PANCREATIC TUMOURS

By Dr. Khyati MehtaP. D. U. MEDICAL COLLEGE, RAJKOT.

PANCREAS- NORMAL ANATOMY

NORMAL HISTOLOGY

Islet of lengarhans

Acinar cells

EXOCRINE TUMOURS ENDOCRINE TUMOURS

DUCTAL ADENOCARCINOMA ANAPLASTIC CARCINOMA CYSTIC PANCREATIC NEOPLASMMICROCYSTIC CYSTADENOMAMICROCYSTIC CYSTADENOCARCINOMA

MUCINOUS CYSTIC NEOPLASM INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM ACINAR CELL TUMOURS AND TUMOUR LIKE CONDITIONS

ACINAR CELL HYPERPLASIA, ADENOMA, CYSTADENOMA, CARCINOMA

SOLID- PSEUDOPAPILLARY TUMOUR PANCREATOBLASTOMA

BETA CELL TUMOURS- INSULINOMASALPHA CELL TUMOURS-GLUCAGONOMAG-CELL TUMOURSVIP-PRODUCING TUMOURSDELTA CELL TUMOURSPP CELL TUMOURSCARCINOID TUMOURSSMALL CELL CARCINOMA\MULTIPLE ENDOCRINE NEOPLASIA- TYPE 1 & 2

MESENCHYMAL & OTHER PRIMARY TUMOURS

LYMPHOID TUMOURS METASTATIC TUMOURS

BENIGN MESENCHYMAL TUMOURSPRIMARY SARCOMASEWINGS SARCOMA/PNETPANCREATIC CHORIO-CARCINOMA INFLAMMATORY MYOFIBROBLASTIC TUMOURS

MALIGNANT LYMPHOMAS LUNGLARGE BOWEL,KIDNEYBREAST

PANCREATIC TUMOURS

PANCREATIC DUCTAL ADENOCARCINOMA

85% of all exocrine pancreatic cancers Risk factors :

1) occupation2) cigarette smoking3) syndromes with genetic susceptibility- familial breast cancer/ BRCA2-familial atypical multiple mole melanoma syndrome/P16-peutz-jeghers syndrome/STK11-LKB1-hereditary nonpolyposis colorectal cancer/DNA mismatch repair genes-hereditary pancreatitis/ cationic trypsinogen gene

4) variations in pancreaticobiliary anatomy5)Age : elderly6)Sex : male:female—1.6:1

CLINICAL FEATURES Characteristic painless obstructive jaundice Pruritus, dark urine, pale stools, steatorrhea If no jaundice, symptoms are vague e.g.

discomfort, anorexia, weight loss Peripheral venous thrombi & diabetes

LABORATORY EVALUATION CBC , ESR, Hepatic function evaluation Coagulation profile Nutritional assessment.

Tumor markers : CEA, CA19-9 Radiological CYTOLOGY GUIDED BIOPSY HISTOPATHOLOGY, IMMUNOHISTOCHEMISTRY &

ELECTRON MICROSCOPY

LOCATION & GROSS FEATURES 2/3 rd – head of the pancreas 1/3 rd – body & tail of pancreas Multiple tumours in 20 % of cases GROSSLY,

- poorly delineated, firm- yellowish grey cut surface- rarely massive cystic degeneration- pancreatic ducts- dilated and plugged

with necrotic tumour- extrapancreatic extension is common

  Gross appearance of typical invasive ductal carcinoma of the head of the pancreas. The tumor is protruding into the duodenal lumen.

MICROSCOPIC FEATURES Grading- well/moderately/ poorly

defferentiated Low power view-

well formed glands, with large lumen, lined by one or few layers of cylindrical or cuboidal epithelium.

irregularities in shape & distribution of glands, prominent concentric

desmoplastic stroma surrounding the glands.

Pancreatic ductal adenocarcinoma.:It is typical of this tumor type to be well differentiated architecturally(low power view)

High power view : epithelium show malignant features i.e. marked nuclear pleomorphism, loss of polarity, prominent nucleoli & mitotic activity

Disparity between high degree of cytologic atypia And low level of archirectural atypia.

Invasion : Perineural invasion, invasion of veins, fat invasion

Carcinoma in situ( high grade pancreatic intra epithelial neoplasm) & atypical hyperplasia

Lobular tissue destroyed, islet cell preserved – “insular pancreas”

Pancreatic ductal adenocarcinoma.:It is typical of this tumor type to be well differentiated architecturally but to show marked cytologic atypia

High power view show marked cytologic atypia.

Non-neoplastic pancreas: Atrophy Chronic inflammation, Fibrosis Ductal dilatation Atypical hyperplasia PanINs

Atypical hyperplastic ductal changes (PanIN) in pancreas affected elsewhere by invasive ductal adenocarcinoma

HISTOCHEMICAL & IHC FEATURES Mucins : gastric & small intestinal type & lack

8-0-acetyl –N-acety lneuraminic acid, MUC 1 positive

Keratins : CK 7,8,18,19, 15/16, 17, 20 EMA,CEA, CA-19-9, B7 & mesothelin M1 & cathepsin E & pepsinogen 2 Villin & mapsin Endocrine & neural markers

MOLECULAR GENETIC FEATURES Structural rearrangements or loss of genes

on 1p, 3p, 6p, 8p & 17 p Mutations of K-RAS Inactivating mutations of P16/CDKN2A Mutations of TP 53 Inactivating mutations of DPC 4 (strongly

suggestive) Overexpression of HER2 Loss or overexpression of DNA mismatch

repair genes

OTHER MICROSCOPIC TYPES Adenosquamous carcinoma Oncocytic carcinoma Clear cell carcinoma Hepatoid carcinoma Signet ring carcinoma Basaloid carcinoma Intestinal type carcinoma Mucinous carcinoma

Mucin-producing adenocarcinoma of the pancreas associated with large pools of extracellular mucin.

SPREAD AND METASTASIS Peri pancreatic soft tissue Invasion into the duodenum & common bile

duct Vascular & neural invasion Lymphnode metastais Distant metastasisTREATMENT

PRIMARILY SURGICAL

PROGNOSISOverall 5 year survival rate is 4 % or less Mean survival of 3 monthsFactors related to prognosis are : Tumour stage microscopic grade Tumor size

Tumour less than 4.5 cm in diameter– longest survival

Blood vessel invasion & retroperitoneal margin of resection—decreased survival

Lymphnode metastasis

DNA ploidy

TGF- β1 expression– related to better differentiated tumours—better outcome

Cytokeratin 20 expression—decreased survival

Mapsin expression—better prognosis

SMAD4 gene mutation—worse prognosis

ANAPLASTIC CARCINOMA Also known as PLEOMORPHIC, SARCOMATOID

OR UNDIFFERENTIATED CARCINOMA Highly distinctive morphology and highly

aggressive course > 50 years, male predilection Three morphologic types: 1)

Large no. of bizzare multinucleated cells Poor cellular cohesion(loss of E-cadherin

expression) Lymphnode & hematogenous metastasis

common

2) tumour largly composed of spindle shaped cells

3)solid tumour of small monotonous round cells

Immunohistochemically, keratin, EMA & CEA positive

Prognosis : extremely poor

Sarcomatoid carcinoma of the pancreas associated with areas of clear-cut glandular differentiation. The two components are sharply separated, resulting in a carcinosarcoma-type appearance.

GIANT CELL TUMOUR OF PANCREAS Distinct morphologic appearance and better

prognosis Grossly, large and hemorrhagic Microscopically, dual polulation :

Uniform spindle cells of mesenchymal origin with cytological atypia

Multinucleated giant cells (=osteoclasts)

Nuclei of osteoclast like cells are uniform small and mitoses and bizarre forms are absent.

Gross appearance of giant cell tumor of pancreas. There is a large hemorrhagic mass in the head of the pancreas that is protruding into the stomach.

Microscopic appearance of giant cell tumor of the pancreas. Osteoclast-like multinucleated giant cells are seen scattered among mononuclear neoplastic elements showing a high degree of atypia

CYSTIC PANCREATIC NEOPLASMS Tumours in which cystic configuration is

universally present and part of their definition(i.e. cystadenoma & cystadenocarcinoma)

Two distinct categories : microcystic and mucinous

MICROCYSTIC CYSTADENOMA Also known as glycogen rich or serous

cystadenoma. Usually in elderly Some cases aassociated with VHL gene

mutations

A and B, Microcystic adenoma of pancreas. A, The tumor, which is sharply outlined, shows numerous small cysts. B, Close-up of another case showing innumerable cystic cavities separated by a thin fibrous wall.

Grossly, large multiloculated mass with individual cavities small and filled with serous fluid; cut surface is spongy.

Microscopically, Multiple small cysts lined by small, flat or cuboidal

cells with abundant amount of glycogen. A layer of myoepithelial cells present. Prominent vascularization is present.

Ultrastructurally, prominent microvilli seen Immunohistochemically, reactive for EMA,

LMW keratin, alpha-inhibin, NSE, MUC6, calponin

Fliud has a low level of CEA level. Excision is curative

Microcystic cystadenoma showing typical multilocular appearance.

High-power view of microcystic cystadenoma showing lining of cuboidal epithelium with optically clear cytoplasm.

MICROCYSTIC CYSTADENOCARCINOMA Microcystic appearance similar to that of

adenoma. Nuclear atypia, perineural invasion and

aneuploid DNA pattern present. Rare metastasis.

MUCINOUS CYSTIC NEOPLASMS Seen in younger age group than microcystic

tumours Predominant in women Mostly in body and tail Two categories: mucinous cystadenoma &

mucinous cystadenocarcinoma Large multilocular cyst lined by tall columnar

mucin producing cells, often forming papillae Stroma is very cellular resembling that of

ovarian stroma(also phenotypically)

Mucinous cystadenoma of pancreas. The lesion is unilocular and contains abundant inspissated mucin.

Mucinous cystadenocarcinoma. This tumor, which was invasive at the microscopic level, shows areas of hemorrhage and solid growth.

Mucinous cystadenoma of pancreas. The lining is monolayered and made up of well-differentiated mucinous epithelium.

Mucinous cystadenoma with underlying ovarian-type stroma: hematoxylin–eosin

Diagnosis of malignancy regquires presence of invasion of wall by neoplastic gland and frank anaplasia of superficial component.

Aspiration of fluid: tall columnar cells, higher levels of CEA & lower levels of elastase1.

Total excision is recommended. Metastasis: usually restricted to abd. Cavity. Histochemically, expression of MUC5AC,

MUC2 with lack of MUC1

INTRADUCTAL PAPILLARY MUCINOUS NEOPLASMS & PANIN Distinct type of intraductal pancreatic tumour Interplay of two factors : epithelial

proliferation and mucinous secretion WHEN EPITHELIAL PROLIFERATION

PREDOMINATE Multicentric involvement of major ducts with

papillary lesion, cribriform pattern and cytologic atypia

Two subtypes: gastric & intestinal WHEN MUCINOUS SECRETION PREDOMINATES

Gross dilatation of ducts filled with mucus Microscopically, epithelium is columnar, mucous

secreting and well differentiated

Gross appearance of intraductal papillary carcinoma. The tumor massively involves several major pancreatic ducts

Microscopic appearance of the same case, showing a complex papillary architecture

Mucus-hypersecreting intraductal carcinoma. There is marked dilation of a major pancreatic duct accompanied by fibrosis and atrophy of the surrounding parenchyma. This duct contained large amounts of mucin in its lumen.

Microscopic appearance of the same case showing a papillary configuration associated with mucin hypersecretion.

Progression : spread slowly & eventually progress to invasive adenocarcinoma

Histochemically, heterogenous mucin expression

At molecular level, mutations of K-RAS gene, overexpression of HER2 product. Protein product of DPC4 gene is present in all cases.

Main D/D : mucinous cystic neoplasms (female predominance, no communication with ducts, ovarian type stroma)

PANCREATIC INTRAEPITHELIAL NEOPLASIA (PANIN) This entity is very similar to IPMN Relate to caliber of duct : large for IPMN &

small for PanIN Thus, IPMN is , as a rule, clinically detectable,

grossly visible with grossly identifiable mucin and well formed papillae AND reverse is true for PanIN.

ACINAR CELL TUMOURS AND TUMOUR LIKE CONDITIONS ACINAR CELL HYPERPLASIA

Incidental finding May be confused with langerhans islets

ACINAR CELL ADENOMA Solid pattern of growth Entity of very doubtful existence

ACINAR CELL CYSTADENOMA Uni/multicystic lesion lined by well differentiated

acinar cells Usually not connected with pancreatic ductal

system.

ACINAR CELL CARCINOMA Uually in adults Intraabdominal mass with or without jaundice Widespread subcutaneous fat necrosis

Grossly, relatively well circumscribed fleshy mass, avergaing 11 cm in diameter, with hemorrhage and necrosis.

Microscopically, Cellular without desmoplastic stroma Pattern: solid, trabecular, glandular, papillary Nuclei round to oval, only mild pleomorphism,

single prominent nucleoli & variable mitotic activity

Cytoplasm-abundant, eosinophilic granular PAS positive diastase resistant zymogen granules Immunoreactivity for trypsin, chymotrypsin,

lipase, amylase, anti- BCL10

Acinar cell carcinoma. The cut surface is solid and has a necrotic center. It lacks the fibrous component usually seen in ductal adenocarcinoma.

Acinar cell carcinoma of the pancreas showing a well-differentiated acinar arrangement of the tumor cells.

Acinar cell carcinoma showing a trabecular pattern of growth that may be confused with that of an endocrine tumor.

Strong immunoreactivity for lipase in acinar cell carcinoma.

SOLID-PSEUDOPAPILLARY TUMOUR Also known as papillary and solid epithelial

neoplasm. Common in young women Grossly, large tumour with well developed

capsule with areas of hemorrhage and necrosis on cut surface.

Microscopically, very cellular. Pseudopapillae covered by several layers of

epithelial cells with thick fibrovascular core having prominent mucinous changes

Nuclei are ovoid & folded with indistinct nucleoli and few mitosis.

Solid and pseudopapillary tumor of pancreas. (low power view)

Solid and pseudopapillary tumor of pancreas. Note the accumulation of myxoid material around the vessels.(high power view)

Immunohistochemically, reactive for keratin, vimentin, desmoplakin, trypsin, insulin & glucagon(capacity for dual differentiation)

Progesterone receptors positive. Genetically, β-catenin gene mutation.

Treatment is surgical Overall prognosis is excellent.

PANCREATOBLASTOMA Most common pancreatic neoplasm in childhood. In some cases, asso. with beckwith-wiedmann

syn and familial adenomatous polyposis of colon Bimodal age: mean- 2.4 & 33 years. Grossly, avg tumour size is 10 cm & partial

encapsulation is the rule. Microscopically, very cellular tumour

Solid sheets and nests of uniform epithelial cell with well formed acinar structure and dilated ductular formations.

‘SQUAMOID CORPUSCLES CONSTANT AND CHARACTERISTIC

Stroma abundant.

Pancreatoblastoma showing a predominantly solid pattern of growth but also small rosette-like glandular formations.

Pancreatoblastoma showing a large squamoid corpuscle surrounded by small glands.

Immnunohistochemically, Evidence of acinar, endocrine and ductal

differentiation. AFP Squamoid corpuscles : CK8/18/19, EMA positive

Genetically, Nuclear translocation of β catenin Loss of heterozogosity of chromosome 11p

Prognosis in infants is favourable.

ENDOCRINE PANCREATIC TUMOURS

GENERAL CLINICAL FEATEURES

Tradinitionally designated as islet cell tumours

Many arise from primitive multipotent cells located within ducts.

Most occur in adults. Many associated with MEN syndromes, VHL

disease, neurofibromatosis type 1 or tuberous sclerosis

GENERAL MORPHOLOGIC FEATURES Common location : body & tail of pancreas. Grossly, pinkish cast resembling spleen or

congested lymphnode. No well defined capsule. May contain large amount of fibrous tissue,

calcification and bone. Microscopically,

Small relatively uniform, cuboidal cells with centrally located nuclei and acidophilic finly granular cytoplasm.

Nuclear enlargement and other abberations.

4 patterns : solid, gyriform, glandular and nondescript reffered to as A/B/C/ &D or 1/2/3/4 Relation with further types :

predominantly gyriform – beta/alpha cell type.

glandular – G or VIP cells.solid tumours – any cell type.

Stroma– highly vascular Abundant hyaline material may be seen. Amyloid in insulin secreting neoplasm(IAPP)

CLINICALLY, May be nonfunctional or functional

Immunohistochemically, Reactive for epithelial markers(CK7 CEA,) Panendocrine markers

NESP-55 Markers specific for various peptide hormones.

Genetically 6q loss, mutation in MEN1 gene, allelic loss of 11q, NO inactivation of DPC4

SPECIFIC TYPES

BETA CELL TUMOURS Most common & better < 10 % affected by MEN 1. Presents with whipples traid when functional. 90% solitary, 70% measures 1.5 cm or less Microscopically, gyriform or solid pattern. Ultrastructurally, dense core secretory

granules. Immunohistochemically, reactive for insulin,

proinsulin, As a rule malignant variety has shorter

history & more pronounced hypoglycemia.

Low power view

High power view

ALPHA CELL TUMOURS Two types

1) associated with glucagonoma syndrome Solitary and large Non discript microscopic pattern Atypical granules ultrastructurally Few cases positive for glucagon.

2)tumours not associated with glucagonoma syndrome Often multiple & small Gyriform pattern of growth Strongly reactive for glucagon Typical alpha granules

Gross appearance of alpha cell tumor (glucagonoma). The tumor shown exhibits foci of hemorrhage and necrosis

Alpha cell tumor showing a prominent gyriform arrangement of the tumor cells. Tumors with this pattern are usually composed of either alpha or beta cells.

G – CELL TUMOUR Can produce Zollinger-Ellison syndrome as a

result of excessive production of gastrin & reffered to as gastrinoma.

Common site- pancreas followed by duodenal wall and gastric antrum.

Solitary and often clinically malignant. Microscopically, solid and or glandular. IHC- gastrin production

Rosette-like gland formation in G-cell tumor (gastrinoma).

OTHER TUMOURS OF ENDOCRINE PANCREAS

VIP producing tumours DELTA CELL TUMOURS –somatostatin

secretion PP CELL TUMOURS -- secondary or minor

component in other tumours CARCINOID TUMOURS– analogous to other

carcinoid tumours seen in G.I . Tract. SMALL CELL CARCINOMA—similar to its more

common pulmonary counterpart.

BEHAVIOUR & PROGNOSIS

WHO has proposed three categories :1. Well differentiated endocrine tumours

A. Benign behaviourwithout extrapancreatic spread or vascular invasion<2 cm in size,<2 mitosis/10hpf,<2% ki-67 positive cells

B. Uncertain behaviourwithout extrapancreatic invasion>2 cm in size,angioinvasive and perineural invasion2-10 mitosis /10hpf,>2% ki-67 positive cells.

2. Well differntiated low grade carcinoma

any tumour with gross local invasion &/or metastasis.

further subdivided into functioning and non-functioning .

3. Poorly differentiated endocrine carcinoma

also includes small cell neuroendocrine carcinoma

Tumours Age/sex Gross microscoic IHC

Ductal adenocarcinoma

Elderly/ M>F

Solid, Poorly delineated, fibrosis in surr ound. Area

Malignant glands with invasion

Mucins : MUC1, CA-19-9, CEA, CKs

Anaplastic carcinoma

>50yrs/M>F Large h’gic tumour

3 patterns CK, CEA, EMA

Microcystic neoplasms

6th/7th decade,F>M

Large multilocular cystic tumour, serous fluid

Small cysts lined by cuboidal epi. With or without atypia

CK, EMA, MUC6, fliud CEA level

Mucinous cystic neoplasm

5th/-6th decade,F>M

Large cysts, mucin filled

Cysts lined by columnar epi + ovarian type stroma

MUC5AC, MUC 2, fluid CEA level

SUMMARY

Tumours Age / sex Gross Microscopic

IHC

IPMN Elderly Involvemenat of ducts, papillary lesion or dilatation

Epithelial proliferation or mucus secretion

Heterogenous mucin expression

Acinar cell carcinoma

Adults Well circumscribed, fleshy, large

Solid, cellular variable patterns

trypsin, chymotrypsin, lipase, amylase, anti- BCL10

Solid pseudopapillary tumour

Young women, F>M

Large encapsulated with h’ge & necrosis

Pseudopapillae thick fibrovascular core having mucinous changes

keratin, vimentin, desmoplakin, trypsin, insulin & glucagon

Pancreatoblastoma

Bimodal age(2.4 & 33 yrs)

Large(~10 cm), partially encapsulated

Solid sheets of epi. Cells + squamoid corpuscles

AFP, CK8/18/19, EMA

REFERENCES ROSAI AND ACKERMAN’S SURGICAL

PATHOLOGY/tenth edition/chapter 15 ROBBINS & COTRAN/ PATHOLOGIC BASIS OF

DISEASE/south asia edition/9th edition/chapter 19

Internet

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