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Intraductal papillary mucinous neoplasm

Section: Hepatobiliary Sub-section: Pancreas Curriculum: Curriculum, page 90

Notes based on the 2024 Kyoto guidelines from the International association of Pancreatology (IAP) - International evidence-based Kyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas, page 1

Definition

  • Grossly visible, mucin-producing epithelial neoplasm of the pancreas, which arise from within the main pancreatic duct or branch.
  • Most often has papillary architecture.
  • Distinguished from mucinous cystic neoplasms (MCNs) by absence of ovarian-type stroma

Three types:

  • Main duct (MD-IPMN) - segmental or diffuse dilation of the MPD of >5 mm
  • Branch duct (BD-IPMN) - cyst >5mm that communicates with the MD
    • Branch type less likely associated with malignancy.
  • Mixed type

Epidemiology

2.04 per 100,000, increases after 6th decade

Risk factors

Aetiology

  • Aetiology unknown.
  • Associated with extrapancreatic primaries (10%)
    • Most commonly colorectal, breast and prostate.
  • Predictor of pancreatic cancer (odds ratio 7.18)

Pathology

Microscopically

  • Surrounding pancreatic parenchyma may appear firm and hard due to scarring and atrophy from obstructive chronic pancreatitis secondary to tumour.
  • Typical appearance is mucin-secreting columnar epithelium with variable atypia
  • Growth pattern varies from flat ducts (ectasia) through to prominent papillae

Morphological subtype

Three types

  • Intestinal
  • Gastric
    • Most often low grade, most favourable prognosis
  • Pancreatico-biliary type differentiation
    • Highest risk of neoplastic progression

Grade

  • IPMN microscopically demonstrates papillary growth of columnar neoplastic cells with mucin hypersecretion.
  • Graded
    • Low grade dysplasia (LGD)
    • High grade dysplasia (HGD)
    • invasive carcinoma (IC)

Genetic alterations

Frequent mutations

  • KRAS (60–70 %)
  • GNAS (50–70 %)
  • RNF43 (15 %)

Location

  • Location
    • Head (70%)
    • Diffusely (5-10%)
    • Body or tail (20-25%)

Differential diagnsis

  • IPMN vs PanIN (pancreatic intraepithelial neoplasia)
    • IPMN – taller more complex papillae
    • Abundant luminal mucin
  • Cystic pancreatic endocrine neoplasm vs. IPMN
    • Presence of coarse and stippled chromatin with a smooth nuclear membrane.

Clinical

Clinical presentation

  • Symptoms related to pancreatic duct obstruction.
    • 60 patients from John Hopkins group
      • Abdo pain (59%)
      • Jaundice (16%)
      • Weight loss (29%)
      • Diabetes
      • 14% had previous acute pancreatitis
  • Incidental from imaging

Investigations

CT or MRI:

Classical features

  • Main duct – segmental or diffuse main pancreatic duct dilatation >5mm.
  • Branch duct – cystic lesions >5mm, grape like configuration
  • Mixed – both of above

High risk stigmata for malignancy:

  • Enhanced mural module or solid component >5mm
  • Jaundice
  • Main pancreatic duct size >10mm
  • Positive or suspicious cytology

Worrisome features

  • Acute pancreatitis
  • Cyst size >3 cm
  • Cystic growth rate >2.5mm/year
  • Increased level of serum Ca19-9 (>37 U/mL)
  • Thickened enhanced cyst walls
  • Enhancing mural nodules <5 mm
  • MPD size 5–9.9 mm
  • Abrupt change in MPD calibre with distal pancreatic atrophy
  • Lymphadenopathy
  • New onset or acute exacerbation of diabetes within one year

Differential diagnosis

  • Differentiating branch type IPMN:
    • Difficult to differentiate from MCN or pseudocysts (need to consider patient’s age, gender, history of pancreatitis or genetic syndromes).
    • Suggest IPMN
      • Localisation within uncinate
      • Detection of non-gravity-dependent luminal filling defects (papillary projections) or grouped gravity dependent luminal filling defects (mucin)
      • Upstream dilatation of ducts (MCN ducts are normal)
  • Differentiating diffuse main duct IPMN (from chronic pancreatitis):
    • Patients with IPMN tend to be 20 years older, lack heavy EtOH hx
    • On imaging
      • Endoluminal filling defects (either mucin or papillary proliferations)
      • Cystic dilatation of collateral branches (particularly uncinate process)
      • Communication of dilated ducts with normal ducts without evidence of obstructing lesion
      • Widely open papilla

EUS

  • Advantage of being able to sample cystic fluid and biopsy solid lesions.
  • Useful to detect high risk/worrisome features

Cyst fluid

  • Purpose
    • Discriminate mucinous cysts from other cysts
      • Mucinous cysts - precursors for HGD/IC and thus require resection or surveillance)
        • IPMN- intraductal papillary mucinous neoplasm
        • IOPN - Intraductal oncocytic papillary neoplasm
        • ITPN- intraductal tubulopapillary neoplasm
        • MCN - Mucinous cystic neoplasm
      • Other cysts
        • Serous cystadenoma/serous cyst neoplasms
        • Pseudocysts
    • Distinguish between LGD and HGD/IC.
  • Tumour markers within cyst fluid not proven to be accurate
  • Molecular assessment is useful
  • Elevate CEA suggests mucinous cyst (but can be elevate in psydocyst) and 30% of IPMN will have a low CEA

ERCP

  • Can be used.
  • Being replaced by MRI.
  • Observation of mucin protruding from widely open papilla is diagnostic.

Tumor markers

  • No tumour markers specific.
  • Ca 19-9 (not CEA) shown to be independent predictor of malignancy.

Management algorithm/surveillance

In a patient fit for surgery

  • Operate on
    • Any high risk features
    • Multiple worrisome features
  • Otherwise surveillance imaging every 6-12 months
  • In some smaller IPMNs without change over 5 years they can be discharged from follow up.

Operative management

Suspicion for invasive carcinoma

  • Radical pancreatectomy with lymph node dissection Low suspicion for invasive carcinoma
  • Organ-preserving pancreatectomy without lymphadenectomy
    • middle pancreatectomy or spleen-preserving distal pancreatectomy

Intra-operative considerations

  • Intra-operative frozen section of the main pancreatic duct
    • HGD or IC - additional resection
    • LGD - additional resection not required
  • May need to continue to total pancreatectomy
    • In total pancreatectomy: long term risk of hypoglycaemia

Adjuvant treatment

  • If IC found then as per pancreatic cancer

Outcome

  • Main determinant of survival is presence of invasive disease
  • Factors associated with poor survival:
    • Presence of jaundice
    • Tumour type (tubular worse than colloid)
    • Vascular invasion
    • Perineural invasion
    • Poorly differentiated
    • % tumour that was invasive
    • Positive lymph nodes (41% of invasive disease)
  • Margin status not associated with worse long-term outcome

Follow up

  • Role of adjuvant therapy for invasive IPMN not addressed in trials. In retrospective series, role is unclear

  • Recurrence

    • Disseminated (arising from invasive disease)
    • Local (within remnant, may or may not be invasive)

  • For invasive or dysplasia – MRI every 1-2 years

  • For those without above – no ongoing surveillance (except mixed-type IPMN or family history of pancreatic cancer)

Graph View

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