Pancreatic (neuro)endocrine tumours

Histopathology

Most islet cell tumours have a characteristic "neuroendocrine" appearance. However, a number of unusual morphological appearances are seen in rare cases:

a clear cell variant, which in some cases is associated with von Hippel-Lindau syndrome.
Lipid-rich variant
abundant mucin granules - this is a neuroendocrine tumour rather than an adenocarcinoma.
oncocytic tumour
rhabdoid neuroendocrine tumour. The rhabdoid morphology is seen in a variety of tumours.

General immunohistochemistry

cytokeratin 7	rarely positive
cytokeratin 8	positive
cytokeratin 18	positive
cytokeratin 19	28/54(insulinomas are usually CK19 negative), prognostically significant1
NSE	positive
PGP9.5	positive
synaptophysin	positive, including non-functioning tumours
chromogranin	positive, except in some non-functioning tumours
Leu-7	positive
prealbumin	positive
neurofilament	rarely positive

Specific tumour types

	insulinoma	gastrinoma	glucagonoma	vipoma
insulin	positive	variable
proinsulin	positive
islet amyloid polypeptide	positive
gastrin		positive
PP		variable	often positive	often positive
glucagon		variable	often weak
proglucagon derivatives			often positive
VIP				usually positive
neurotensin				sometimes positive
calcitonin				sometimes positive

Prognosis

Predicting behaviour of pancreatic endocrine tumours is difficult. The Capella prognostic classification divides tumours into four categories:

Insulinoma or well differentiated tumour	<2 cm	benign
	2-3 cm	borderline
	> 3 cm or angio-invasion	low grade malignant
Gastrinoma or VIPoma or glucagonoma or with Cushing's syndrome or carcinoid syndrome	< 1 cm	benign
	1-2 cm	borderline
	> 2m or angio-invasion	low grade malignant
Highly atypical cells resembling small cell carcinoma	any size	high grade malignant

The 2004 WHO classification recognises four prognostic groups2:

	WHO 1a	no adverse critera
	WHO 1b	tumour >= 2 cm >= 2 mitoses/10 HPF, angioinvasion or MIB1 index > 2%
	WHO 2	well differentiated endocrine carcinoma with gross local invasion or metastasis
	WHO 3	poorly differentiated endocrine carcinoma with >= 10 mitoses / 10 HPF

CK19 has been shown to be an additional adverse prognostic marker independent of the WHO criteria, while COX2, p27 and p27 were not:

	MIB1 index > 2%	22/822
	CK19	38/782
	COX2 positive in more than 5% of cells	64/942
	p27 positive in more than 5% of cells	24/942
	CD99 positive in more than 5% of cells	53/942

In one study1, mitoses, necrosis, vascular invasion, perineural invasion and CK19 staining (but not Capella classification) were all prognostically significant on univariate analysis, but only CK19 staining was significant on multivariate analysis (p=0.0008).

	Alive and well	died or alive with disease
CK19 negative	25/251	0/251
CK19 positive	10/231	13/23(10 died, 3 alive with disease)1

Differential diagnoses

References

Diagnostic histopathology of tumors. Edited by CDM Fletcher. 2nd edition. Churchill Livingstone. Pages 1087-1091.

1 Deshpande, V., C. Fernandez-del Castillo, et al. (2004). "Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors." Am J Surg Pathol 28(9): 1145-53.

2 Schmitt AM, Anlauf M, Rousson V, et al. WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors. Am J Surg Pathol 2007; 31:1677-82

This page last revised 30.12.2007.