Dr. Ralph H. Hruban
Dr. Günter Klöppel
Case 6 -
Combined Serous Cystadenoma and Well-Differentiated Pancreatic Endocrine Carcinoma in a Patient with von Hippel-Lindau Disease
Service d'Anatomie Pathologique
Hôpital Cochin, Paris, France
This 34-year-old female underwent a computed tomography scan for chronic
postprandial abdominal pain. Her past medical history included retinal and cerebellar hemangioblastomas
and a resection of a clear cell carcinoma of the kidney. CT scan showed a pancreas entirely replaced by
numerous cysts of various sizes compressing the main pancreatic duct. Intermingled within the cysts, an
hypervascular mass of 32 mm was present in the head of the pancreas. A duodenopancreatectomy with
pancreaticogastric anastomosis was performed. At macroscopic examination the pancreas was entirely
involved by multilocular cysts containing serous fluid. Some cystic lesions showed central scars. A
solid yellow tumor of more than 3cm was observed in the head of the pancreas at proximity of the duodenal
wall. At distance a second centimetric tumor was detected.
The selected slide is from the cystic pancreatic lesions and the largest
Case 6 - Figure 1
Microscopic examination of the pancreatic slide shows a biphasic pattern with alternating cystic
areas and solid areas:
Based on this histology, additional information was asked to the clinicians. In fact, this patient
had a family history of von Hippel-Lindau (VHL) disease with a germline mutation of the VHL gene.
- Cystic areas consist of an aggregation of small
cysts irregularly distributed and separated by abundant collagen bands. Typical stellate scar and
calcifications are not observed. The cysts are lined by a single layer of monomorphous cuboidal cells
with hyperchromatic central nuclei and clear cytoplasm. Small papillary projections are present in some
cysts. The cells are rich in intracytoplasmic glycogen on PAS stain and are negative on Alcian Blue
- Solid areas consist of nest cells arranged in
trabecular or lobular or occasionally acinar patterns separated by numerous small vessels and large
fibrous bands. The majority of the neoplastic cells are uniform in size and are closely intermingled
with cystic lesions. They present an eosinophilic cytoplasm and contain round nuclei with coarse
chromatin. Rare pleomorphic cells with irregularly hyperchromatic nuclei are interspersed without
necrosis or vascular invasion. Rare mitoses were observed. However a contiguous lymphatic node is
infiltrated by tumoral cells. Another peripancreatic lymph node is also invaded. Strong positive
cytoplasmic immunoreactivity for chromogranin A and synaptophysin is observed. In contrast no labeling
was observed for different hormone peptides (insulin, gastrin, glucagon, somatostatin, calcitonin, VIP,
The pathologic diagnosis proposed is a combined serous cystadenoma and
well-differentiated pancreatic endocrine carcinoma in a patient with von Hippel-Lindau disease.
SEROUS CYSTIC NEOPLASMS OF THE PANCREAS
Serous cystic neoplasms (SCNs) of the pancreas are benign and cytologically monomorphous neoplasms.
Their histologically and immunohistochemically profiles suggest that they differentiate along lines
similar to centroacinar cells. SCNs occur in adults (mean age of 61 years) and affect female twice as
frequently as males. Most patients are asymptomatic or present non-specific symptoms such as abdominal
pain, vomiting or weight loss. Less commonly palpable abdominal mass, obstructive jaundice or recurrent
pancreatitis can occur. SCNs usually present as relatively large masses, mostly in the body or tail of
the pancreas . Although heterogeneous in their gross appearance, the microscopic features of
the tumor cells are remarkably invariable. The cysts which contain proteinaceous fluid are lined by a
single layer of clear cuboidal or flattened epithelial cells. They are negative for mucin stains, and
the glycogen can be highlighted by the PAS stain . They contain uniform round hyperchromatic
nuclei. Immunohistochemistry is usually not necessary to perform the diagnostic. Like centroacinar
cells and intra-lobular ducts, SCN express frequently MUC1 (34%) and MUC6 (70%) . They are
also positive in 80% and 100% of cases for alpha-inhibin and NSE respectively.
Based on their gross appearance five different subtypes of SCN have been described:
Identifying a pancreatic mass as a SCN on imaging is important because this tumor, unlike the other
cystic tumors of the pancreas, may not require a systematic surgical resection even if few cases have
been reported to metastasize or to show an aggressive local behaviour without evidence of significant
cytological atypia. However, because post-operative mortality can be significant in elderly or other
patients who are poor operative risks, typical microcystic SCN should be treated conservatively whenever
possible. Despite progress of imaging, macrocystic SCN remains difficult to distinguish from mucinous
cystadenoma, pseudocyts or rare congenital cysts.
- The most common form is the microcystic SCN. This lesion, well characterized on imaging, correspond to
multilocular cystic lesion containing a central stellate scar. They are often large in size (>10cm)
and do not communicate with the pancreatic ductal system. They are composed of innumerable tiny cysts
with a sponge-like appearance on cross section
- The serous oligocystic or
macrocystic form of SCN is a well delimitated unilocular or less frequently plurilocular cystic
lesion of the pancreas composed of cysts measuring more than 2cm in diameter . No central
stellate scar is present. They are difficult to distinguish clinically with pseudocysts or mucinous
cystadenoma. Millimetric cysts within the wall of unilocular macrocystic lesions permit their diagnostic
by endoscopic ultrasonography .
- The solid non cystic variant
of serous adenoma, usually of small size (<3cm), may be confused with pancreatic endocrine
tumor or metastatic renal cell carcinoma .
- The SCN occurring in patients
with von Hippel-lindau disease (see below) are multiple, diffusely distributed in pancreas and
show the coexistence of microcystic and oligocystic forms .
- The exceptionally rare serous
cystadenocarcinoma has histological features similar to those of SCN. However they show an
aggressive behavior displaying perineural or perivascular invasion, involvement of a regional lymph node
and/or the liver . Despite some well documented observations, the interpretation of the
tumors as malignant remains controversial. We cannot exclude that some of these cases correspond in
reality to VHL patients having complex lesions with voluminous serous cysts associated or not with
endocrine pancreatic tumor.
PANCREATIC LESIONS ASSOCIATED WITH VON HIPPEL-LINDAU DISEASE
VHL disease is an autosomal dominant syndrome that results from a germline mutation in the VHL tumor
suppressor gene located on chromosome 3p25 . The main function of VHL protein is the
negative regulation of hypoxia-inducible factor-1 (HIF-1). Dysfunction of
VHL protein caused by the VHL gene abnormality results in the absence of HIF-1 degradation and consequent overproduction of different growth factors.
Affected individuals are predisposed to develop a variety of neoplasms in multiple target organs. These
lesions include hemangioblastoma of the central nervous system, retinal angioma, endolymphatic sac tumor,
renal cell carcinoma, pheochromocytoma and cyst of the kidneys and epididymis. Pancreatic involvement
occurs in 60 to 80% of patients
It can be the unique organ affected in 8% of patients
with VHL disease. Majority of pancreatic lesions are usually asymptomatic and discovered during
systematic screening of family members with VHL. Most of them correspond to multiple and more rarely
isolated cystic lesions corresponding to microcystic and/or macrocystic forms of SCN. Compared with
sporadic cases, they show a much wider range of number, size and distribution within the pancreas. The
involvement can be limited to a minute cystic dilatation of a centroacinar lumen or in contrast affected
the entire pancreatic gland as in our case. Compression of the main pancreatic duct or neighboring
organs occurrs in 20% of patients. No malignant forms have been described. Associated to these cystic
lesions, pancreatic endocrine neoplasms (PENs) may be encountered in 10 to 17% of VHL patients
Association of these 2 rare tumors within the pancreas is highly suggestive of VHL
disease. PENs can be difficult to distinguish on CT scans from a solid form of vascularized SCN.
Although the architecture and immunohistochemical profile permit easily the diagnosis of PENs, some
particular features suggest VHL associated PEN from their sporadic counterparts. Prominent nuclear
atypia are observed as well as a clear cell morphology. This pattern observed in 60% of cases is due to
the presence of numerous cytoplasmic lipid droplets . This feature is not specific of PENs
associated with VHL as it has recently been described in rare sporadic cases . Like in our
observation, PENs in VHL patients are often multiple and disseminated throughout the pancreas making
therapeutic decisions difficult. This multiplicity of endocrine lesions raise the differential diagnosis
with multiple endocrine neoplasia type 1. However, frequency of PENs and symptomatic hormone
hypersecretion appear higher in this later genetic syndrome. Like in MEN1, there is a risk of malignant
transformation of PENs in VHL patient and metastatic progression has been shown to occur in 25% of
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