Ma Many Fa Faces of of Neur Neuroendocr oendocrine Neoplasms - - PowerPoint PPT Presentation

Ma Many Fa Faces of

• f Neur

Neuroendocr

• endocrine Neoplasms

Neoplasms (Gas (Gastr troen

• enteric

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

acid protein

• A member of the Granin family of

proteins and polypeptides, found in secretory granules alongside the tissue‐specific secretion products

• Being ubiquitous within

neuroendocrine tissues, CGA is a useful marker for neuroendocrine neoplasms, including carcinoids, functioning and nonfunctioning islet cell tumors, and other APUD tumors

• Serum CGA used in conjunction

with, or alternative to serum or whole blood serotonin, urine serotonin, and urine 5‐HIAA and imaging studies, in patients with suggestive carcinoid syndrome, i.e. with flushing

• It can also serve as a sensitive

mean for follow‐up of patients with known or treated carcinoid tumors to gauge recurrence or residual disease

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

• f 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

• f Car

Carcinoi

• id 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 Tumor

Large clusters Prominent nucleoli Granular chromatin Big cytoplasm Naked nuclei Single-cell

DIFFERENTIAL DIAGNOSIS:

Thyroid carcinoma? Hepatocellular neoplasms? Adrenal cortical carcinoma ?

• Vs. NET ?

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

• n 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, <1 I‐ lamina propria/submucosa, <2 cm I: T1 N0 M0 II‐ muscularis propria, >1 II ‐muscularis propria, >2cm IIA: T2 N0M0 IIB: T3 N0M0 III‐ invades subserosa III ‐ invades subserosa IIIA: T4 N0M0 IIIB: T4 N1M0 IV‐ invades serosa or adj

• rgans

IV‐ invades serosa or adj

• rgans

IV: Any T, Any N, M1

Treatment

• Resection
• Octeriotide and interferon
• Relatively good survival, even despite metastasis compared to

carcinomas

Neur Neuroendocrine

• endocrine Car

Carcinom inomas as (N (NEC) of

• f 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

• f the

the GI GI Tr Tract (m (mor

• re ag

aggr gressiv essive one)

• ne)

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

• f NE

NE neopl neoplasm sms of

• f the

the GI GI pancr pancreatic origin

• rigin
• 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

• ctreotide (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