- Email: [email protected]
The dark side of T1 non-appendiceal small bowel neuroendocrine tumors
The dark side of T1 non-appendiceal small bowel neuroendocrine tumours Zena Salih, Angela Lamarca, Daisuke Nonaka, Richard A Hubner, Nicola de Liguori-Carino, Mair´ead G McNamara, Paul Fulford, Annamaria Minicozzi, Sarah O’Dwyer, Bipasha Chakrabarty, Juan W Valle PII: DOI: Reference:
S0046-8177(17)30146-6 doi: 10.1016/j.humpath.2017.02.030 YHUPA 4208
To appear in:
Human Pathology
Received date: Accepted date:
28 January 2017 23 February 2017
Please cite this article as: Salih Zena, Lamarca Angela, Nonaka Daisuke, Hubner Richard A, de Liguori-Carino Nicola, McNamara Mair´ead G, Fulford Paul, Minicozzi Annamaria, O’Dwyer Sarah, Chakrabarty Bipasha, Valle Juan W, The dark side of T1 non-appendiceal small bowel neuroendocrine tumours, Human Pathology (2017), doi: 10.1016/j.humpath.2017.02.030
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT The dark side of T1 non-appendiceal small bowel neuroendocrine tumours.
T
Dear Editor,
RI P
We read with interest the article published by Walsh et al [1] and would like to congratulate the authors on their work. In their retrospective series, they presented 21 patients
SC
diagnosed with small (≤1 cm) ileal neuroendocrine tumours (NETs). Walsh et al reported that, although thought to have a benign behaviour due to small size, these tumours are still
MA NU
capable of lymph node (LN) spread in a high proportion of patients (67%). The rate of LN metastases increased with increasing T stage (T1 [33%], T2 [50%], T3 [50%]) and was up to 71% when only patients with LN assessment were included. This rate is higher than previously reported (rates between 40% and 60%) [2].
ED
The authors rightly point out that “a size of 2 cm is generally regarded as a cut-off
PT
point for risk of metastasis in NETs of the gastrointestinal tract. However, non-appendiceal small intestinal tumours are well recognised to behave more aggressively than NETs at other
CE
sites with the potential for metastasis in smaller lesions.” Based on this, most guidelines
AC
suggest curative resection of the primary tumour, including removal of locoregional lymph nodes for patients diagnosed with non-appendiceal small bowel well-differentiated NETs [3,4].
Although we agree with the above statements, we believe that the focus should be on the depth of invasion (T stage) rather than on size alone. In support of this, the current Tumour/Node/Metastasis (TNM) classification for small bowel (jejunum and ileum) NETs is mainly based on tumour depth of invasion. Thus, tumours measuring ≤1 cm can be classified as T2 or T3 according to whether they reach the muscularis propia or subserosa, respectively [5]. Malignancies that are T1 are those tumours ≤1 cm confined to the mucosa or submucosa
ACCEPTED MANUSCRIPT [5]. We hypothesise that the high rate of total lymph node metastases identified in the series by Walsh et al [1] is mainly due to the high number of T2 and T3 tumours included.
T
When considering patients with T1 tumours only, Walsh et al report 3 such patients in
RI P
their series (Table) [1]. In our institutional experience, 68 patients with well-differentiated small bowel NETs (appendiceal primary NETs were excluded from this search) were
SC
identified between March 2015 and January 2017; ≤1 cm and T1 small bowel NETs are rare events (5/68 [7.4%] and 3/68 [4.4%], respectively). Amongst the three patients with T1-stage
MA NU
disease, one patient (33%) was node negative, and one (33%) had LN involvement (in keeping with the results from Walsh et al, also 1/3 patients), and LN status was not assessed (no lymphadenectomy) in another (33%). A further detailed database search identified an
ED
additional two patients with T1N1 tumours at our centre (the characteristics are summarised in the Table, together with those from similar patients in the Walsh et al series [1]). A
PT
reliance on tumour size alone will miss patients who should have an oncological resection as tumours <1cm may range in stage from T1 to T3, and even patients with T1 disease may
CE
have involved LNs. This highlights the importance of all patients diagnosed with non-
AC
appendiceal small bowel NETs, with even small (≤1 cm) lesions that are T1 stage (regardless of grade) having lymphadenectomy at resection, as recommended in clinical practice guidelines [3,4].
We agree with the authors that even though these situations are unusual and rare, they should always be considered, and that all patients should undergo oncological resection with regional lymphadenectomy. Concerted multicentre efforts to identify these cases and data from long-term follow up using registries are vital to further refine the European Neuroendocrine Tumour Society classification system.
Zena Salih1,*,
ACCEPTED MANUSCRIPT Angela Lamarca Department of Medical Oncology, The Christie ENETS Centre of Excellence, Manchester,
RI P
T
UK
Daisuke Nonaka
MA NU
SC
Department of Pathology, The Christie ENETS Centre of Excellence, Manchester, UK
Richard A Hubner
ED
Department of Medical Oncology, The Christie ENETS Centre of Excellence, Manchester, UK
Nicola de Liguori-Carino
CE
PT
Department of Surgery, Central Manchester University Hospitals, Manchester, UK
Mairéad G McNamara
AC
Department of Medical Oncology, The Christie ENETS Centre of Excellence, Manchester, UK and Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
Paul Fulford Annamaria Minicozzi Sarah O’Dwyer Department of Surgery, The Christie ENETS Centre of Excellence, Manchester, UK
Bipasha Chakrabarty
ACCEPTED MANUSCRIPT Department of Pathology, The Christie ENETS Centre of Excellence, Manchester, UK
T
Juan W Valle
RI P
Department of Medical Oncology, The Christie ENETS Centre of Excellence, Manchester, UK, and Division of Molecular & Clinical Cancer Sciences, University of Manchester,
SC
Manchester Academic Health Science Centre, Manchester, UK
MA NU
E-mail address: [email protected]
References
[AU: degrees, postal codes?]
[1] Walsh JC, Schaeffer DF, Kirsch R, et al. Ileal “carcinoid” tumors—small size belies
ED
deadly intent: high rate of nodal metastasis in tumors ≤1 cm in size. HUM PATHOL
PT
2016;56:123-7.
[2] Soga J. Early stage carcinoids of the gastro-intestinal tract: an analysis of 1914 reported
CE
cases. Cancer 2005;103:1587-95.
AC
[3] Niederle B, Pape UF, Costa F, et al. ENETS consensus guidelines update for neuroendocrine neoplasms of the jejunum and ileum. Neuroendocrinology 2016;103:12538.
[4] Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 2010;39:753-66. [5] Rindi G, Klöppel G, Couvelard A et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007;451:757-62.
ACCEPTED MANUSCRIPT Table Summary of main characteristics of small bowel NETs diagnosed at T1 stage Patient Primary tumor Lymph node Gradea Size (mm)
Stage Assessed? Stage (I/A)
2
1
No
n/a
Walsh et al [1] 2 Ileum
3
1
No
n/a
Walsh et al [1] 3 Ileum
10
1
Yes
3
1
Yes
Salih 2
Ileum
5
1
Yes
Salih 3
Ileum
7
1
Yes
AC
CE
PT
ED
NOTE. Appendices were excluded. Abbreviations: n/a, not applicable; I, involved; A, assessed. a World Health Organisation classification.
G1
N1 (2/10)
G1
N1 (2/14)
G1
SC
Ileum
MA NU
Salih 1
G1
RI P
Walsh et al [1] 1 Ileum
T
Site
N1 (2/20)
G1
N1 (1/10)
G1
S0046-8177(17)30146-6 doi: 10.1016/j.humpath.2017.02.030 YHUPA 4208
To appear in:
Human Pathology
Received date: Accepted date:
28 January 2017 23 February 2017
Please cite this article as: Salih Zena, Lamarca Angela, Nonaka Daisuke, Hubner Richard A, de Liguori-Carino Nicola, McNamara Mair´ead G, Fulford Paul, Minicozzi Annamaria, O’Dwyer Sarah, Chakrabarty Bipasha, Valle Juan W, The dark side of T1 non-appendiceal small bowel neuroendocrine tumours, Human Pathology (2017), doi: 10.1016/j.humpath.2017.02.030
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT The dark side of T1 non-appendiceal small bowel neuroendocrine tumours.
T
Dear Editor,
RI P
We read with interest the article published by Walsh et al [1] and would like to congratulate the authors on their work. In their retrospective series, they presented 21 patients
SC
diagnosed with small (≤1 cm) ileal neuroendocrine tumours (NETs). Walsh et al reported that, although thought to have a benign behaviour due to small size, these tumours are still
MA NU
capable of lymph node (LN) spread in a high proportion of patients (67%). The rate of LN metastases increased with increasing T stage (T1 [33%], T2 [50%], T3 [50%]) and was up to 71% when only patients with LN assessment were included. This rate is higher than previously reported (rates between 40% and 60%) [2].
ED
The authors rightly point out that “a size of 2 cm is generally regarded as a cut-off
PT
point for risk of metastasis in NETs of the gastrointestinal tract. However, non-appendiceal small intestinal tumours are well recognised to behave more aggressively than NETs at other
CE
sites with the potential for metastasis in smaller lesions.” Based on this, most guidelines
AC
suggest curative resection of the primary tumour, including removal of locoregional lymph nodes for patients diagnosed with non-appendiceal small bowel well-differentiated NETs [3,4].
Although we agree with the above statements, we believe that the focus should be on the depth of invasion (T stage) rather than on size alone. In support of this, the current Tumour/Node/Metastasis (TNM) classification for small bowel (jejunum and ileum) NETs is mainly based on tumour depth of invasion. Thus, tumours measuring ≤1 cm can be classified as T2 or T3 according to whether they reach the muscularis propia or subserosa, respectively [5]. Malignancies that are T1 are those tumours ≤1 cm confined to the mucosa or submucosa
ACCEPTED MANUSCRIPT [5]. We hypothesise that the high rate of total lymph node metastases identified in the series by Walsh et al [1] is mainly due to the high number of T2 and T3 tumours included.
T
When considering patients with T1 tumours only, Walsh et al report 3 such patients in
RI P
their series (Table) [1]. In our institutional experience, 68 patients with well-differentiated small bowel NETs (appendiceal primary NETs were excluded from this search) were
SC
identified between March 2015 and January 2017; ≤1 cm and T1 small bowel NETs are rare events (5/68 [7.4%] and 3/68 [4.4%], respectively). Amongst the three patients with T1-stage
MA NU
disease, one patient (33%) was node negative, and one (33%) had LN involvement (in keeping with the results from Walsh et al, also 1/3 patients), and LN status was not assessed (no lymphadenectomy) in another (33%). A further detailed database search identified an
ED
additional two patients with T1N1 tumours at our centre (the characteristics are summarised in the Table, together with those from similar patients in the Walsh et al series [1]). A
PT
reliance on tumour size alone will miss patients who should have an oncological resection as tumours <1cm may range in stage from T1 to T3, and even patients with T1 disease may
CE
have involved LNs. This highlights the importance of all patients diagnosed with non-
AC
appendiceal small bowel NETs, with even small (≤1 cm) lesions that are T1 stage (regardless of grade) having lymphadenectomy at resection, as recommended in clinical practice guidelines [3,4].
We agree with the authors that even though these situations are unusual and rare, they should always be considered, and that all patients should undergo oncological resection with regional lymphadenectomy. Concerted multicentre efforts to identify these cases and data from long-term follow up using registries are vital to further refine the European Neuroendocrine Tumour Society classification system.
Zena Salih1,*,
ACCEPTED MANUSCRIPT Angela Lamarca Department of Medical Oncology, The Christie ENETS Centre of Excellence, Manchester,
RI P
T
UK
Daisuke Nonaka
MA NU
SC
Department of Pathology, The Christie ENETS Centre of Excellence, Manchester, UK
Richard A Hubner
ED
Department of Medical Oncology, The Christie ENETS Centre of Excellence, Manchester, UK
Nicola de Liguori-Carino
CE
PT
Department of Surgery, Central Manchester University Hospitals, Manchester, UK
Mairéad G McNamara
AC
Department of Medical Oncology, The Christie ENETS Centre of Excellence, Manchester, UK and Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
Paul Fulford Annamaria Minicozzi Sarah O’Dwyer Department of Surgery, The Christie ENETS Centre of Excellence, Manchester, UK
Bipasha Chakrabarty
ACCEPTED MANUSCRIPT Department of Pathology, The Christie ENETS Centre of Excellence, Manchester, UK
T
Juan W Valle
RI P
Department of Medical Oncology, The Christie ENETS Centre of Excellence, Manchester, UK, and Division of Molecular & Clinical Cancer Sciences, University of Manchester,
SC
Manchester Academic Health Science Centre, Manchester, UK
MA NU
E-mail address: [email protected]
References
[AU: degrees, postal codes?]
[1] Walsh JC, Schaeffer DF, Kirsch R, et al. Ileal “carcinoid” tumors—small size belies
ED
deadly intent: high rate of nodal metastasis in tumors ≤1 cm in size. HUM PATHOL
PT
2016;56:123-7.
[2] Soga J. Early stage carcinoids of the gastro-intestinal tract: an analysis of 1914 reported
CE
cases. Cancer 2005;103:1587-95.
AC
[3] Niederle B, Pape UF, Costa F, et al. ENETS consensus guidelines update for neuroendocrine neoplasms of the jejunum and ileum. Neuroendocrinology 2016;103:12538.
[4] Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 2010;39:753-66. [5] Rindi G, Klöppel G, Couvelard A et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007;451:757-62.
ACCEPTED MANUSCRIPT Table Summary of main characteristics of small bowel NETs diagnosed at T1 stage Patient Primary tumor Lymph node Gradea Size (mm)
Stage Assessed? Stage (I/A)
2
1
No
n/a
Walsh et al [1] 2 Ileum
3
1
No
n/a
Walsh et al [1] 3 Ileum
10
1
Yes
3
1
Yes
Salih 2
Ileum
5
1
Yes
Salih 3
Ileum
7
1
Yes
AC
CE
PT
ED
NOTE. Appendices were excluded. Abbreviations: n/a, not applicable; I, involved; A, assessed. a World Health Organisation classification.
G1
N1 (2/10)
G1
N1 (2/14)
G1
SC
Ileum
MA NU
Salih 1
G1
RI P
Walsh et al [1] 1 Ileum
T
Site
N1 (2/20)
G1
N1 (1/10)
G1