case report: gastric neuroendocrine neoplasma

1
case report gastric neuroendocrine neoplasma
Dimitrios Thomas, Endocrinologist
Endocrine Department, Pathophysiology Clinic,
Laikon Hospital, National and
Kapodistrian University of Athena
Laikon Hospital
2
Case report
? Female patient, 46 years old presented with
hematemesis (December 2003). Oesophago-gastro-duo
denoscopy (OGD) revealed peptic ulcer disease
(PUD), chronic gastritis, HP infection
mild hyperplasia. Medical management.
Previous medical history POF (37 years old), hypertension, osteoporosis, pernicious anemia Family history Coronary heart disease, hypertension, vitiligo, Hashimotos thyroiditis
Smoking (-), alcohol consumption (-) Allergy none
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Case report
Within the following month she relapsed
(hematemesis). 2nd OGD excision of a polypoid
lesion of the antrum.
HISTOLOGY CARCINOID TUMOR OF THE STOMACH
Abdominal computed tomography (CT) hepatic
metastases.
She underwent gastrectomy (Billroth-II) (January,
2004), LMN resection and surgical removal of 2
hepatic lesions.
4
Case report
HISTOLGY (report) Well diferentiated
neuroendocrine carcinoma, dmax3,5cm, tumor
penetrates gastric wall and serosa (stage
T3). Mitoses 0-3/10HPF, ki-67 2. No
vascular invasion or necrosis. 17 resected
LMNs were negative, but one from the celiac trunk
was invaded by the tumor. The two hepatic
metastatic foci had size of 5 and 2.3 mm in their
larger diameter and the proliferative index Ki-67
was found 8. ICH CgA, NSE, synaptophysin
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Case report
The patient was considered to suffer from
sporadic gastric carcinoid type-3 tumor, with LMN
and liver metastases. However, she was
followed-up in the immediate post-operative
period with serial CTs, magnetic resonance
imaging (MRI) and octreoscan, without any drugs
or chemotherapeutic regimens.
Single tumor, dmax3,5cm
LMN and liver metastases
Ki-67 2 (8 in hepatic lesions)
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Case report
Serial CTs were undertaken, firstly every 3
months and subsequently every 6 months. The
identified metastatic areas which were evident in
the first imaging studies were completely
resolved 3 years later. Octreoscan remained
negative in all following studies (2004, 2005).
2004 2007
7
Case report
The patient visited our Department (January 2007)
for further management. A full haematological and
biochemical investigation, neuroendocrine markers
and imaging study, at the time, did not show any
evidence of disease, but she had ? Increased
thyroid peroxidase (anti-TPO) and thyroglobulin
(anti-Tg) autoantibodies levels and ? Increased
anti-parietal cell antibodies (APCA).
8
Case report

• Because of her indolent course and regression of
  hepatic lesions a revision of the pathological
  report was requested. Furthermore, the following
  had to be further investigated
• Gastrin and CgA levels were not measured before
  the initial operation.
• APCA, anti-TPO and anti-Tg levels were increased
  post-surgically.
• ICH was strongly positive for CgA.
• The number of mitoses/HPF was relatively small.

9
Case report
REVISION OF PATHOLOGICAL REPORT Linear and
diffuse ECL hyperplasia (of fundus and body) and
positive ICH for CgA. G-cell hyperplasia (body
and pyloric mucosa) No multiple ulcers.
Chronic, atrophic body gastritis. Ki-67 1,5
? Based on recent ENETS guidelines, the tumor was
a stage IV, grade 1 well differentiated gastric
type-1 NEN.
Rindi G et al. Digestive and Liver Disease
2011. WHO 2010 classification.
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CASE REPORT
The patient remains well and healthy 10 years
after her primary surgery and she is followed-up
yearly with haematological and imaging studies,
without findings indicative of recurrence or
distant metastasis. ? OGD (yearly) mild
atrophy, HP infection ? Octreoscan (2008 ?a?
2013) normal findings. ? abdominal MRI
(/6months) and us (yearly) no evidence of tumor
relapse. ? Bone scan no pathological findings ?
Colonoscopy (2008, 2009, 2010, 2013) large bowel
polyps and diverticulosis, haemorrhoids. ? Bone
densitometry (yearly) ße?t??s? t?? T-score
(lumbar spine) -4,1 (2008), -2,9 (2014). ?
Biochemical tests, neuroendocrine makers
(/6months) B12 and iron deficiency.
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To summarize, the patient had
??tta?a ECL ECL ECL Non-ECL, PDECS, mixed
S?et??eta? µe ?????a at??f??? ?ast??t?da Gast????µa sta p?a?s?a s??d??µ?? ???-1 - -
?p?peda ?ast????? a???µ??a ????µ??a/p??? a???µ??a F?s???????? F?s????????
Gast???? pH ????µ??? ??att?µ??? F?s???????? F?s????????
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In addition
Obestatin ECLH
? G-cell and ECL hyperplasia ? No evidence for
MEN 1 syndrome ? low ki-67 (lt2) ? APCA, ?T?,
POF
diagnostic for gastric type-1 NEN Kaltsas G et
al. Clin Endocrinol 2014 Li TT et al. WJG
2014 Burkitt MD et al. Aliment Pharmacol Therap
2006
13
ALTHOUGH...
The patient presented with stage IV disease, she
is still alive, since deaths from gastric type-1
NENs are extremely rare.
Moreover, in a recently published study of 254
patients with gastric NEN, was observed that the
percentage of patients with LMN (4,7) or liver
(3,1) metastatic disease was low. Despite tumor
relapses no deaths were recorded during 82 months
follow-up period.
Thomas D et al. Eur J Endocrinol 2012
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Thank you for your attention!
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???sµ?s
????e?ta? ??a s?????? ?a?? d?af???p???µ??a, µ?
e????t??? ?e?p??sµata e?te?????µaf??????
??tt???? (ECL cells), p??e???µe?a ap? t?
ß?e??????? t?? st?µ???? (?????? t?? s?µat?? ?a?
t?? ?????), µe s?et??? ete?????e?a ?a? p??????
ß???????? s?µpe??f???. ? pa?a??te?? ?at?ta??
ßas???ta? st?? eµß????????? t??? p????e?s? ap?
t? p??s??? ??te?? (foregut), a?af????ta? ??
?a?????e?d? st?µ????, ? s?µe???? ?at?ta?? t???
pa?ap?µpe? st? ???a?? p????e?s?? (?e???e?d??????
?e?p??sµata st?µ????, ??? st?µ????)
Lung Thymus Stomach Duodenum Pancreas
18
??at?µ?a-?st?????a
?????te??? µ. st?ß?da
ß????a
T????
?????d???? ep??????
????????
t????µat???
Teµ???a ??ttta?a
pt????
???? µ. st?ß?da
G-??tta?a ECL ??tta?a (40) P/D1 ??tta?a
(20-30) D-??tta?a ECL ??tta?a-se??t?????
?e???e?d?????? ??tta?a (APUD) st?µ????. St?
?at?te?? 3µ???? t?? ?ast????? ß?e????????. 1,5
t?? ????? t?? ?ast????? ep???????.
19
? st?µa??s ?s (?e???)e?d???????? ???a??
?????? ??? ????G???? ???T?S?? ????GOG?S ??G??? S????S ???S?
Gast???? ??e???????? st?µ???? (?????? G-cells p???????? ??t???) ?a???s?a pept?d??? ?a? aµ??????? st? st?µa?? St?µa??? ?????s? ?ast????? ad????, ????s? st?µ????
Gast???? ??e???????? st?µ???? (?????? G-cells p???????? ??t???) ?a???s?a pept?d??? ?a? aµ??????? st? st?µa?? ?ept? ??te?? ????? s?st???
Gast???? ??e???????? st?µ???? (?????? G-cells p???????? ??t???) ?a???s?a pept?d??? ?a? aµ??????? st? st?µa?? ???e?t?f???? ßa?ß?da ???as?
Gast???? ??e???????? st?µ???? (?????? G-cells p???????? ??t???) ?a???s?a pept?d??? ?a? aµ??????? st? st?µa?? ?a?? ??te?? ?????e? µa????? ????se??
G??e???? ??e???????? st?µ???? (?????? ap? ta P/D1-cells) ??ste?a ?p????aµ?? ???µ?e? t?? p??s???? t??f?? (???µ?s? pe??a? ?a? ???esµ??)
?staµ??? ??e???????? st?µ???? (ECL-cells) ?a???s?a t??f?? st? st?µa?? St?µa??? ??e?e??e? ta t????µat??? ??tta?a ?a pa?????? HCL
Se??t????? ??e???????? st?µ???? (ECL-cells) ?a???s?a t??f?? st? st?µa?? St?µa??? S?spas? µ??? st?µ????
S?µat?stat??? ??e???????? p???????? ??t??? (a??? ?a? 12d??t???) ?a???s?a t??f?? st? st?µa?? ?a? s?µpa??t??? d???e?s? St?µa??? ?e??????e? t?? ?ast????? e????se??, t?? ????t???t?ta ?a? t?? ????s? t?? st?µ????
S?µat?stat??? ??e???????? p???????? ??t??? (a??? ?a? 12d??t???) ?a???s?a t??f?? st? st?µa?? ?a? s?µpa??t??? d???e?s? ?????ea? ?e??????e? t?? pa???eat???? e????se??
S?µat?stat??? ??e???????? p???????? ??t??? (a??? ?a? 12d??t???) ?a???s?a t??f?? st? st?µa?? ?a? s?µpa??t??? d???e?s? ?ept? ??te?? ??att??e? t?? a?µat??? ??? ?a? pe??????e? t?? ap????f?s? t??f??
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?a????µ?s? (Who 2010 classification)
ECL ??? t?p?? ?, ??, ??? (ta p?? s????)
?e???e?d?????e?? ????? (NETS), ?a??
d?af???p???µ???? (d???t??? ?a????e??)
non-ECL se??t?????, ?ast????, ACTH,
s?µat?stat??? (sp???a)a,ß,?,d
?e???e?d???????? ?a?????µata (NECs) pt???
d?af???p???µ??a (Poorly Differentiated Endocrine
Carcinomas, PDECs)e
?p? µ???? ??tta?a (SC) (6) p??? ep??et???,
e????st? ??tta??p?asµa, d????t? p??t?p?
a??pt????, a???µ???? de??t?? Ki-67
?p? µe???a ??tta?a (LC) ep?s?? ep??et???, µe
?f???? ??tta??p?asµa
???t? (Mixed Adeno-Neuroendocrine Carcinoma)
???t?? p????sµ?? ??tt???? (se d??f??e? a?a????e?)
aRindi J et al. Gastroenterology 1999 ßSoule JC
et al. Arch Fr Mal App Dig 1976 ?Hirata Y et al.
Cancer 1976 dPrachayakul V et al. Clin Endosc
2013 eNilsson O et al. Neuroendocrinology 2006
?. ?pe?p?as?a/d?sp?as?a (p??d??µe? ß??ße?)
Tumor-like lesions
21
??????????G??
Jao JC et al. J Clin Oncol 2008
? ?a ??? st?µ???? ap?te???? t? 4,1 ???? t?? ???
?a? t? 8,7 t?? ??? t?? ?ast?e?te????? (Modlin IM
et al, Cancer 1997).
? ? ep?pt?s? de?ap?as??st??e ta te?e?ta?a 30
?????a (ap? 0,03/100.000/?t?? t? 1975 se
0,4/100.000/?t?? t? 2005). ?e? ??e? d?e??????ste?
a? p???e?ta? ??a p?a?µat??? a???s? ? a?ta?a???
t?? a???µ??? ???s? ?e?ape??? µe a?t?????a, t??
e????? p??sßas? se µe??d??? e?d?s??p?s?? ? t??
ße?t??µ??e? te?????? ?st???????? d?????s??.
WHO 2000, Pathology and genetics of tumors of Digestive System ??p?? ? (70-80) ??p?? ?? (5-6) ??p?? ??? (14-25) PDECS (SC)
G??a??e?/??d?e? 21 11 12,8 1 2
??s? ?????a d?????s?? (e????) 63 (15-88) 50 (28-670 55 (2178) 63 (41-71)
22
ep?d?µ??????a

?e?p??sµata p?? pa?????? ?ast???? lt1 t?? ??? st?µ????. Se ?????e? 55-77 et??. Soule JC et al. Arch Fr Mal App Dig 1976
?e?p??sµata p?? pa?????? se??t????? ? ACTH ???? sp???a Quinonez G et al. Arch Pathol Lab Med 1998 Hirata Y et al. Cancer 1976
?e?p??sµata p?? pa?????? s?µat?stat??? ?pa?t??? s????te?a st? p????ea? ?a? st? 12d??t???, ???e? pe????afe?se? pe??pt?se?? st? st?µa??. S????te?a se ???a??e? (d?aß?t??, steat?????a, ????????as?, d??????e?) Prachayakul V et al. Clin Endosc 2013
23
??p?? ?e? st?µa???
??tta?a ECL ECL ECL Non-ECL, PDECS, mixed
S?et??eta? µe ?????a at??f??? ?ast??t?da Gast????µa sta p?a?s?a s??d??µ?? ???-1 - -
?p?peda ?ast????? a???µ??a ????µ??a/p??? a???µ??a F?s???????? F?s????????
Gast???? pH ????µ??? ??att?µ??? F?s???????? F?s????????
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?a???e?e?a-pa???????? f?s??????a
St??f? se ???e? µ??f?? ??tt????, d?ata?a?? t??
f?s????????? a?a????a? p????a/p??t?p?asµa
Burkitt MD et al. Aliment Pharmacol Therap 2006
25
?a???e?e?a-pa???????? f?s??????a
? pa???s?a ?pe?p?as?a? ECL ??tt???? se ?daf??
d?sp?ast???? ß?aß?? a????e? 26 f???? t?? ???d???
a??pt???? ECL ?e?p?as???1 ?a? ??????? µp??e? ?a
?d???se? st? ???es? ?e???e?d?????????
?e?p?asµ?t?? (NEN) st?µ???? (e?d??? t?p?? 1), se
p?s?st? 0,8-2,81,2,3.
Reg gene 1a BCL-2
1Annibale B et al. Eur J Gastroenterol Hepatol
2001 2Vannella L et al. Aliment pharmacol Ther
2011 3Sjoblom SM et al. Scand J Gastroenterol 1998
? ?pe?p?as?a ap? µ??? t?? de? fa??eta? ?a
p???a?e? ??? (Crosby DA et al, Digestive Surgery
2012)
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??T?G?????-??T???G??? F?S????G??
F?s???????? ep?????? F?s???????? pH F?s????????
?ast???? CgA-
??? st?µ???? t?p?? 3 ?a? 4

G???d?? ?e????? p
FHIT 3p14.2 gt0,05
RASSF1A 3p21.3 gt0,05
MEN1 11q13 gt0,05
p53 17p13.1 0,009
?p??e?a ete??????t?a? st?? pe????? 17p13.1 ?a? ?pe???f?as? t?? p53. ?p??e?a ete??????t?a? st?? pe????? 17p13.1 ?a? ?pe???f?as? t?? p53. ?p??e?a ete??????t?a? st?? pe????? 17p13.1 ?a? ?pe???f?as? t?? p53.
Pizzi S et l. Cancer 2003
27
??????? e????a
?? e?d??? s?µpt?µata a??t???? pept???? ?a?
d?e?e???s? a?a?µ?a? e??a? ?? s????te??? ????? p??
?d????? st? d?????s? NEN st?µ???? t?p?? 1, se
p?s?st? gt70. ???et?? as?e?e?? e??a?
as?µpt?µat????.
?t?p? ?a?????e?d?? s??d??µ? de? ?fe??eta? st?
se??t????? (?p?? sta ??? e?t????), a??? st??
5HTP, ? ?p??a de? µp??e? ?a µetat?ape? se
se??t?????. ?a?at??e?ta? ?????? flushing ?a?
t??a??e?a?tas?e? ?a? ????te?? s???? d??????e?.
Se as?e?e?? µe ??? st?µ???? t?p?? 2 ep???at???
s?µpt?µata p?? s?et????ta? µe t?? ?pe??????s?
?ast????? ap? ?????? (?ast????µata) ?????? st?
12d??t??? (ZE syndrome) ?ept??? ?????
(?p?t??p?????, a??e?t??? st? ?e?ape?a).
???????e?. St? 25 t?? as?e??? µp??e? ?a
s???p?????? ?a? s?µpt?µata ap? ???a ???a?a
pa?a???e?e?de?? (80-90), ?p?f?s? (30-60),
p????ea? (40-80) sta p?a?s?a t?? s??d??µ??
???-1 (???s??? a???µ???? ep?p??asµ?? ???
st?µ???? t?p?? 2 se ZES, a? t? te?e?ta??
d?a?????s?eta? sta p?a?s?a ???-1).
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??????? ??????
Se as?e?e?? µe ??? st?µ???? t?p?? 3 ?a? 4
ep???at??? s?µpt?µata p?? s?et????ta? µe
µe?a??te??? µe?????? d????t???? µ??e?, ?p??
?????a?? (ep???st???) ?????, ap??e?a
s?µat???? ß????? ?a? s?ßa?? a?µ???a??a
a??t???? pept????
Borch K et al. Ann Surg 2005
29
??a???s? (enets 2012)
? ??????? ?p???a, ?st????? ? ??d?s??p?s? a??t????
pept????, ß????e?, ?st??????? e??tas?ICH
S????????S? ?????µ???? de??t?? ?ast????,
CgA. ?p?peda APCA, B12, e????ßa?t???d??
p??????. ??t??s? ?ast????? pH?.
Burkitt MD et al. Aliment Pharmacol Therap 2006
30
??tas? ??s??-ape?????st???s e?e???s
??d?s??p???? ??e???? a??t???? pept???? S?????? e??a? a??et?? ??a NEN st?µ???? t?p?? 1 ?a? 2
??d?s??p??? ?pe???????f?µa G?a ??????gt1cm, p??? t?? e?d?s??p??? e?t?µ? t???
CTs, MRIs, SRS ?e? ??e?????ta? ??a ta ??? st?µ???? t?p?? 1, a??? µp??e? ?a e??a? ???s?µa ??a ta t?p?? 2, e?d??? sta p?a?s?a d?a???st???? p??s????s?? ??? 1.
CTs, MRIs, SRS ?pa?t???ta? ?ta? ?p???e? ?s???? ?p???a ? ??de??? µetastat???? ??s??, ?d?a?te?a se ??? st?µ???? t?p?? 3 ? 4
ENETS 2012 ENETS 2012
31
S?????????S?-??T??????S?
T4 tumor invades adjacent structures
32
S?????????S?-??T??????S?
33
S?????????S?-??T??????S?
?a??noµ?s? GEP-NET
WHO 2010 ?a?µ?p???s?
?e???e?d??????? ?e?p?asµa G1
?e???e?d??????? ?e?p?asµa G2
?e???e?d??????? ?a?????µa G3 ???????tta???? µe?a????ttta????
34
S?????????S?-??T??????S?
Ba?µ?? (grade) ???t???a
?aµ???? ?a????e?a? G1 lt2 ??t?se?? / 10 ?? ?a? lt3 ?i67
??d??µes?? ?a????e?a? G2 2-20 ??t?se?? / 10 ?? ? 3-20 ?i67
?????? ?a????e?a? G3 gt20 ??t?se?? / 10 ?? ? gt20 ?i67
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Te?ape?a-a?t?µet?p?s?
??? st?µ???? t?p?? 2 ?p?sd?p?te e?d?s??p???
e?t?µ?, a??? aµf?sß?te?ta? ? ap?te?esµat???t?t?
t?? se p???ap???? ?????? ta a?????a
s?µat?stat???? ap?te???? ep?????, e?d??? se
p???ap???? ?????? p?? de? e??a? d??at? ?
e?d?s??p??? t??? e?a??es? (Tomassetti P et al. N
Engl J Med 2000)
??? st?µ???? t?p?? 3 ?a? 4 ? a?t?µet?p?s? de?
d?af??e? ap? t?? a?t?st???? t??
ade???a?????µ?t?? Gast?e?t?µ? ?eµfade?????
?a?a??sµ?? ??µe???e?ape?a (DellE Fave G et al.
ENETS consensus guidelines for the management of
patients with gastroduodenal neoplasms 2012)
Se p??????µ??? ??s? PRRT, SSA (??a G1
??????) Cisplatinetoposide (??a G3
??????) (ENETS 2012)
Kaltsas G et al. Clin Endocrinol 2014
36
???G?OS?
??? st?µ???? t?p?? 1 (?at? t? d?????s?)
?eµfade????? µetast?se?? lt5 ap?µa???sµ??e?
µetast?se?? lt3 ???at?? (µ.? pa?a???????s?? 76
µ??e?, e???? 12-348) 0
??p?? 1 2
??p?? 3
??p?? 4
Borch K et al. Ann Surg 2005
Grozinsky-Glasberg S et al. WJG 2013. Thomas D
et al. Eur J Endocrinol 2012. Li TT et al. WJG
2014.
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???G?OS?