Ma Many Fa Faces of of Neur Neuroendocr oendocrine Neoplasms Neoplasms (Gas (Gastr troen oenteric eric and and Pa Pancreatic) Authors: Maryam Zenali MD & Ramin Zargham MD PhD Pre Presen enter ters: Liam Liam Do Donn nnelly lly MD MD and and Rami Ramin Za Zargham ham MD MD PhD PhD NECLA meeting October 2018 DISCLOSURE: Is there anything to disclose? No
Overview • NET, NEC, MANEN, all NE but: Different histomorphology Diagnostic methods Progression rate Treatment options
Case presentation • 58 y.o women presents with vomiting, diarrhea without abdominal pain, fevers, a travel history. Complains of large volume diarrhea that is tea colored that is more than 1L per day. The diarrhea occurs during the day and at night. • Vitals: tachycardia, low blood pressure, • Labs: hypokalemia, metabolic acidosis, hypercalcemia.
• Additional studies: secretory diarrhea (low osmotic gap), bacterial cultures negative VIP (vasoactive intestinal peptide): elevated
GE ‐ NE Neoplasms Classifications • Embryologic ‐ based (foregut/midgut/hindgut, Sandler/ Williams 1960s) and tumor ‐ based classification (size, LVI, type of hormone production, proliferation, localization and differentiation WHO 2000) revised due to incomplete prediction capacity • WHO 2000 1 ‐ well differentiated endocrine tumor (WDNET), 2 ‐ well ‐ differentiated endocrine carcinoma (WDEC) , 3 ‐ poorly differentiated endocrine carcinoma/small ‐ cell carcinoma (PDEC), 4 ‐ mixed exocrine–endocrine carcinoma (MECC), 5 ‐ tumor ‐ like lesions • WHO 2010 1 ‐ NET G1 (WDET or WDEC according to staging), 2 ‐ NET G2 (WDET or WDEC according to staging), 3 ‐ NEC G3 (PDEC), 4 ‐ Mixed exocrine–endocrine carcinoma, MANEC (Now proposed MANEN)
Neuroendocrine Tumors (NET) • 1907: Oberndorfer published a specific neoplastic entity, term carcinoid, broadly successful • Not quiet like conventional cancers “carcinoid”, rare and possibly benign • 1964: Unveil of amine precursors uptake and decarboxylation (APUD) properties of GI tract, now carcinoids defined as apudoma by Pearse • Again sounding alike… mimicking adenoma and thus a benign nature
Chromogranin A • Chromogranin A (CGA) is an amino • Serum CGA used in conjunction acid protein with, or alternative to serum or whole blood serotonin, urine • A member of the Granin family of serotonin, and urine 5 ‐ HIAA and proteins and polypeptides, found in imaging studies, in patients with secretory granules alongside the suggestive carcinoid syndrome, i.e. tissue ‐ specific secretion products with flushing • Being ubiquitous within • It can also serve as a sensitive neuroendocrine tissues, CGA is a mean for follow ‐ up of patients with useful marker for neuroendocrine known or treated carcinoid tumors neoplasms, including carcinoids, to gauge recurrence or residual functioning and nonfunctioning disease islet cell tumors, and other APUD tumors
Chromogranin A • Different immunoassays react with subcomponents of CGA • Each test baseline different • Not good standardization • Sequential tests rather than one number • False positives: PPI use, atrophic gastritis, renal and hepatic dysfunction
Detection of NETs • Over ‐ expression of somatostatin receptors (SSTR) in NETs • Octreotide a synthetic analogue of somatostatin • Exploited in radioimmunoscintigraphy (RIS) • SSTR indicated for detection of the primary, staging, monitoring response to therapeutic somatostatin and treatment planning for SSTR directed Radionuclide therapy • Sensitivity of the study depends on the density of the SSTR and the type of analogue used in the study
ADVANTAGES TO CYTOPATHOLOGY • Easier to obtain material • Cheaper • Shorter turn around time • Less aggressive and less complications • No need of general anesthesia
Methods of preparation Direct Smears • Alcohol fixed • Air dried Cell Block Preparations • Rinsing and dedicated pass into RPMI • If cellularity is scant for cell block, process fluid as cytospin, ThinPrep
Ke Key Fe Feat atures of of Car Carcinoi oid Tu Tumor (N (NET) ET) • Uniform small cells, both single and aggregated • Scanty cyanophilic cytoplasm • Often eccentric nucleus • Nuclei: round to slightly ovoid • Chromatin: finely coarse • Clean background. Bibbo, cytopathology, 2014
FACES OF Neuroendocrine Large clusters Prominent nucleoli Tumor Granular chromatin Big cytoplasm DIFFERENTIAL DIAGNOSIS: Thyroid carcinoma? Hepatocellular neoplasms? Adrenal cortical carcinoma ? Vs. NET ? Naked nuclei Single-cell IHC confirmation Needed
NET NETs common common in in the the GI GI tr tract/ act/ particu rticularly ly sto stomach and and sm small all bow bowel Monotonous, Monotonous, nes nested/ ed/ tr trabecular abecular cy cytoplasm asmic gr granul anules es et etc
NET of the Pancreas
NET • 1980s: Detailed profiling of the cells with endocrine properties, isolation of hormones, immunoproxidase and in ‐ situ hybridization techniques, ultrastructural levels > organ specific carcinoid subtyping • Synaptophysin and chromogranin identified as reliable and effective markers of NE differentiation • 1980s: carcinoids are a family of neoplastic cells, diverse in their composition depending on location
GE ‐ NET Grading • Based on histologic degree of proliferation: Labeling index (MIB/Ki67) Mitotic rate Recommended to use the highest of mitoses or Ki ‐ 67 when both available Pancreaticoenteric NET: CDX2 + vs. lung NET that is TTF1 +
GE ‐ NET: primary tumor stage can vary between GE organs but comparable N & M Parameters: Depth of Invasion, Tumor size and status of LNs Stomach/ Small bowel T Colon T TNM N0: Neg LNs N1: Pos regional LN I ‐ lamina propria/submucosa, I ‐ lamina I: T1 N0 M0 <1 propria/submucosa, <2 cm II ‐ muscularis propria, >1 II ‐ muscularis propria, IIA: T2 N0M0 >2cm IIB: T3 N0M0 III ‐ invades subserosa III ‐ invades subserosa IIIA: T4 N0M0 IIIB: T4 N1M0 IV ‐ invades serosa or adj IV ‐ invades serosa or adj IV: Any T, Any N, M1 organs organs
Treatment • Resection • Octeriotide and interferon • Relatively good survival, even despite metastasis compared to carcinomas
Neur Neuroendocrine oendocrine Car Carcinom inomas as (N (NEC) of of the the GI GI tr tract act • Overall very rare in the GI tract • Exclude metastasis from other sites before considering primary GI NEC • Most common in esophagus, where more likely NEC than NET • Can be associated with other carcinomas and adenocarcinoma • In bowel they can arise in association with adenomas/ polyps
Neuroendocrine Carcinomas of the GI tract • Aggressive • High metastatic rate and very poor outcome • Not associated with NETs
Survival NEC versus NET Shia et al (PMID:18360283) and Zell JA et al (PMID:17372250)
NE NEC High N/C, Molding , crush artifact, High mitosis, High apoptosis
Neuroendocrine Carcinomas of the GI tract • High grade neoplasms with high grade morphology that also express neuroendocrine markers • Obviously malignant tumors versus neuroendocrine tumors with high proliferation rate • Finely speckled chromatin and high N/C ratio, nuclear molding • Thus NEC looks different than NET and behaves different • Also Treated different, chemotherapy, i.e. platinum based
MANEN • AKA MANEC • Although a single diagnostic entity, encompasses a whole spectrum of low to high grade lesions. The epithelial component can range from dysplasia to invasive adenocarcinoma, while the neuroendocrine elements can vary from well differentiated (neuroendocrine tumor, NET) to poorly differentiated (neuroendocrine carcinoma, NEC) • Histogenesis remains controversial, “collision” or “composite” ??
• Yoshioka S et al., 2018 Early detection of the NEC component by cytological examination is very important
MANEN of the GI Tract (more indolent one) Javier De Luca ‐ Johnson and Maryam Zenali. A Previously Undescribed Presentation of Mixed Adenoneuroendocrine Carcinoma , PMID: 27965908
MA MANE NEN of of the the GI GI Tr Tract (mor (m ore ag aggr gressiv essive one) one) Brathwaite SA et al. Mixed adenoneuroendocrine carcinoma: A review of pathologic characteristics, PMID: 29288693
MANEN • Thus, MANEN entails heterogeneous morphology, progression and prognosis • A wide ‐ spectrum disease, ranging from indolent (more like NET) to highly aggressive in behavior (more like NEC) • Is managed and its prognosis is derived according to the more aggressive tumor component
Sum Summary ary of of NE NE neopl neoplasm sms of of the the GI GI pancr pancreatic origin origin • NET, more indolent, yield on Chromogranin A / Octreotide detection methods, usu. uniform and low grade morphology – in GI ‐ P most common in intestine/ pancreas, resection only or with/ without octreotide (FNA good screen) • NEC, more aggressive, bad prognosis, angry cells with crush and necrosis – in GI ‐ P more common in esophagus, chemotherapy (platinum based) (FNA good screen) • MANEN, spectrum from high to low grade, tissue section more diagnostic, variable treatment
Questions? Maryam.Zenali@uvmhealth.org Ramin.Zargham@uvmhealth.org Liam.Donnoly@uvmhealth.org
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