endoscopic microsurgery in the treatment of rectal carcinoid tumor. Surg Endosc 2007; 21: 970 – 974 54 Suzuki H, Furukawa K, Kan H et al. The role of transanal endoscopic microsurgery for rectal tumors. J Nihon Med Sch 2005; 72: 278 – 284 55 Kumar AS, Sidani SM, Kolli K et al. Transanal endoscopic microsurgery for rectal carcinoids: the largest reported United States experience. Colorectal Dis 2012; 14: 562 – 566 56 Colonoscopy Study Group of Korean Society of Coloproctology. Clinical characteristics of colorectal carcinoid tumors. J Korean Soc Coloproctol 2011; 27: 17 – 20 57 Bensoussan M, Lamarque D, Dousset B et al. [What is the place of the endoscopic treatment in the endocrine tumors of the rectum? ] Gastroenterol Clin Biol 2008; 32: 985 – 988 58 Jeon SM, Lee JH, Hong SP et al. Feasibility of salvage endoscopic mucosal resection by using a cap for remnant rectal carcinoids after primary EMR. Gastrointest Endosc 2011; 73: 1009 – 1014 59 Hurlstone DP, Shorthouse AJ, Brown SR et al. Salvage endoscopic submucosal dissection for residual or local recurrent intraepithelial neoplasia in the colorectum: a prospective analysis. Colorectal Dis 2008; 10: 891 – 897 60 Merg A, Wirtzfeld D, Wang J et al. Viability of endoscopic and excisional treatment of early rectal carcinoids. J Gastrointest Surg 2007; 11: 893 – 897
de Mestier Louis et al. Management of rectal NETs … Endoscopy 2013; 45: 1039–1046
Downloaded by: University of Arizona Library. Copyrighted material.
1046
1039
Updating the management of patients with rectal neuroendocrine tumors
Authors
Louis de Mestier1, Hedia Brixi1, Rodica Gincul2, Thierry Ponchon2, Guillaume Cadiot1
Institutions
1
submitted 30. January 2013 accepted after revision 11. July 2013
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1344794 Published online: 25.10.2013 Endoscopy 2013; 45: 1039– 1046 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Guillaume Cadiot, MD, PhD Department of Hepatogastroenterology and Digestive Oncology Robert-Debré University Hospital Avenue du Général Koenig 51092 Reims Cedex France Fax: +33-3-26784061 [email protected]
Department of Hepatogastroenterology and Digestive Oncology, University Hospital Robert-Debré, Reims, France Department of Hepatogastroenterology, Hospital Edouard Herriot, Lyon, France
Rectal neuroendocrine tumors (NETs) account for approximately one-third of all digestive NETs, with an increasing incidence and good overall prognosis. Although recent guidelines have been published, endoscopic techniques have expanded substantially and the most recent reports should be taken into account for clinical practice. The ob-
jectives of this report were to review the latest advances on prognosis, pre-interventional explorations, treatment– with particular focus on endoscopy – and surveillance of well-differentiated rectal NETs, excluding poorly differentiated and metastatic tumors.
Introduction
accounting for 2 % – 5 % [1, 2, 7]. Avenel et al. reported that 73 % of 50 rectal carcinoid cases were asymptomatic and were diagnosed during screening colonoscopies [3]. All tumors were < 20 mm in diameter (mean size 8.9 mm) and 96 % were at a localized stage. Rectal NETs are generally solitary, set in the wall, often polypoid, and small submucosal nodules. Because the diagnosis is mostly suspected during endoscopy, local excision is commonly performed without biopsy, and therefore diagnosis is usually confirmed after endoscopic resection. Alternatively, tumors are biopsied and marked for future removal. The European Neuroendocrine Tumors Society (ENETS) recently published consensus guidelines for the management of patients with colorectal neuroendocrine neoplasms [7]. However, several reports on endoscopic techniques have been published since the guidelines were issued and should therefore be taken into account for practical NET management. This review highlights the prognostic factors of rectal NETs (excluding poorly differentiated and metastatic tumors, the prognoses of which are similar to that of adenocarcinomas [12]) and the latest advances in their management. In particular, the latest insights in preinterventional procedures, resection techniques, long-term results, additional investigations, and salvage therapies are described and discussed.
!
Rectal neuroendocrine tumors (NETs) account for approximately one-third of all digestive NETs, and are almost as frequent as ileal NETs [1 – 8]. In the most recent surveillance, epidemiology, and end results (SEER) analysis, the rectum was the second most common location of digestive NETs (34.6 %) after the small intestine (36.5 %) [2]. The most informative data may come from a prospective cohort including almost all cases of Austrian digestive NETs over 1 year [9]. The rectum was the fourth location (n = 40, 15.4 %) of all digestive NETs. A total of 26 (65 %), 9, and 5 tumors were classified as benign, uncertain, and malignant (1 well and 4 poorly differentiated) tumors, respectively [9]. Asian series showed higher frequencies of rectal NETs (approximately 50 %), which might be a reflection of more frequent screening and ethnic factors [10, 11]. However, the real incidence may be underestimated, as all benign rectal carcinoids are not systematically reported in registers. According to SEER data, the rise of the incidence of rectal NETs has been one of the highest among all NETs over the past few decades [1, 2]. This rise may be linked to the expansion of colorectal cancer screening, improved detection through recent endoscopic developments, and better clinical awareness. A consequence of this enhanced detection is that rectal carcinoids are now predominantly detected at an early stage. Regional and metastatic spreading are uncommon at the time of diagnosis, each
de Mestier Louis et al. Management of rectal NETs … Endoscopy 2013; 45: 1039–1046
Downloaded by: University of Arizona Library. Copyrighted material.
2
Review
Table 1 Main factors predicting metastases in patients with rectal neuroendocrine tumors.
Predictive factor [ref]
Odds ratio
95 % confidence interval
Tumor size > 14 mm [16]
57.5
23.3 – 1002.6
vival was 100 % [16]. Although muscularis invasion was not evaluated in this study, it appeared to be a significant prognostic fac" Table 1). tor in another study [20] (●
Mitotic index ≥ 2 /10 HPF [16]
56.2
2.4 – 1295.8
Pre-interventional explorations
Lymphovascular invasion [16]
65.1
1.1 – 3846.7
!
Muscularis layer invasion [20]
37.9
5.0 – 290
ENETS and recent expert reviews have defined the recommended pre-interventional explorations [7, 13, 16]. The approach de" Fig. 1). pends on how the diagnosis is made (● When biopsies are taken before excision, pre-interventional endoscopic ultrasonography (EUS) should be performed systematically to evaluate the precise tumor size, depth (especially invasion of the muscularis layer), and lymph node invasion [6, 7, 13, 23 – 25]. The accuracy of EUS determination of the invasion depth is high (91 % – 100 %) [16, 24, 26]. Pelvic magnetic resonance imaging (MRI) (otherwise, computed tomography [CT] scan) is recommended for tumors ≥ 10 mm in diameter [7]. Octreotide scintigraphy should be performed for well-differentiated tumors ≥ 20 mm in diameter (ENETS/WHO T2/T3/T4) [7]. When the tumor is first resected endoscopically and the diagnosis is confirmed retrospectively, the explorations required depend on the predictive risk of local/distant recurrence. No additional testing is recommended for rectal NETs < 10 mm with low risk predictive factors (ENETS/WHO T1a) [7, 13]. In cases of high risk factors predictive of metastases, EUS should be performed to search for residual tumor and suspicious lymph nodes. MRI should be considered in this setting and is recommended when the tumor has not been removed completely [7, 16]. Finally, colonoscopy is recommended for all patients with rectal NETs, in order to exclude concomitant colonic cancer and possible synchronous colorectal NET.
HPF, high-power field.
Prognostic factors !
Disease stage is the main prognostic factor of rectal NETs [1, 7, 8]. The 5-year overall survival rates are 94 % – 100 %, 54 % – 74 %, and 15 % – 37 % for patients with localized (ENETS/World Health Organization (WHO) stages I/II/IIIa), nodal-positive (ENETS/WHO stage IIIb), and metastatic (ENETS/WHO stage IV) rectal NETs, respectively [1, 13]. Reported risk factors for metastases are tumor size, depression in or ulceration of the lesion, muscularis invasion, histoprognostic grade (proliferation and mitotic index), and lymphovascular invasion [4, 7, 12 – 21]. The risk of metastases has been reported to be 0 % – 10 %, 4 % – 30 %, and 57 % – 80 % for tumors < 10 mm, 10 – 19 mm, and ≥ 20 mm in diameter, respectively [15, 22]. However, previous studies differ too much to enable pooled analysis of all prognostic factors and the determination of meaningful relative risks. In the largest prognostic study on rectal NETs (n = 347) [16], independent factors predictive of metastasis retained by multivariate analysis were size > 14 mm, mitotic rate ≥ 2 /10 high-power fields (HPF), and lymphovascular invasion " Table 1). In the absence of the other factors predictive of me(● tastases, the optimal cut-off size to predict the metastatic risk was 14 mm (receiver operating characteristics curve, 100 % sensitivity and 92 % specificity). Ulceration and central depression were not retained as significant predictors of metastases in the analysis. Patients without any factors predictive of metastases had no lymph node or distant metastasis and their 3-year overall sur-
Rectal NET
Primary resection
Primary biopsy
Histologically confirmed diagnosis
Histologically confirmed diagnosis EUS
Size 20/10 HPF should always be subjected to regional and distant follow-up, as for other aggressive digestive NETs.
de Mestier Louis et al. Management of rectal NETs … Endoscopy 2013; 45: 1039–1046
Fig. 3 Endoscopic submucosal dissection of a residual rectal neuroendocrine tumor after primary polypectomy. a Electrocautery dots (ICC200, ERBE, Tübingen, Germany) using a dual knife (Olympus, Tokyo, Japan), indicating the minimal internal circumference of the lesion to assure an adequate safety margin. b First circumferential incision along the outer perimeter of the marking dots, after saline injection. c Directly visualized dissection along the submucosal plane, using the dual knife. d Endoscopic appearance after dissection.
Downloaded by: University of Arizona Library. Copyrighted material.
1044
Conclusions !
Although rectal NETs are still rare tumors, their incidence has increased during the past few decades. This rise is linked to the increasing number of colonoscopies, which have mostly enabled their diagnoses at an early stage. Risk factors for future relapse and/or metastases are becoming better characterized: tumor size ≥ 10 mm (and probably ≥ 15 mm in the absence of other risk factors), mitotic index ≥ 2/10 HPF, and muscularis propria and/or lymphovascular invasion. EUS is the most accurate technique for pre-therapeutic determination of the invasion depth. Endoscopic resection is recommended for low risk rectal carcinoids, and ESMR-L and ESD are techniques that are better adapted than standard polypectomy. Surgical excision should be performed for high risk tumors. In the case of incomplete resection margins following local excision, transanal resection (e. g. TEM) or radical surgery has to be considered, except for tumors with low predictive risk of metastases. Other than small well-differentiated rectal NETs, these tumors have substantial risk of relapse and/or spreading, and must be followed for at least 5 years. However, the long-term evolution of rectal NETs remains to be specified in order to determine the relevance of their current management strategies. Competing interests: None
Acknowledgment !
The authors thank Mrs. Janet Jacobson for technical assistance in the preparation of the manuscript.
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