Patozone

Autoimmune pancreatitis

May be suggested by (+)-hx of other autoimmune dz's (Sjogrens, UC, and PSC), can form a mass mimicking adenocarcinoma

- affects middle aged females

3 types (?):

Type 1 - lymphoplasmacytic sclerosing type pancreatitis; Older pts (7th decade), usually male

Sx: Periphlebitis and frank vasculitis

Micro: Benign ducts surrounded by dense lymphoplasmacytic inflam and expansion of periductal space c sclerosis

- storiform fibroblastic prolif [2]

- > 10 IgG4-plasma cells / HPF

Lab: Inc serum IgG4 (>135 mg/dL)

Type 2 - Not an IgG4-related disease, (IgG4 serum levels are not elevated), and IgG4 plasma cells not seen, although has dense periductal lymphoplasmacytic infiltrate, Intraepithelial neutrophils and occasional eos also seen (Granulocytic Epitheial Lesions)

- younger pts (5th to 6th decades), M=F, rarely in Asians

IHC: PDL1 in Autoimmune Pancreatitis and Mimics

• Specificity for type 2 AIP -> 95%

• Sensitivity for type 2 AIP–>70%

Reactivity less than 5% in:

– Pancreatic ductal adenocarcinoma

– Type 1 autoimmune pancreatitis

– Other forms of chronic pancreatitis

Type 3 - Mixed???

Groove Pancreatitis (paraduodenal pancreatitis)

Middle aged men, EtOH abuse

- macroscopic findings are critical

Similar with those of pancreatic carcinoma, may present with Pancreatic head mass, Pancreatic ductal stricture, Duodenal strictures [2]

Follicular pancreatitis

• Mass forming pancreatic lesion

– Rarely mimics an IPMN

Micro: Characterized by reactive lymphoid follicles

– Pancreatic parenchyma

– Main pancreatic duct

Tx: Steroids

– Induction

• Some require steroid sparing agent

– Maintenance

• Steroid sparing agents

– Rituximab

Lymphoepithelial cyst

No assoc c HIV or autoimmune conditions (unlike lymphoepithelial cysts of the salivary glands)

Micro: stratified keratinized epithelium surrounded by lymphoid tissue with follicle

- lumen can have keratinous debris and cholesterol crystals

- mucinous cells can be present and sebaceous differentiation can be seen

Labs: 1/2 have inc CA19-9

Tx: conservative, with limited or extended resection

Px: b9, no risk of malig transformation

Pseudocyst

MCC (~3/4) pancreatic cysts, usually tail of pancreas

- seen c alcoholic pancreatitis

- form due to an accumulation of blood, pancreatic enzymes, and necrotic material usually from some type of pancreatitis

Labs: Inc amylase and lipase

Micro: Contain granular necrotic debris (not mucin), blood, and lots of pancreatic enzymatic juices without a cystic epithelial wall (which is why they are "pseudo"-cysts)

- peripancreatic (just outside the pancreas) and unilocular

- usually resolves spontaneously, though some can be formed 2/2 bacterial infx

Dx: Endoscopic Ultrasound (EUS) - needle guided bx for lesions too small to be id'd by CT/<RI or lesions encased by a vascular structure (making a percutaneous bx difficult)

Cyst fluid analysis [2]:

CEA >800ng/ml (>200ng/ml) --> Neoplastic mucinous cysts

CEA <5ng/ml --> Serous cystadenoma or a  Pseudocyst

Amylase <250 U/L --> Not a pseudocyst

Molecular (NGS):

• The distinction of IPMN/MCN from non mucinous cysts of the pancreas

-- KRAS and/or GNAS (IPMN)  [Sensitivity > 90%, Specificity > 95%]

• The identification of advanced pancreatic cysts

– TP53 PTEN CDKN2A , SMAD4

• Diagnosis of serous cystadenoma

-- VHL mutations

Tx: drain if lasts > 6wks, painful, or rapidly growing

- debride necrotic tissue

Retention cyst

adf

Pancreatic Intraepithelial Neoplasia (PanIN)

Grossly undetectable (usually <0.5 cm) and often found next to infiltrating neoplasms, thus most likely precedes invasive carcinoma

Broken into 3(.5) stages based on cytogenetic abnormalities:

1A: Columnar cells c telomere shortening and KRAS mutations

1B: same genetics as 1A, but start to form papillary projections

Micro: (1A) flat lesions c tall columnar cells c basal nuclei and lots of supranuclear mucin, c small round oval nuclei

1B: epithelial lesion c papillary, micropapillary or basally pseudostratified architecture; very similar to 1A

- commonly found in resections; do not require tx

2: p16 / CDKN2A inactivation

Histo: mild disorganization, nuclear enlargement and hyperchromasia, pleomorphism, mild dyspolarization of nuclei towards lumen (apically) and rare mits above BM

3: TP53 / SMAD4 / BRCA2 inactivation

Histo: terrible polarity loss, very atypical cells c inc N:C, tufting c detached cell clusters, necrosis and mits

- 3 should be treated as neoplastic

IHC: (+) MUC1, MUC4, DPC4

- neg MUC2, CDX2

Pancreatic Ductal Adenocarcinoma (DA)

MCC (85%) of pancreatic neoplasms

- 4th MCC death from neoplasm in USA

- assoc c BRCA2 mutations, familial P16 multiple mole / melanoma syndrome, Peutz-Jeghers, HNPCC, and hereditary pancreatitis

Presents c PAINLESS JAUNDICE (2/3 in head of pancreas), pain radiating to back, weight loss (from anorexia and malabsorption), palpable gallbladder (Courvoisier's sign) and migratory thrombophlebitis (redness and tenderness on peripheral palpation [Trousseau's syndrome])

- avg age at dx: 63 years

- assoc c cigarrette, but not EtOH use

- inc risk in Jewish and black males

- has usually already met'd at time of presentation

- well-diff tumors can be very difficult to dx on frozen section

Gross: entirely submit tumors <2 cm; else 2 samples per cm

Micro: loss of polarity, nuclear stratification, nuclear hyperchromasia, and prominent nucleoli

- desmoplastic stroma around gland

IHC: (+) CK7, CA19-9, CEA, B72.3, MUC1, MUC5AC, DUPAN2, focal CK20

- neg vimentin, MUC2

- loss of SMAD4/DPC4 is characteristic (though also seen in 1/5 gallbladder ca, 1/10 colon ca)

Labs: CEA and CA19-9

Genes: KRAS mutation (in >9/10), TP53 mutation, SMAD4 inactivation involved in pathogenesis

- may be familial in 1/10 cases

- pts c Peutz-Jeghers syndrome c germline mutation in STK11/LKB1 gene have 132-time increase risk of developing pancreatic cancer

- BRCA2 mutations also put at inc risk

- atypical multiple mole melanoma syndrome assoc c inc risk

Tx: neoadjuvant therapy improves resectability, recurrence-free survival, disease-free survival, and helps deliver chemotherapy pre-surgery

Px: < 6 mo survival (very aggressive)

Pancreatic Endocrine Neoplasms (PEN)

- aka Pancreatic Neuroendocrine Tumors (PanNET)

- sometimes called pancreatic islet cell tumors

- 1-2% of pancreatic tumors [1]

Most occur with MEN, tuberous sclerosis, vHL or NF1

- usually are in the tail (where most of the islets are), looking pink and maybe like a big lymph node

- 1/2 are secretory

Insulinoma: 3/4 of PanNET, B-cells, MEN1, clinical triad (?), benign and solitary

Gastrinoma: ~1/4 of PanNETs, MEN1, ZE syndrome, up to 90% are malignant

Glucagonoma: perimenopausal women, MEN1, inc plasma glucagon levels

*** 4 D's: DM, Dermatitis (necrolytic migratory erythema), DVT, Depression ***

- > 50% liver mets at presentation

VIPoma: solitary, large, tail of pancreas, severe diarrhea, hypokalemia, achlorhydria

Somatostatinoma: inc plasma somatostatin, DM, cholelithiasis, diarrhea / steatorrhea

*** Sugar, Stone, Steatorrhea = Somatostatin! ***

Malignant, assoc c MEN1

Micro: small nests or trabeculae of cuboidal cells c central nuclei, stippled chromatin, and granular cytoplasm, growing as trabecular, solid, glandular, gyriform (ribbons and festoons) or nondescript forms (and are histologically classified as such)

- highly vascular stroma

- salt n peppa chromatin

Can secrete multiple types of hormone

IHC: (+) CEA / CEACAM1, individual islet markers (glucagon, insulin...), NSE, chromogranin A / B, synaptophysin, opioid peptides, PR, PAX-8, CD56

- neg: vimentin, acinar markers (trypsin, chymotrypsin, PAS/D), CD10 (1/10+), nuclear B-catenin, ER

Px: dependent on Size and Mitotic / Ki67 levels

- most are low grade (well-differentiated and solitary)

Acinar Cell Carcinoma

MC in older adults (60 yo), 1-2% of pancreatic neoplasms in adults, up to 15% of pancreatic neoplasms in children, 2M>1F, assoc c skin rash

Gross: can occur anywhere in pancreas, but MC In head; large (10 cm) well-circumscribed, fleshy c areas of necrosis

- may have large areas of necrosis 2/2 lipase secretion (causing skin rash, subcutaneous fat necrosis, and polyarthralgia when metastatic)

Micro: Uniform large cells c prominent nucleolus and bluish cytoplasm w/o surrounding desmoplastic rxn

- can grow in acinar, solid, trabecular, glandular, or papillary patterns

- have PAS(+) / diastase resistant cytoplasmic zymogen granules

IHC: (+) BCL10, trypsin, lipase, chymotrypsin, cytokeratins (Cam5.2), may stain for neuroendocrine markers

- negative CHR/SYN (var), CD10, CEA, nuclear B-catenin

BCL10 sensitive and specific (recognized COOH-terminal of carboxyl ester lipase, an enzyme produced by pancreatic acinar cells)

Genes: APC/B-catenin mutation and -11p (similar to pancreatoblastoma); no hallmark genetic alteration

DDx: pancreatic neuroendocrine tumor, pancreatoblastoma, solid pseudopapillary neoplasm

Px: highly aggressive, 25% 5-year survival

- mets present in 1/2 of cases at diagnosis, usually to liver and regional lymph nodes

Colloid carcinoma

>80% of tumor is mucinous with scant floating tumor cells

- assoc c intraductal papillary mucinous neoplasm (virtually always arises in an intestinal type IPMN), mucinous cystic neoplasm (MCN) and ampullary / duodenal tubulovillous adenoma

- usually head of pancreas

- may be complicated by pseudomyxoma peritonei

Gross: large, well-demarcated

Micro: >80% shows large extracellular stromal mucin pools with scant carcinoma cells floating in mucin pools

- carcinoma cells usually cuboidal / columnar with cribriforming, strips of cells or signet ring cells

Extravasated mucin does NOT equal invasive carcinoma

- find IPMN

IHC: (+) CDX2, MUC2, CEA in basal aspect of cells, focal SYN or CHR ok

- neg MUC1

DDx: cPDAC (MUC2-)

Px: probably better than conventional pancreatic ductal adenocarcinoma (cPDAC); 5-yr survival up to 72%

- expression of MUC2 (gel forming mucin, rare in cPDAC) and absence of external lamina or basement membrane may lead to accumulation of extracellular mucin, which limits tumor spread and apears to have tumor suppressor activity

Pancreatoblastoma

MCC pancreatic cancer in Asian kids (~4 yo), but overall is rare

- may be assoc c FAP and Beckwith-Wiedmann syndromes

- can come from acini, ducts, or endocrine cells

-- basically is the kid version of acinar cell ca

Labs: inc serum AFP (b/c is a primitive-type of tumor)

Gross: Large (10 cm), well-demarcated, solid, multilobulated

Micro: Cellular sheets of round cells c nuclear inclusions and squamoid corpuscles

- corpuscles have clear nuclei due to biotin accumulation

- epithelial parts can have acinar, solid or squamoid nests

IHC: (+) CK AE1/3, trypsin, lipase, CEA, synaptophysin, chromogranin, NSE, B-catenin, chromogranin,

- squamoid corpuscles: (+) CK8/18/19, cyclin D1, EMA and are CK7 negative

- may show some positivity with BCL10 in the acinar component (do not confuse with acinar cell tumor)

Genes: most common genetic alteration is loss of heterozygosity of chromosome 11p

- like acinar cell ca, can have mutated B-catenin (CTNNB1) or APC gene

- may have alterations in the Wnt pathway and allelic loss on 11p

- also has loss of heterozygosity of 11p (as in Wilms tumor and hepatoblastoma; both of which can be part of Beckwith-Weidmann syndrome)

Px: Poor (25% 5-year survival) [?], sometimes favorable

Serous (microcystic) cystadenoma

MC in women; also assoc c vHL, head of pancreas

Gross: so many little cysts looks like a well-circumscribed sponge

- MC in body / tail; often has a central stellate scar

- large size and location in the head predict aggressive behavior

Imaging: pancreatic head, has typical "honey-comb" appearance 2/2 large numbers of cystic spaces

Cyst fluid analysis [2]:

CEA >800ng/ml (>200ng/ml) --> Neoplastic mucinous cysts

CEA <5ng/ml --> Serous cystadenoma or a  Pseudocyst

Amylase <250 U/L --> Not a pseudocyst

Micro: Simple cuboidal epithelial layer filled c glycogen (clear-cells)

IHC: (+) alpha-inhibin, CAM5.2, CK7/8/18/19, MUC6, EMA (1/3), calponin

- negative serum CEA, CA19-9, CA125, CD31, Factor VIII

Genes: vHL and cr 10q translocations

Molecular (NGS):

• The distinction of IPMN/MCN from non mucinous cysts of the pancreas

-- KRAS and/or GNAS (IPMN)  [Sensitivity > 90%, Specificity > 95%]

• The identification of advanced pancreatic cysts

– TP53 PTEN CDKN2A , SMAD4

• Diagnosis of serous cystadenoma

-- VHL mutations

Px: Benign, does not recur

Mucinous cystic neoplasms (MCN)

Almost always in perimenopausal women

- tumor does not communicate with pancreatic ductal system (vs IPMN)

Gross: MC in pancreatic tail c multiloculated cysts filled c mucin

Micro: lined by tall, simple cuboidal epithelium on top of a stroma so dense it looks like ovary

- smear is hypocellular, has thick mucous and columnar cells and is CEA (+)

- if cell lining is very atypical or glands are invading into capsule or beyond, dx is mucinous cystadenocarcinoma

- can see gastric foveolar, pseudopyloric, small and large intestine-type epithelium

- can grade dysplasia as low, medium, or high

IHC: (+) SMA/inhibin /ER/PR in ovarian stroma, cytoplasmic PAS, CEA/EMA and CK 19/7/8/18 in epithelial cells

Genes: mutated p53 and RNF43 tumor suppressor genes and KRAS oncogene, also SMAD4/DPC4

- however these tumors rarely show (+) nuclear P53 on IHC, though can be positive in malignant variants (?)

Molecular (NGS):

• The distinction of IPMN/MCN from non mucinous cysts of the pancreas

-- KRAS and/or GNAS (IPMN)  [Sensitivity > 90%, Specificity > 95%]

• The identification of advanced pancreatic cysts

– TP53 PTEN CDKN2A , SMAD4

• Diagnosis of serous cystadenoma

-- VHL mutations

Tx: Excision is sufficient, except for those found to have carcinoma

Px: ~1/3 have invasive carcinoma (mucinous cystadenocarcinoma), thus it is of utmost importance to remove ASAP

- 1/2 of pts c carcinoma die from the tumor; usually mets are local to peritoneum or ovary

Large Duct Type Invasive Ductal Pancreatic Adenocarcinoma

Can look a lot like IPMN [2]

Intraductal Papillary Mucinous Neoplasm (IPMN)

MC in elderly pts, esp male smokers

- spectrum of behavior from benign, to borderline to malignant

IPMN issues to address:

• Invasion Yes/No

• Grade Low/High

• Type Gastric, intestinal, pancreatobilliary

• Main duct versus branch duct

Gross: mucous-producing tumors found in the larger ducts in the head of the pancreas and can be multifocal

- intraductal cystic dilatation c mucinous lining

Micro: distinguished from mucinous cystic neoplasm by lack of dense "ovarian"-type stroma and involvement of the ducts

IHC: (+) MUC2, CDX2, S100p

- MUC1

- has intestinal phenotype

Genes: mutated KRAS / GNAS oncogenes and TP53,p16,  SMAD4, and RNF43 tumor suppressor genes

Tx: IPMN is generally not an indication for neoadjuvant therapy

• Remind your clinicians:  Adenocarcinoma ≠ Invasion

Px: spread slowly throughout the ductal system and finally lead to invasive carcinoma (in ~1/3 of resections)

Oncocytic-type Intraductal Papillary Mucinous Neoplasm

- previously Intraductal Oncocytic Papillary Neoplasm

Rare subtype of IPMN first seen in case series in 1996

- most have enough cytoarchitectural atypia to be called HG-dysplasia or carcinoma in situ, and invasive ca can arise also

Micro: eosinophilic neoplasm c complex arborizing papillae, cribriform or solid foci

- papillae lined by several layers of cuboidal or columnae cells

- consistently has abundant granular, eosinophilic cytoplasm from accumulation of mitochondria

IHC: (+) MUC6, CK7, HepPar1, anti-mitochondrial stains

- neg CK20 and CDX2`

Medullary carcinoma

Very rare tumor; assoc c microsatellite instability (1/2), colonic aca, and family history of cancer

Micro: sheets of carcinoma cells c abundant cytoplasm, large vesicular nuclei with prominent nucleoli, intraepithelial lymphocyte infiltration

Genes: usually no KRAS mutations but 1/5 have inactivation of DNA mismatch repair system

Px: Good

Osteoclast-like Giant Cell Carcinoma (OGCC)

- undifferentiated carcinoma c osteoclast-like GCs; is a subtype of ductal adenocarcinoma with prominent osteoclast-like giant cells

Gross: well-circumscribed

Micro: large pleomorphic spindle cells and giant cells in a background of scant fibrous stroma and hemorrhage

- giant cells vary in size and osteoclast-like giant cells are present

IHC: (+) CD45/68 in giant cells

- neg keratin in giant cells

- undifferentiated carcinoma is claudin 4 positive, whereas undifferentiated sarcoma is clauding 4 negative [2]

Genes: KRAS mutation in 90%

- TP53 and HER-2/NEU also seen

DDx: mets

Tx: Treatment is similar to pancreatic ductal adenocarcinoma

Px:  clinical behavior is unpredictable

– Some patients behave similar to pancreatic ductal

adenocarcinoma

– Other patients behave unexpectedly well

- Histopathological features such as tumor grade and level of cellular atypia do not adequately predict outcome

Solid PseudoPapillary Neoplasm (SPPN)

MC in young (30 yo) women (9:1 F:M), usually tail of pancreas

Gross: Usually has a good capsule, but can have micro-infiltration

Micro: Pseudopapillae covered in several layer of endothelial cells

- nuclei are oval and folded up with grooves

- cells farthest away from vasculature are dyscohesive and necrotic

- also can see Hyaline globules and some (foamy) macrophages

IHC: (+) nuclear B-catenin, CD10 / 56, vimentin (10/10), claudin, progesterone receptor (PR)

- neg: CK (var) [1], CHR, ER, trypsin

- cystic fluid will be CEA negative

Genes: Uniformly have B-catenin (CTNNB1) mutation and cyclin D1 overexpression

Tx: 9/10 pts are cured c excision; the rest may have mets to liver or peritoneum

Px: excellent