Neuroendocrine tumors of GI and Pancreatobiliary tracts. N. Volkan Adsay, MD
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1 Neuroendocrine tumors of GI and Pancreatobiliary tracts N. Volkan Adsay, MD
2 New (2017) WHO
3 WHO 2017 (endocrine book; for pancreas)
4 WHO 2017 (endocrine book; for pancreas) PD-NE ca WD-NE Tumor Intended to be used also for GI NETs
5 Change # 1: Tumor vs Carcinoma further clarified (but still problematic)
6 I have a metastatic NE neoplasm in the liver, what do I call it?
7 How do we report a NET in the liver?
8 CASE: WD neuroendocrine neoplasm in the liver DIAGNOSIS: METASTATIC WELL-DIFFERENTIATED NEUROENDOCRINE TUMOR*, GRADE 1 Comment: This tumor is a WDNET. It is NOT a PD carcinoma (not a high grade neuroendocrine carcinoma). Mitotic activity is < 2/10 ; Ki67 < 2% (Grade 1 of 3).
9 Change #2: Ki67 > 20% can be tumor OR carcinoma
10 Change #3: Ki67 between 2 and 2.99 is G1 (not G2)
11 Change #3: Ki67 between 2 and 2.99 is G1 (not G2) ~ 15% of PanNETs fall to this 2-3% range (Reid, M. Modern Pathol, 2014)
12 WDNETs Diagnostic pitfalls
13 WDNET Diagnostic problems Crush artefacts (in biopsies) Atypical patterns Especially tubular patterns Chromogranin-A negativity (common in appendiceal and rectal ones)
14 Problem: Limited bx - Mucosal component can be small - Artifacts common
15 Degenerated gland appearance
16 Ampullary tumor: Original dx, adenoca. Pitfall: Glandular patterns
17 Ampullary somatostatinoma ( GLANDULAR psammomatous carcinoid )
18 Ampullary somatostatinoma Glandular psammomatous carcinoid Glandular pattern Psammoma bodies Neurofibromatosis LN metastasis in % (despite their small size )
19 Intraluminal mucin may be prominent, but no convincing intracytoplasmic mucin
20 Tubular WDNET (carcinoid) of appendix
21 PanNETs: Morphologic spectrum is wider than appreciated In addition to the classical nested and trabecular patterns
22 PanNETs: Nucleoli may be prominent on cytology
23 Lipid-rich PanNETs:
24 Oncocytic PanNETs: Probably more aggressive
25 Pleomorphic Variant of PanNET: Has no clinical significance Note single plasmacytoid cells and cells with focal degenerative endocrine atypia
26
27 CHROMOGRANIN CHROMATIN
28 Benign ducts can be prominent in PanNETs (NO significance) CK19 (good ductal marker)
29 Ductulo-insular PanNET
30 WDNETs Determinants of outcome; Reporting
31 Determinants of biologic behavior in GI WDNETs ( carcinoids ) 1. Location 2. Cell type 3. Clinical setting, syndromic background 4. Size (stage) 5. Grade 6. Adjunct histologic/biologic parameters
32 Most appendiceal classical WDNETs (carcinoid) are asymptomatic Most are microscopic; 2% of autopsies Most rectal ones are non-metastatic Most < 1 cm Ileal or colonic: Mets are common Most are advanced at diagnosis
33 Determinants of biologic behavior in NETs 1. Location 2. Cell type / hormonal status Most insulinomas are benign but they are also small at diagnosis (> 70% are < 1 cm). Most glucagonomas are malignant but they are also higher stage (large; >3 cm) at diagnosis 3. Clinical setting, syndromic background 4. Size (stage) 5. Grade 6. Adjunct histologic/biologic parameters
34 Determinants of biologic behavior in GI NETs ( carcinoids ) 1. Location 2. Cell type 3. Clinical setting, syndromic background 4. Size (stage) 5. Grade 6. Adjunct histologic/biologic parameters
35 The importance of clinical setting Example: Gastric NETs Type I (hypergastrinemia-related / ELC cell) Typically benign course Type II (ZE or MEN syndrome) Type III (Sporadic) Typically aggressive
36 Stomach- Enterochromaffin-like cell lesions Etiology Atrophic gastritis Medication Gastrinoma Hypo or achlorhydria Sustained hypergastrinemia Genetic factors? ELC Hyperplasia ELC Dysplasia ELC NET (carcinoid)
37 Enterochromaffin- like cell lesions in the stomach Hyperplasia Rare cells Linear Micronodular
38 Dysplasia Nodules > 150 microns Conglomerated micronodules Microinfiltration in the lamina propria New stroma ENETS /TNM proposal: Tis (In-situ tumor/dysplasia); Vanoli et al, Human Pathol, 2013
39 SP Report If it is all composed of tiny clusters Stomach, bx: ELC-cell proliferation in the background of atrophic gastritis If it also shows conglomerated, large clusters Minute WDNET of type A (see comment), arising in the background of ELC-cell proliferation and atrophic gastritis
40 Type A or type 1 carcinoid (NET)
41 The importance of clinical setting Example: Gastric NETs Type I (hypergastrinemia-related / ELC cell) Typically benign course Type II (ZE or MEN syndrome) Type III (Sporadic) Typically aggressive
42 Determinants of biologic behavior in NETs 1. Location 2. Cell type 3. Clinical setting, syndromic background 4. Stage (depth, size and mets) 5. Grade 6. Adjunct histologic/biologic parameters
43 Determinants of biologic behavior in GI NETs 1. Location 2. Cell type 3. Clinical setting, syndromic background 4. Size (stage) 5. Grade 6. Adjunct histologic/biologic parameters
44 WHO 2017 (endocrine book; for pancreas)
45 Problems with Ki67: How to count?
46 Problems with Ki67: How to count? 1. Refuse to count? 2. Eyeballing 3. Counting # of cells by live microscope 4. Have the machine count it (automated) 5. Have someone else count it 6. Counting # of cells by static field pictures from a computer
47 Problems with Ki67: How to count? 1. Refuse to count 2. Eyeballing (guess-timating)
48 Results of eye-balling of Ki67 index by 18 observers in 45 cases illustrates striking inter-observer variability (as well as grade variability)
49 Problems with Ki67: How to count? 1. Refuse to count 2. Eyeballing About 60 % of the cases have an index close to the categorical cut-offs: Only ~ 5% are in the extremes (< 1% and > 30%) Reid et al. Mod Pathol. 2014
50 Problems with Ki67: How to count? 1. Refuse to count 2. Eyeballing 3. Counting # of cells by live microscope
51 Problems with Ki67: How to count? 1. Refuse to count 2. Eyeballing 3. Counting # of cells by live microscope
52 Problems with Ki67: How to count? 1. Refuse to count 2. Eyeballing 3. Counting # of cells by live microscope 4. Have the machine count it (automated)
53 Problems with Ki67: How to count? 1. Refuse to count 2. Eyeballing 3. Counting # of cells by live microscope 4. Have the machine count it (automated) Machine also counts: Hemosiderin Lymphocytes Endothelial cells Etc
54 Problems with Ki67: How to count? 1. Refuse to count 2. Eyeballing 3. Counting # of cells by live microscope 4. Have the machine count it (automated) 5. Have someone else count it
55 Problems with Ki67: How to count? 1. Refuse to count 2. Eyeballing 3. Counting # of cells by live microscope 4. Have the machine count it (automated) 5. Have someone else count it Counting # of cells by static field pictures from a computer
56 Manual count on camera-captured-printed image is the most applicable approach (practical and accurate) in daily life
57
58
59 37 (pos) (37 pos neg) 10%
60 Current Surg Path Report Ileum; resection: - Well differentiated neuroendocrine tumor (classical carcinoid), Grade 1 of 3 in the WHO-2010 classification (see comment). Size: 2 cm Depth of invasion: Deep in muscularis propria VI: - ; PNI: - Margins: - LNs: 0/14. AJCC-stage: T2, N0; ENETS-Stage: T2, N0 Comment: - Mitotic activity: 1/10 HPF - Ki-67: 1.8 % - Neuroendocrine markers: Not performed (classical carcinoid)
61
62 Beyond WDNET. NET-3 vs PDNEC
63 Well-differentiated PanNET (2 examples)
64 (Morphologically) Well-differentiated but Ki67 > 20%
65 (Morphologically) Well-differentiated but Ki67 > 20%: [ GRADE DISCORDANT NE TUMOR] Diagnosis: Well-differentiated PanNE TUMOR, grade 3 of 3 by Ki67 proliferation index Comment: NET-3 (per WHO 2017) NOT a PDNEC Reference: Basturk et al, Am J Surg Pathol, 2014 Basturk et al, Am J Surg Pathol, 2015
66 Poorly differentiated NE carcinoma
67 IHC for confirming NE differentiation Chromogranin Synaptophysin CD56 (cautiously) But, NOT NSE or others It is advisable to have the support of at least one of these markers in order to distinguish true NECs from incomplete examples or its mimickers
68 PD NE carcinoma (ki67 typically > 50%) Diagnosis: Poorly differentiated neuroendocrine carcinoma Reference: Basturk et al, Am J Surg Pathol, 2014 Basturk et al, Am J Surg Pathol, 2015
69 Poorly diff NEC- Problem: DDx from other PD neoplasms Focal NE differentiation in the classical carcinomas. Poor prognosis? Poorly differentiated carcinoma, NOS Medullary carcinoma Basaloid/cloacogenic-type squamous ca Melanoma Sarcomas with epithelioid features
70 Poorly diff NEC- Problem: DDx from other PD neoplasms Focal NE differentiation in the classical carcinomas. Poor prognosis? Poorly differentiated carcinoma, NOS Medullary carcinoma Basaloid/cloacogenic-type squamous ca Melanoma Sarcomas with epithelioid features Any convincing NE component should be recognized and reported duly
71 Poorly diff NECs of GI/PB Often associated with conventional adenocarcinoma and adenoma component Most are not transformation of WD-NET Aggressive behavior (worse than ordinary carcinomas of respective sites). Small cell therapy protocol may work better than ordinary ca protocols (inadequate data).
72 And then there are the tougher ones
73
74 Ambiguous group : WD? PD? Ki %
75 Loss of RB; positivity of P53: PDNEC If present, loss of ATRX/DAXX: WDNET Rb loss Tang et al, Am J Surg Pathol Jun 1
76 Conclusions NENs can display unusual morphologies that ought to be kept in mind All NENs are malignant neoplasms (although incipient precursor lesions do occur but difficult to define) WDNETs ought to be graded and staged as any other malignancy WHO 2017 clearly distinguishes WDNET from PDNEC based on the morphology (not Ki67)
77 Conclusions Grade-discordant NETs (well-diff by morphology but Ki67> 20) now has a specific home as WDNET-G3 G3 NEN does NOT mean PDNEC Ambiguous cases (in between WDNET and PDNEC) do occur Associated w/ increased aggressive behavior relative to G1/2 tumors but better than G3 PDNEC New molecular/ihc markers (p53, Rb, DAXX, ATRX) can help with classification
78
79 CASE FOR DISCUSSION Appendiceal tumor: relatively intact wall; layers preserved
80 A subtle infiltrate of very well-formed glandular units
81 Composed of goblet cells; very similar to colonic crypts
82 Classical Goblet cell carcinoid Is it really a carcinoid? Chromogranin, only focal Ordinary carcinoid pattern is very very uncommon If low-grade/low-stage (confined to the appendix), behaves like a carcinoid (prognosis is good)
83 THIS CASE ALSO SHOWED Compressed, ill-defined, irregular glandular units
84 Areas with stromal mucin deposition was prominent
85 Mucin was associated with disorganized neoplastic cells
86 CHROMOGRANIN
87 CASE -Diagnosis ADENOCARCINOMA EX-GCC APPENDICEAL CRYPT CELL ADENOCARCINOMA WHO: Mixed GCC-adenocarcinoma
88
89 Distinctive features of adenoca ex GCC (appendiceal crypt cell adenocarcinoma) allow it to be recognized as an appendiceal primary even in metastatic sites: 1. Goblet cells (with voluminous pale-basophilic cytoplasm) 2. Crypt like structures 3. Small clusters of goblet cells 4. Microglandular units
90 Small glandular units composed of goblet type cells
91 Signet-ring like cells with voluminous cytoplasm, in small clusters: Most likely appendiceal (less likely gastric)
92 Especially if they form small, round glandular elements
93 Small round glands resembling crypts, even if without goblet cells: Still, highly suggestive of appendiceal origin
94 NEGATIVE < 10% 10-75% DIFFUSE (> 75%) Chromo Synapto CD
95 NEGATIVE < 10% 10-75% DIFFUSE (> 75%) Chromo Synapto CD Appendiceal crypt cell adenocarcinoma (Adenocarcinoma ex-goblet-cell- carcinoid ) is NOT a neuroendocrine tumor
96 Morphologic ddx is upper- GI (gastric) carcinoma signet-ring like cells small tubular configuration IHC: Lower-GI profile CDX2 98% MUC2-76% CK20-90% Upper GI markers mostly negative: (MUC1 11%, MUC5AC 20%, MUC6 2%; CK7 16%).
97 Conclusions NENs can display unusual morphologies that ought to be kept in mind All NENs are malignant neoplasms (although incipient precursor lesions do occur but difficult to define) WDNETs ought to be graded and staged as any other malignancy WHO 2017 clearly distinguishes WDNET from PDNEC based on the morphology (not Ki67)
98 Conclusions Grade-discordant NETs (well-diff by morphology but Ki67> 20) now has a specific home as WDNET-G3 G3 NEN does NOT mean PDNEC Ambiguous cases (in between WDNET and PDNEC) do occur Associated w/ increased aggressive behavior relative to G1/2 tumors but better than G3 PDNEC New molecular/ihc markers (p53, Rb, DAXX, ATRX) can help with classification
99 Conclusion Adenocarcinoma ex-gcc is NOT a neuroendocrine tumor per se, but rather an appendiceal type adenocarcinoma with cyrpt cell differentiation
100
101 Determining the site of origin of a metastatic NET Is it needed? Is it possible?
102 Determining the site of origin of a NET Often not possible; lots of overlaps Often not necessary WD-NET is a perfectly adequate diagnosis Don t be cornered by your clinicians to commit Imaging studies (octreotide scan and PET) and serologic studies (serotonin etc) are very successful in identifying the primary Having said that, few site-specific patterns do exist (and good to be aware of)
103 NET in the pancreas:
104
105 CDX2 Islet is negative
106 Isl1 (islet-1)
107 Ileal tumor resected subsequently
108 The current impression on the sitespecificity of the markers Yang et al, AJSP, July, 2017,
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