1. Abbas Agaimy, MD Erlangen, Germany
The 10th Arkadi M. Rywlin International Pathology Slide Seminar Symposium in Anatomic Pathology, May 21 – 23, 2018 Split, Croatia
CASE #23
Abbas Agaimy, MD Erlangen, Germany

2. Objectives of this case
Distinguish primary versus metastatic GIST.
Recognize features suggestive of hereditary versus sporadic disease.
Recognize value and limitations of genotyping.

3. CASE #23 Index patient (slide not submitted)
32 y/o female, no family history
2008: 2 intermediate risk intestinal GIST, no adjuvant therapy.
2013: multiple nodules (up to 5 mm) along intestine/cecum.
Clinical diagnosis: „disseminated metachronous mets“
One block sent for mutational testing before imatinib therapy.
Agaimy et al, unpublished

4. Submitted block from a „mets“ for molecular testing

7. primary GIST, not mets

9. difuse band-like interstitial cell of Cajal hyperplasia
CD117

10. Diagnosis Diffuse Cajal cell hyperplasia.
Multiple primary small GIST (0 risk; Miettinen et al).
No mets.
No indication for TKI therapy.
Findings highly suspicious for KIT germline mutation.

11. Molecular analysis of 2 nodules + normal tissue (after signed consent)
KIT exon 17
germline mutation
(N822Y)

12. January 2015: her brother diagnosed with cecal &
Diffuse linear ICC
hyperplasia
January 2015: her brother diagnosed with cecal &
appendiceal tumor + smaller nodules on intestinal wall
Her younger brother presented in January 2015 with large cecal tumor + intestinal nodules + appendix diverticulum
CD117
GIST cecum
Large cecal GIST

13. Brother: grossly unremarkable intestinal wall
CD117

14. Brother: appendix looked grossly like a giant diverticulum
CD117

15. Familial GIST syndrome due to KIT exon 17
Final Diagnosis
Familial GIST syndrome due to KIT exon 17
germline mutation
(N822Y)

16. Syndromes featuring GISTs
Type 1 neurofibromatosis (NF1 germline): most frequent cause.
SDH germline mutations: possibly 2nd most common but underdiagnosed.
KIT germline mutations: rare (some 40 families reported).
PDGFRA germline: exceedingly rare.

17. Familial GIST syndromes due to KIT germline mutations
To date, ̴ 40 families reported worldwide.
Overrepresentation of exon 13 (22%) & 17 (15%).
Multiple primary GIST at any GI site (age: <50 y).
Diffuse Cajal cell hyperplasia.
Pigment anomalies of skin/nevi (can be mistaken for NF1).
Urticaria pigmentosa (rare)/ cutaneous mastocytosis.
Dysphagia.

18. KIT exon 11 germline L576P (Neuhann et al, Li et al) Nevi-like skin pigmentation to activation of melanocytes

19. GIST – sporadic vs. Syndromic?
~ 10% associated with other neoplasms (incidental?)
~ 3-5% of sporadic GIST bifocal/oligofocal (field effect?)
~ 5% in syndromic setting (inherited or idiopathic).

20. Objective 1: Can we distinguish multifocal primary GIST from metastases by histology?

21. Can we distinguish multifocal primary GIST from metastases by histology?

22. Primary versus metastatic GIST?
Pedicle-like or intra-/intermuscular
Component highly specific for
Primary GIST

23. Primary versus metastatic GIST?
Primary: mainly on antimesenteric serosa
associated with external muscle layer.
Mets: mainly on fatty peritoneum
Primary: on serosa
Mets: mainly on fat
Li et al

24. Extragastrointestinal GIST versus mets?
Dear Dr. Agaimy, ……having read your paper, I agree that most of these (EGIST) are GIST that have lost their connection to the GI wall during late growth……
(Markku Miettinen, from 2006)

25. Extragastrointestinal GIST versus mets?
desmin
desmin

26. Recognize features suggestive of hereditary versus sporadic disease.
GIST originate from or differentiate similar to interstitial cells of Cajal (ICCs)
ICCs are KIT signalling
dependant.
Normal finding

27. Sporadic incidental microGIST of sigmoid surrounded by normal Auerbach plexus and normal interstitial cell of Cajal (ICCs) population
CD117: normal

28. Precursor lesions—difuse ICC hyperplasia: more consistent in germline KIT mutation than in NF1
Normal finding
Germline mutation

29. Segmental or multifocal nodular ICC hyperplasia (germline KIT, NF1 or possible mosaicism)
Rectal resection from undiagnosed Pt with KIT mut

30. Limited sensitivity of age & multifocality (Wozniak et al, Int J Cancer 2008)
52 y/o male with pararectal spindle cell sarcoma (CD117+).
4 yrs later bleeding endorectal tumor (similar histology).
Oncological diagnosis:
Disease progression
Put on Imatinib 400 mg/d: stable disease for 58 mo.
8 yrs later his 45 y/o brother with similar rectal tumor.

31. Limited sensitivity of age & multifocality (Wozniak et al, Int J Cancer 2008)
Mutational analysis of peripheral blood and tumors:
Same KIT exon 11 mutation (p.Q575_P577delinsH).
Final diagnosis: familial GIST syndrome caused by germline KIT exon 11 mutation.
Reappearance of GIST at same site might be a new primary

32. Mimics of hereditary GIST diseases

33. Rare lateral spreading of sporadic GIST may mimic hereditary disease

34. 2 primary gastric GIST in a 84 yo male; different mutations
Del K550-E554
Del K558-V559

35. Sporadic GIST in a family are rare but documented
Father 79 yo, gastric GIST; exon 11 V560del.
Son 54 yo, gastric GIST; exon 11 V del.
Peripheral blood: no mutation.

36. Algorithm for evaluation of multiple GIST nodules of unknown aetiology
Multiple GIST tumors
Typical involvement of muscularis propria
Site-typical histology and immunoprofile
Peritoneal location, M. propria not involved
Concordant histology/immunoprofile
High risk features
Distinct mutations
Similar mutations
All tumours wild-type
Similar mutations
+/- secondary mutations
Analysis of normal tissue
Wild-type sequence
Germline mutation
Exclude metastasis!
Multiple primary
sporadic GISTs
Multiple primary sporadic
GISTs with identical mutations
Familial GIST
syndromes
NF1 or other rare syndromes?
Metastatic disease
Agaimy et al, Virchows Arch, 2009

37. Algorithm for evaluation of multiple GIST nodules of unknown aetiology
Multiple GIST tumors
Typical involvement of muscularis propria
Site-typical histology and immunoprofile
Peritoneal location, M. propria not involved
Concordant histology/immunoprofile
High risk features
Distinct mutations
Similar mutations
All tumours wild-type
Similar mutations
+/- secondary mutations
Analysis of normal tissue
Wild-type sequence
Germline mutation
Exclude metastasis!
Multiple primary
sporadic GISTs
Multiple primary sporadic
GISTs with identical mutations
Familial GIST
syndromes
NF1 or other rare syndromes?
Metastatic disease
Agaimy et al, Virchows Arch, 2009

38. Take-home-message Suspect syndromic GIST if:
Unusual young age (<45 yrs!!!).
Multifocal disease or reappearance at same site.
Presence of precursor lesions (ICC hyperplasia)
Unusual or specific histology.
Association with certain tumor types.

39. Thank you for your attention
Sunrise, Nile province, Sudan
Pathol. Institute, Erlangen