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 abbas.agaimy@uk-erlangen.de

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

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 Agaimy et al, unpublished

Submitted block from a „mets“ for molecular testing

primary GIST, not mets

difuse band-like interstitial cell of Cajal hyperplasia CD117

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.

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

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

Brother: grossly unremarkable intestinal wall CD117

Brother: appendix looked grossly like a giant diverticulum CD117

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

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.

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.

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

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).

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

Can we distinguish multifocal primary GIST from metastases by histology?

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

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

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, email from 2006)

Extragastrointestinal GIST versus mets? desmin desmin

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

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

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

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

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.

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

Mimics of hereditary GIST diseases

Rare lateral spreading of sporadic GIST may mimic hereditary disease

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

Sporadic GIST in a family are rare but documented Father 79 yo, gastric GIST; exon 11 V560del. Son 54 yo, gastric GIST; exon 11 V557-559del. Peripheral blood: no mutation.

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

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

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.

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