Serous oligocystic adenoma of the pancreas: a clinicopathological and immunohistochemical study of three cases with ultrastructural findings

Pathology (2002 ) 34, pp. 148– 156

ANATOMICAL

PATHOLOGY

Serous oligocystic adenoma of the pancreas: a clinicopathological and immunohistochemical study of three cases with ultrastructural findings LEONARDO D. SANTOS, CHRISTOPHER CHOW, CHRISTOPHER J. A. HENDERSON, DAVID N. BLOMBERG*, NEIL D. MERRETT*, ALAN R. KENNERSON AND MURRAY C. KILLINGSWORTH Department of Anatomical Pathology, South Western Area Pathology Service, Liverpool, and *Department of Surgery, Bankstown-Lidcombe Hospital, Bankstown, NSW, Australia

Summary Aims: Serous oligocystic adenoma of the pancreas is an uncommon benign neoplasm and is a recently described entity. To date, there are 19 adult cases of this tumour. We report three additional cases, two with macrocystic and one with unilocular types. We describe their clinicopathological , immunohistochemical and ultrastructural findings and review the world’s literature. Methods: For a 10-year period, we reviewed all benign cystic lesions of the pancreas with emphasis on serous oligocystic adenoma. We characterised serous oligocystic adenoma as an ill-demarcated or encapsulated mass, composed largely or exclusively of macrocysts (cysts measuring 20 mm or more) but few in number (oligolocular). Grossly, it may contain only a single cyst (unilocular) of any size with a few satellite cysts observed on histological examination. Special stains and immunohistochemistry as well as electron microscopy were performed on three and two cases of serous oligocystic adenoma, respectively. Results: Between 1990 and 2000, we collected 26 benign cystic lesions of the pancreas, three of which were serous oligocystic adenomas (two with macrocystic and one with unilocular types). Many of the cells lining the cysts showed PAS positivity. There was negative staining for PAS with diastase digestion, Alcian blue and mucicarmine. All cases showed positive staining for CAM5.2, AE1/AE3, EMA and CK7. The proliferation index marker was low. There was negative staining for CK20, insulin, glucagon, somatostatin, synaptophysin, chromogranin A, CEA and p53. Ultrastructural studies on two cases revealed similar findings. The single row of uniform epithelial cells lining the cysts was composed of simple cuboidal to flat cells which rested on a thin basal lamina. Their nuclei were round to ovoid. Glycogen granules were identified in the cytoplasm. Short microvilli emerged from the epithelial apical surface. Adjacent tumour cells were connected by microfilaments. Conclusions: Serous oligocystic adenomas of the pancreas are uncommon benign tumours. Prior to this study, 19 adults with these lesions were reported in the world’s literature. No correct pre-operative diagnosis was carried out on all 22 cases. The 20 patients with follow-up ranging from 2 months to 5 years did not show tumour recurrence or malignant transformation.

Key words: Serous cystadenoma, serous oligocystic adenoma, microcystic adenoma, macrocystic adenoma, macrocystic serous cystadenoma , unilocular cyst, serous cystic tumours, electron microscopy, immunohistochemistry. Received 26 April, revised 17 August, accepted 20 August 2001

INTRODUCTION Serous cystadenomas of the pancreas are uncommon benign neoplasms.1–20 They are composed of epithelial cells that produce serous fluid and show evidence of ductular differentiation. 21 They are subdivided into serous microcystic ( glycogen-rich ), solid serous1 and serous oligocystic adenoma ( SOA).2–19,21 The former is the most common and well-known group. The latter, a recently described entity which has been clearly characterised,2–19,21 exhibits distinctly different macroscopic features from and is much less common than serous microcystic adenoma. A Medline search revealed 19 published adult cases of SOA.2–11 We report three additional cases ( two of macrocystic type and one of unilocular type).

MATERIALS AND METHODS A review of the computerised surgical pathology files of South Western Area Pathology Service for a 10-year period ( from 1 December 1990 to 30 November 2000) revealed three cases of serous oligocystic adenoma ( of macrocystic and unilocular types). We characterised oligocystic adenoma as an ill-demarcated or encapsulated mass, composed largely or exclusively of macrocysts ( cysts measuring 20 mm or more) but few in number ( oligolocular), or containing only a single macroscopic cyst ( unilocular ) of any size, with a few satellite cysts observed on microscopic examination. This definition is based on the criteria originally described by Lewandrowski et al. 11 and Egawa et al. 3 Gross photographs were available for two of the tumours. All specimens for light microscopic examinations were immediately fixed in 10% buffered formalin and embedded in paraffin. Five-mm-thick sections were stained with H&E. Between 10 and 30 slides from different paraffin blocks were reviewed per case, with a mean of 18 slides per case. Selected sections were also stained with periodic acid–Schiff ( PAS) with

ISSN 0031–3025 printed/ISSN 1465– 3931 online/02/020148 – 09 © 2002 Royal College of Pathologists of Australasia DOI:10.1080/003130201201117963

149

SEROUS OLIGOCYSTIC ADENOMA PANCREAS

TABLE 1

Antibodies used, their sources and results

Antibodies Low molecular weight keratin ( LMWK) High molecular weight keratin ( HMWK) Low and intermediate weight keratin Epithelial membrane antigen ( EMA) Carcinoembryonic antigen ( CEA) Neuron-specific enolase ( NSE) Chromogranin A Synaptophysin CA19.9 Vimentin CK7 CK20 Ki67 Insulin Glucagon Somatostatin p53

Source*

Concentration

Polyclonal/monoclonal

Case 1†

Case 2†

Case 3†

Becton-Dickinson Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako Dako

1:3 1:75 1:100 1:150 1:50 1:1000 1:1000 1:200 1:100 1:150 1:100 1:75 1:100 1:3 1:3 1:3 1:100

Clone CAM 5.2 Clone 39bE12 Clone AE1/AE3 Clone E29 Clone II-7 Polyclonal Clone DAK-A3 Clone SY 38 Clone 116–NS–19–9 Clone V9 Clone OV-TL 12/30 Clone Ks 20– 8 Clone Ki67 Polyclonal Polyclonal Polyclonal Clone DO-7

5+, S 1+, W 5+, S 5+, S – 3+, M – – 4+, S – 5+, S – 1+, M – – – –

5+, S – 5+, S 5+, S – – – – – 1+, W 5+, S – 1+, M – – – –

4+, S 3+, M 5+, S 2+, M – 2+, W – – – 5+, S 5+, S – 1+, M – – – –

* Becton, Dickinson and Dako, NSW, Australia. † –, 0%; 1 + , < 5%; 2 + , 5– 25%; 3 + , 26–50%; 4 + , 51–75%; 5 + , > 75% of the cells are staining; W, weak staining; M, moderate staining; S, Strong staining.

RESULTS Between December 1990 and November 2000, we collected 26 benign pancreatic cystic lesions ( Table 2). During this 10-year period, there were approximately 187 000 gynaecological and non-gynaecological surgical cases. The most common cystic masses of the pancreas were benign mucinous cystadenomas with nine cases ( age range, 18–78 years; mean, 49.4 years), followed by pseudocysts with eight cases ( age range, 28–76 years; mean, 44.3 years). We had only one surgical case of a congenital true cyst. For benign serous cystic lesions, there were five microcystic ( glycogen-rich ) and three oligocystic adenomas (of macrocystic and unilocular types). The clinical data of the latter were obtained from the attending doctors and from medical records and are shown at the top of Table 3.

and without diastase digestion, Alcian blue at pH 2.5, Mayer’s mucicarmine, Von Kossa, Perl’s, orcein and Masson’s trichrome stains. Immunohistochemistry was also performed on paraffin-embedde d tissue, employing the streptavidin– biotin method. The tumours were tested with the following monoclonal antibodies: low molecular weight cytokeratin ( LMWK), high molecular weight cytokeratin ( HMWK) , low and intermediate molecular weight cytokeratin, cytokeratin ( CK) 7, CK20, epithelial membrane antigen ( EMA), monoclonal carcinoembryonic antigen ( CEA), CA19.9, p53, Ki67, vimentin, synaptophysin and chromogranin A. For EMA, CA19.9, synaptophysin, chromogranin A, vimentin and Ki67, the sections underwent microwave antigen retrieval. For LMWK, HMWK, CK7, CK20 and CEA, the sections underwent protease antigen retrieval. Polyclonal antibodies to insulin, glucagon, somatostatin and neuron specific enolase ( NSE) were also performed ( Table 1). Selection criteria for optimal staining were intensity of positive staining and absence of non-specific background staining. From these test batches, suitable positive controls were used to monitor batch variation and, as a reference, for determining intensity of staining in each test. The staining reaction was either negative or positive. According to the staining intensity, the latter was divided into weak, moderate or strong. The percentage of positive staining cells was divided into 1 + ( < 5% of the cells were positive ), 2 + ( 5–25% ), 3 + ( 26– 50% ), 4 + ( 51–75% ), and 5 + ( 76–100% ). Normal rabbit and mouse sera were used in the place of primary antibodies as negative staining controls. Positive staining controls were included for each antibody and, when present in the specimen, internal staining controls were also checked for appropriate reactions with each antibody. Electron microscopy was performed on samples from the two cases. One case had tissue selected from fresh tumour and one from formalin-fixed tissue. Ultrathin sections were cut at 120 nm and photographed on a Zeiss EM 109T TEM ( Carl Zeiss, Australia Pty Ltd) at 80 kV.

TABLE 2

Gross pathology Case 1 The specimen consisted of body and tail of pancreas measuring 115 ´ 60 ´ 27 mm with attached spleen measuring 120 ´ 80 ´ 50 mm. On sectioning, there was a well-circumscribed, unilocular cyst measuring 30 mm in diameter containing clear fluid. The cyst wall thickness measured 1 mm. The inner surface of the cyst was smooth and glistening. The spleen was normal. Case 2 The specimen consisted of the distal end of the pancreas measuring 70 ´ 50 ´ 30 mm with surrounding fat

Benign pancreatic cystic lesions from 1990 to 2000, South Western Area Pathology Service

Pathological diagnosis Serous oligocystic adenoma Microcystic serous cystadenom a Benign mucinous cystadenoma Pseudocysts Congenital true cyst

Number of cases

Percentage of all cystic lesions

Female

Male

( range, years)

3 5 9 8 1

11.5 19.2 34.6 30.8 3.8

2 4 8 2 1

1 1 1 1 0

34– 53 49–78 18–78 28–76 21

Age

53, F

47, M

34, F

66, F

46, M

69, M

60, F

67, F

50, F

69, M

2*

3*

411

511

611

711

811

98

103

Incidental ( duodenal ulcer surgery)

Head

Head

Tail

Head

Head

Tail

Body

Tail

Tail

Body

Location

Multilocular cyst

Multicystic

50 ´ 35 ´ 30

80 ´ 65 ´ 40

Unilocular cyst

Oligolocular cyst

110, max

50 ´ 45

Oligolocular cyst

Oligolocular cyst

80 ´ 80 ´ 70 35, max

Unilocular cyst

25, max

Unilocular cyst

Multilocular cyst

35 ´ 35 ´ 30

25, max

Unilocular cyst

Macroscopic description

30, max

Size ( mm)

None

MCN or pseudocyst

MCN

MCN

MCN or pseudocyst

Tumour or pseudocyst

MCN

MCN or pseudocyst

Cystic tumour

MCN

Pre-operative diagnosis ND

ND

No malignant cells noted

ND

ND

ND

ND

ND

ND

Frozen section diagnosis

ND

Serous cystadenoma

ND

ND

Pseudocyst

Simple cyst

Serous cystadenoma

ND

Insufficient material ND

ND

FNAB cytological findings

Not specified

Tumour enucleation

Distal pancreatectomy

Subtotal pancreatectomy

Whipple procedure

Distal pancreatectomy

Subtotal pancreatectomy

Distal pancreatectomy and splenectomy

Distal pancreatectomy and splenectomy

Distal pancreatectomy and splenectomy

Surgical treatment

3.6 years, died of AMI

2 months, AW

Follow-up on Cases 4 to 8 ranged from 6 months to 5 years, mean 1.8 years, AW

5 months, AW

8 months, AW

3 years, AW

Follow-up

SANTOS et al.

Vague indigestion and constipation for 2 months

Mild upper abdominal pain for 8 months

Mild right upper quadrant discomfort

Episodic nausea and vomiting with dull epigastric pain for 2 weeks

Incidental ( resection of duodenal gastrinoma)

Upper abdominal fullness for 2 years

Upper abdominal pain

Constant back pain for 6 months

Upper abdominal pain

Age ( years)/sex Symptoms

Clinicopathological features of 22 cases of pancreatic serous oligocystic adenoma from 1992 to 2000 including 19 cases reported in the literature and three cases from the present study

1*

Case no.

TABLE 3

150 Pathology (2002 ), 34, April

61, F

67, M

35, F

28, F

70, F

48, F

47, F

35, M

59, F

30, F

59, M

123

133

142

159

1610

176

187

194

204

214

225

Upper abdominal pain and weight loss

Incidental ( abdominal trauma due to car accident)

Mild epigastric pain for 1 year

Asthenia and mild dyspepsia for 6 months

Left hypochondriac discomfort for 2 months

Right hypochondriac pain

Epigastric discomfort

Upper abdominal pain for 9 months

Mild upper abdominal pain

Oppressive sensations in the upper abdomen

Obstructive jaundice

Obstructive jaundice, steatorrhoea

Body and tail

Body

Head

Head

Body and tail

Tail

Head

Head

Body

Head

Head

Head

Location

Oligolocular cyst

40 ´ 30 ´ 20

Cystic

Multilocular cyst

75 ´ 125

Multicystic

40, max

120, max

Multilocular cyst

Oligolocular cyst

50 ´ 45 ´ 30

80, max

Unilocular cyst

50, max

Polycystic

Unilocular cyst

15 ´ 10 35, max

Oligolocular cyst

30, max

Oligolocular cyst

Oligolocular cyst

70 ´ 40 ´ 40

40, max

Macroscopic description

Size ( mm)

MCN

Haematoma

MCN

MCN

MCN

MCN

MCN

Pseudocyst

MCN

None

None

None

Pre-operative diagnosis

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

FNAB cytological findings

ND

Macrocystic serous adenoma

ND

Lymphangioma

ND

ND

ND

Benign

ND

ND

ND

ND

Frozen section diagnosis

Subtotal pancreatectomy

Tumour excision without pancreatectomy

Pancreaticoduodenectomy

Tumour excision without pancreatectomy

Distal pancreatectomy and splenectomy

Distal pancreatectomy

Pancreaticoduodenectomy

Tumour enucleation

Tumour enucleation

Not specified

Not specified

Not specified

Surgical treatment

* Present study. Abbreviations: AMI, acute myocardial infarction; AW, alive and well; FNAB, fine needle aspiration biopsy; max, maximum dimension; MCN, mucinous cystic neoplasm; ND, not done.

60, M

Age ( years)/sex Symptoms

113

Case no.

TABLE 3 ( Continued)

Unknown

2 months, AW

1 year, AW

17 months, AW

14 months, AW

30 months, AW

9 months, AW

Unknown

14 months, AW

0.7 years, AW

3.3 years, AW

4 years, AW

Follow-up

SEROUS OLIGOCYSTIC ADENOMA PANCREAS

151

152

Pathology (2002 ), 34, April

SANTOS et al.

Case 3 The specimen consisted of the distal pancreas measuring 90 ´ 55 ´ 30 mm with attached spleen measuring 90 ´ 70 ´ 30 mm and omentum measuring 150 ´ 90 ´ 15 mm. Within the pancreas, there was an intact, multiloculated, circumscribed cyst measuring 50 ´ 35 ´ 30 mm and containing bloodstained, watery fluid. The cyst wall thickness measured up to 3 mm. The inner surface of the cyst was smooth. There was no evidence of a central stellate scar. The surrounding pancreatic tissue showed no signs of necrosis or haemorrhage. The spleen was unremarkable.

Fig. 1 Case 2. The bisected serous oligocystic adenoma of the pancreas shows a few large cysts filled with brownish or watery clear fluid.

and attached spleen which measured 80 ´ 70 ´ 35 mm. The cut surface of the pancreas showed an intact, multiloculated, well-circumscribed, cystic tumour measuring 35 ´ 35 ´ 30 mm which was surrounded by pancreatic tissue ( Fig. 1 and 2). The cysts measured from 3 to 30 mm in diameter and were filled with watery clear or brownish fluid. The inner lining of the locules was smooth. The cyst wall thickness measured up to 3 mm. There was no stellate scar. The surrounding pancreatic tissue showed no evidence of haemorrhage, necrosis or perforation. The spleen showed no significant abnormalities.

Light microscopy The well-circumscribed, unilocular cyst of Case 1 was lined by a single layer of simple cuboidal to flat epithelium composed of uniform cells with regular nuclei and clear cytoplasm. A few cells showed eosinophilic cytoplasm. The round to oval nuclei were centrally located. Nucleoli and mitoses were not seen. In places, the lining epithelium was focally undulating without being frankly papillary in nature. In areas, the lining was denuded. There were prominent small blood vessels in the cyst wall. Focally, calcification was present. Occasional minute satellite cysts were seen. The adjacent pancreatic tissue showed no abnormality. Excision of the cyst was complete. This cyst was typical of the unilocular type of serous oligocystic adenoma of the pancreas. The two multiloculated cysts (Cases 2 and 3) showed similar histology (Fig. 3 and 4). The cysts of variable sizes were few in number and were lined by a single layer of

Fig. 2 Case 2. A CT scan showing a well-defined cystic mass in the tail of the pancreas.

SEROUS OLIGOCYSTIC ADENOMA PANCREAS

Fig. 3 Case 3. A section of serous oligocystic adenoma showing cysts of variable sizes ( H&E, original magnification, ´20 ).

regular cuboidal to attenuated cells with bland, central round to slightly oval nuclei with inconspicuous nucleoli. Most of the epithelial cells contained abundant clear cytoplasm. Occasional cells showed granular, pink cytoplasm. Degenerative changes were observed in other epithelial cells. Nuclear pleomorphism and mitoses were absent. In places where the epithelium was denuded, the adjacent stroma showed a focal, chronic inflammatory reaction with occasional foreign body giant cells, sheets of haemosiderin-laden macrophages and cholesterol crystals. Intracystic papillary projections were not seen. The septa separating the cysts measured from 0.1 to 3.8 mm in thickness. The thick septa were dense, fibrotic, hyalinised and paucicellular. Scattered randomly within the septa were small islands of pancreatic acinar elements as well as some nerves and blood vessels. In areas, there was oedema as well as inflammatory cell infiltrates composed predominantly of lymphocytes and a few plasma cells, eosinophils and, rarely, neutrophils. Sometimes, a band of lymphocytes was present beneath the lining epithelium. A few nerves were surrounded by lymphocytes. Scattered pigment-laden macrophages in the stroma were positive for Perl’s stain. Both cystic masses were circumscribed, focally lobulated and were completely excised. An incomplete fibrous capsule seemed to surround the lesions. Case 2 was completely encompassed by pancreatic tissue. Case 3 was

Fig. 4 Case 3. This septum is lined on both sides by a single layer of cuboidal epithelium ( H&E, original magnification, ´100).

153

focally surrounded by fatty tissue. These cysts were typical of the serous oligocystic adenoma of macrocystic type. Many of the cells lining the cysts in these three cases showed PAS positivity. There was loss of PAS staining after diastase digestion. Alcian blue and mucicarmine were negative. Masson’s trichrome highlighted the dense connective tissue stroma in the thick septa just beneath the lining epithelium and around the cystic masses. Scattered elastic fibres were seen with the orcein stain. The three cases showed positive membranous staining for epithelial membrane antigen (EMA) as well as uniform cytoplasmic staining with membranous accentuation for CAM5.2, AE1/AE3 and CK7 ( Table 1). Two of the cases were immunoreactive for HMWK, NSE and vimentin. One case was positive for CA19.9. There was negative staining for CK20, insulin, glucagon, somatostatin, synaptophysin, chromogranin A, carcinoembryonic antigen ( monoclonal CEA) and p53. Less than 1% of the cells showed intranuclear staining for Ki67 ( low proliferation marker index). Ultrastructural studies of Cases 2 and 3 revealed almost similar findings. The single row of uniform epithelial cells lining the cysts was composed of simple cuboidal to flat cells which rested on a thin, well-formed basal lamina. The nuclei were round to ovoid with generally smooth nuclear membranes. Some cells showed prominent clumps of chromatin. A few nuclei contained a prominent nucleolus. The cytoplasm contained glycogen granules, some mitochondria and occasional lysosomes. Golgi complexes and rough endoplasmic reticulum were rare. Zymogen and secretory granules were not identified. Beneath and close to the neoplastic epithelial cells, there was a delicate network of capillaries with prominent endothelial cells. The stromal compartment contained unremarkable collagen fibres and fibroblasts. Short, blunt, irregularly spaced microvilli emerged from the epithelial apical surface and projected into the lumen. These did not contain microfilaments. Dense core rootlets were not observed. Adjacent tumour cells were connected by desmosomes ( Fig. 5).

DISCUSSION Prior to 1960, little was known about the natural history and histological characteristics of pancreatic cystic tumours.20 In the past, there was tendency to include all cystic lesions of the pancreas in the same pathological group. This caused considerable confusion and controversy among pathologists. 20 Pancreatic cystic lesions account for less than 0.01% of all hospital admissions.14 They can be classified into cystic neoplasms, acquired cysts and congenital true cysts.12,22 Examples of acquired cysts are parasitic cysts ( hydatid cyst and cysts due to tapeworms) and pseudocysts which include chronic pseudocysts and cystic necrosis of the pancreas and peripancreatic tissue. Congenital cysts include enterogenous cysts, dermoid cysts and single true cyst(s). Although numerous reports on pancreatic cysts have been published, the vast majority has dealt with non-neoplastic pseudocysts, which constitute perhaps 90% of pancreatic cystic lesions.22 Pancreatic cystic neoplasms have been known since 1824. 14 They account for less than 1% of all pancreatic

154

SANTOS et al.

Pathology (2002 ), 34, April

Fig. 5 Case 2. The cyst is lined by cuboidal cells with round, centrally located nuclei. Some cells show clear cytoplasm. Desmosomes can be seen between adjacent epithelial cells. Occasional short microvilli emerge from the epithelial apical surface. The stroma contains collagen and endothelial-lined vascular spaces ( EM, original magnification, ´5430 ).

tumours. 20 The most common cystic neoplasms include serous cystadenoma ( classic microcystic and macrocystic types ), mucinous cystic neoplasms ( benign, borderline and malignant varieties), solid pseudopapillary tumours and intraductal papillary-mucinous neoplasms.19 The most common types are the mucinous and serous cystadenoma.4,6,23 The former is believed to be the most frequent4 and the most widely recognised type.15 Recent reports have mentioned that mucinous cystic neoplasms are encountered about half as frequently as serous cystic tumours.19 Serous cystadenomas (SCs) of the pancreas are relatively rare benign neoplasms.1–19 From 1978 to 1991, there have been 211 cases reported in the literature.12 These adenomas occupy a unique place among the cystic neoplasms of the pancreas because they are universally benign24 with indolent biological behaviour, diverse pathological features and distinctive clinical presentation.19 They have only recently been clearly defined and delineated from mucinous cystadenoma. 18 Serous cystadenomas of the pancreas are formed of epithelial cells that produce serous fluid. The morphological

spectrum and biological diversity of SCs have expanded in recent years. The current World Health Organization,25 in recognition of the macroscopic variation in locule size that SCs may exhibit, subclassifies them into serous microcystic adenoma ( SMA) and serous oligocystic adenoma ( SOA). Synonyms of the latter that have been used in the literature include macrocystic serous cystadenoma ( a term introduced and defined by Lewandrowski et al. in 1992)11 and serous oligocystic and ill-defined adenoma ( a term proposed by Egawa et al. in 1994 ).3 A single case of solid serous adenoma, the third subtype of SOA, has been recently reported. 1 SOA is composed of only a few relatively large cysts lined by simple epithelial cells showing evidence of ductular differentiation.21 SOA, which is much less common than the classical serous microcystic ( glycogen-rich ) cystadenoma, includes macrocystic serous cystadenoma, serous oligocystic and ill-demarcated adenoma,2,3,11 and the cystadenomas observed in children.26–29 Review of the world’s literature revealed 19 cases of SOA ( Table 3).2–11 These adult patients showed no

SEROUS OLIGOCYSTIC ADENOMA PANCREAS

evidence of coexistent malignant tumours in the pancreas and there was no association with von Hippel-Lindau disease. SOA has been reported in children; however, the criteria for diagnosis in these cases are unclear from the articles.26–29 Serous oligocystic adenoma shows a female predilection. Adults are usually 50 years and over (age range, 28–70 years; mean, 52.7 years). The aetiology of SOA is unknown. The molecular biology of serous cystadenomas appears to differ from that of mucinous cystic tumours, intraductal papillary-mucinous tumours and ductal adenocarcinoma. Serous cystadenomas lack p53 and K-ras mutations; the latter are early genetic events common to the majority of mucin-producing tumours.30–33 The most common symptom in adult patients was abdominal pain which was present in nine of 22 patients ( 41% ). The pain was located in the upper abdomen, epigastric, right upper quadrant or right hypochondrium . One patient complained of back pain. Abdominal discomfort was the main symptom in four patients ( 18% ). Obstructive jaundice was observed in two patients ( 9% ). Other symptoms included upper abdominal fullness, steatorrhoea, episodic nausea and vomiting, vague indigestion and constipation. Three tumours were discovered incidentally: two during surgery for duodenal lesions3,10 and one during a laparotomy4 ( Table 3). SOAs typically present as well-circumscribed, encapsulated, sometimes ill-defined or lobulated cystic neoplasms with a diameter of 15–125 mm. The tumours are most commonly composed of a few cysts 15–20 mm in diameter and filled with clear or brown fluid, but can contain cysts up to 80 mm in diameter and sometimes only a single cyst. The cysts are irregularly arranged and separated by mostly broad septa. Often, there is one large dominant cyst and a few small satellite cysts. A central stellate scar, which is characteristically seen in serous microcystic adenoma, is absent. Table 3 shows that 11 cystic neoplasms were located in the pancreatic head.3,4,8–11 Five lesions were described macroscopically as unilocular cysts.6,8,9,11 In our cases, the cystic tumours ranged in size from 30 to 50 mm. The two cystic neoplasms (macrocystic type) were located in the tail of the pancreas. The third, which was unilocular, was situated in the body and showed a few scattered, peripheral, minute cysts not apparent on gross examination. SOAs show the same microscopic features as serous microcystic ( classical or glycogen-rich) cystadenomas. The lining epithelium of the cysts is a single layer, composed of cuboidal to flat, generally monomorphous cells with mostly round, centrally located nuclei. The cytoplasm is clear due to the presence of glycogen but can be sometimes eosinophilic. Mitoses and cytological atypia are characteristically absent. Mucin stains are all negative. The cyst lining epithelium can be focally or extensively denuded.8,11 The septa separating the cysts are usually broad and contain entrapped acini, ducts, nerves, blood vessels and inflammatory cells.1,3,10 SOAs consistently show diffuse membranous staining for epithelial membrane antigen (EMA) and diffuse cytoplasmic staining for cytokeratins.19,21 CA19.9 and B72.3 may be focally positive. There is negative staining for CEA, trypsin, HMB45, S100 protein, desmin, actin, factor XIII and other endothelial-associated antigens. About 40% of cells are positive for neuron-specific enolase ( NSE), but immunostaining for neuroendocrine or islet cell differentiation, such as chromogranin, synaptophysin,

155

chromogranin A, insulin, glucagon, somatostatin, vasoactive intestinal polypeptide and pancreatic polypeptide is uniformly negative.1–3 Interestingly, two of our cases were immunoreactive for vimentin. Previous studies have shown negative staining for this marker.8,19,21 There was only a single report of SOA in an adult patient with electron microscopic and cytological findings.8 The ultrastructural features of this case were generally similar to our two cases. The fine-needle aspiration biopsy ( FNAB) results showed rare clusters of large cells in monolayered sheets with a honeycombing pattern, and with abundant, faintly granular to clear cytoplasm with no mucin vacuoles. The small nuclei contained inconspicuous nucleoli. Neither intranuclear inclusions nor nuclear grooves were present.8 FNAB was performed in one of our cases but the material was insufficient for diagnosis. The differential diagnosis of SOA is very important before surgery because of its close similarity to mucinous cystic tumours ( MCTs), pseudocysts, lymphangioma and congenital true pancreatic cyst. Its prognosis is much better than MCTs.4 The macroscopic and radiological features of the malignant and potentially malignant ( or tumours of unknown malignant potential)25 types of MCT may be similar to SOA.4,6–8,11,19,21 Only on microscopic examination can one definitely distinguish one lesion from another. The main differences between SOA and SMA are the absence of a central stellate scar in the former and the presence of innumerable, mostly minute ( often less than 1 mm in diameter) cysts in the latter tumour. SOA often has a thick, fibrous capsule and thick, fibrous septa between the locules.2,10 On gross examination, SOA may closely resemble both mucinous cystic tumour and pseudocyst because of the presence of thick walls, peripheral calcifications and a small number of relatively large cystic structures. 19 However, the cyst contents are different. SOA contains clear, thin, watery, straw-coloured fluid or fluid that is bloody or haemosiderin-stained, while mucinous tumours typically contain thick, viscous fluid. Pseudocysts typically contain turbid, grummous material.19,21 Pre-operative diagnosis of SOA is difficult.7 In the cases reported in the literature, no correct diagnosis was made prior to frozen section and histological examination.2–11 Fourteen of the 18 cases were thought to be mucinous cystic neoplasms; others were called pseudocysts. The preoperative diagnosis relies mainly on imaging studies and biochemical features of the cyst fluid. Preoperative percutaneous needle aspiration biopsy may be useful, despite its inherent limitations.8 Computed tomography ( CT), endoscopic ultrasonography, magnetic resonance imaging and magnetic resonance cholangiopancreatography are useful in pre-operative evaluation. Pre-operative diagnosis of serous pancreatic tumours by imaging tends to rely on the central scar and small size of the cystic spaces. Misdiagnosis often occurs in SOAs because these tumours appear similar to that of mucinous cystic neoplasms and, if unilocular, pseudocysts.18,20 Intra-operative consultations were utilised only seven times.4,9,11,15 The frozen section diagnoses included serous cystadenoma ( three cases), simple cyst and pseudocyst. One was simply called ‘benign’. Lymphangioma was diagnosed in a tissue sample from a denuded cystic wall with underlying capillary layer.4 Multiple frozen sections might be necessary before a correct diagnosis is reached in cases where there is an extensive denudation of the cyst epithelial lining.8

156

SANTOS et al.

Complete surgical resection of symptomatic cystic mass is curative.11,21 The surgical treatment has not been uniform ( Table 3). Tumour enucleation without pancreatectomy was performed in five cases. Most of the cases were treated with some form of pancreatectomy. A fistula developed in two cases ( Cases 2 and 9). The authors of one report4 suggested that SOA located at the head of the pancreas should be excised without pancreatectomy, but another report counselled against tumour enucleation.12 Drainage of the cyst is not an option because of a high risk of pancreatico-jejunal fistula. SOA located in the body or tail, on the other hand, may be excised with12 or without pancreatectomy.4 The 20 patients mentioned in these studies2–4,6–8,10,11 have followup ranging from 2 months to 5 years. Two patients have no known follow-up.5,9 Nineteen patients are alive and well and show no evidence of recurrence or malignant transformation. One patient died of acute myocardial infarction 3.6 years after the surgery.3 When he was alive, tumour recurrence or malignant transformation was not detected.3 Our three patients have been regularly followed up. The follow-up time ranges from 5 months to 3 years and there has been no evidence of recurrence. The prognosis of SOA is excellent because this tumour is benign.3,4,12,18,20,24,25 In contrast, some of the mucinous cystic tumours are potentially malignant or frankly malignant.18,20,21,25 It is, therefore, important to separate SOA from MCTs because it exhibits a different biological pattern and requires a different surgical approach.4,21 The only way to distinguish one from the other is by histological examination. ACKNOWLEDGEMENTS The authors are grateful to Ms Heidi Otten, Ms Stephanie McDonald, Mr Joseph L. Santos and Mr Shane Pride for their expert technical support. Address for correspondence: Dr L. D. Santos, Department of Anatomical Pathology, South Western Area Pathology Service, Locked Mail Bag 7090, Liverpool BC, NSW 1871, Australia. E-mail: [email protected] w.gov.au

References 1. Perez-Ordonez B, Naseem A, Lieberman PH, Klimstra DS. Solid serous adenoma of the pancreas: the solid variant of serous cystadenoma? Am J Surg Pathol 1996; 20: 1401–5. 2. Mori K, Takeyama S, Hirosawa H, et al. A case of macrocystic serous cystadenoma of the pancreas. Int J Pancreatol 1995; 17: 91–3. 3. Egawa N, Maillet B, Schr¨oder S, Mukai K, Kl¨oppel G. Serous oligocystic and ill-demarcated adenoma of the pancreas: a variant of serous cystic adenoma. Virchows Arch Pathol Anat 1994; 424: 13–7. 4. Casadei R, Santini D, Greco VM, et al. Macrocystic serous cystadenoma of the pancreas. Diagnostic, therapeutic and pathological considerations of three cases. Ital J Gastroenterol Hepatol 1997; 29: 54–7. 5. Heindryckx E, Van Hoe L, Vanbeckevoort D, et al. Quiz case of the month. Eur Radiol 1998; 8: 1497– 8. 6. Gouhiri M, Soyer P, Barbagelatta M, Rymer R. Macrocystic serous cystadenoma of the pancreas: CT and endosonographic features. Abdom Imaging 1999; 24: 72–4. 7. Fujiwara H, Ajiki T, Fukuoka K, Mitsutsuji M, Yamamoto M, Kuroda Y. Macrocystic serous cystadenoma of the pancreas. J Hepatobiliary Pancreat Surg 2000; 7: 92–6. 8. Huh JR, Chi JG, Jung KC, Choe KY, Yoon YB. Macrocystic serous cystadenomas of the pancreas – a case report. J Korean Med Sci 1994; 9: 78– 85.

Pathology (2002 ), 34, April 9. Yoon MJ, Hyunee Y, In JC. Pancreatic serous cystadenoma mimicking pseudocyst. Yonsei Med J 1997; 38: 63– 5. 10. Inoue S, Yamaguchi K, Shimizu S, et al. Serous cystadenoma of the pancreas with atypical imaging features: a new variant of serous cystadenoma of the pancreas. Pancreas 1998; 16: 102–6. 11. Lewandrowski K, Warshaw A, Compton C. Macrocystic cystadenom a of the pancreas: a morphologic variant differing from microcystic adenoma. Hum Pathol 1992; 23: 871–5. 12. Pyke CM, Van Heerden JA, Colby TV, Sarr MG, Weaver AL. The spectrum of serous cystadenoma of the pancreas: clinical, pathologic, and surgical aspects. Ann Surg 1992; 215: 132– 9. 13. Yamaguchi K, Enjoji M. Cystic neoplasms of the pancreas. Gastroenterology 1987; 92: 1934– 43. 14. Alpert LC, Truong L D, Bossart MI, Spjut HJ. Microcystic adenoma ( serous cystadenom a) of the pancreas: a study of 14 cases with immunohistochemical and electron-microscopic correlation. Am J Surg Pathol 1988; 12: 251–63. 15. Shorten SD, Hart WR, Petras RE. Microcystic adenomas ( serous cystadenomas) of pancreas: a clinicopathologic investigation of eight cases with immunohistochemical and ultrastructural studies. Am J Surg Pathol 1986; 10: 365–72. 16. Nyongo A, Huntrakoon M. Microcystic adenoma of the pancreas with myoepithelial cells: a hitherto undescribed morphologic feature. Am J Clin Pathol 1985; 84: 114– 20. 17. Bogomoletz WV, Adnet JJ, Widgren S, Stavrou M, McLaughlin JE. Cystadenoma of the pancreas: a histological, histochemical and ultrastructural study of seven cases. Histopathology 1980; 4: 309– 20. 18. Compagno J, Oertel JE. Microcystic adenomas of the pancreas ( glycogen-rich cystadenoma s): a clinicopathologic study of 34 cases. Am J Clin Pathol 1978; 69: 289– 98. 19. Compton CC. Serous cystic tumors of the pancreas. Semin Diagn Pathol 2000; 17: 43–55. 20. Albores-Saavedra J, Gould EW, Angeles-Angeles A, Henson DE. Cystic tumors of the pancreas. In: Rosen PP, Fechner RE, editors. Pathology annual. Part 2, Vol 25. Connecticut: Appleton & Lange, 1990; 19–50. 21. Solcia E, Capella C, Kl¨oppel G. Tumors of the Pancreas. Atlas of Tumour Pathology. 3rd series, Fascicle 20. Washington: AFIP, 1997; 31– 39, 41– 53. 22. Howard JM. Cystic neoplasms and true cysts of the pancreas. Surg Clin North Am 1989; 69: 651– 65. 23. Montag AG, Fossati N, Michelassi F. Pancreatic microcystic adenoma coexistent with pancreatic ductal carcinoma: a report of two cases. Am J Surg Pathol 1990; 14: 352–5. 24. Warshaw AL, Compton CC, Lewandrowski K, Cardenosa G, Mueller PR. Cystic tumors of the pancreas: new clinical, radiologic, and pathologic observations in 67 patients. Ann Surg 1990; 212: 432– 45. 25. Kl¨oppel G, Solcia E, Longnecker DS, Capella C, Sobin LH. Who Histological Typing of Tumors of the Exocrine Pancreas. 2nd ed. Berlin: Springer, 1996; 1–11. 26. Chang CH, Perrin EV, Hertzler J, Brough AJ. Cystadenoma of the pancreas with cytomegalovirus infection in a female infant. Arch Pathol Lab Med 1980; 104: 7– 8. 27. Amir G, Hurvitz H, Neeman Z, Rosenmann E. Neonatal cytomegalovirus infection with pancreatic cystadenoma and nephrotic syndrome. Pediatr Pathol 1986; 6: 393– 401. 28. Warfel KA, Faught PR, Hull MT. Pancreatic cystadenoma in an infant: ultrastructural study. Pediatr Pathol 1988; 8: 559– 65. 29. Gundersen AE, Janis JF. Pancreatic cystadenoma in childhood: report of a case. J Pediatr Surg 1969; 4: 478–81. 30. Bartsch D, Bastian D, Barth P, et al. K-ras oncogene mutations indicate malignancy in cystic tumors of the pancreas. Ann Surg 1998; 228: 79– 86. 31. Jimenez RE, Warshaw AL, Z’graggen K, et al. Sequential accumulation of K-ras mutation and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy. Ann Surg 1999; 230: 501–11. 32. Flejou J-F, Boulange B, Bernades P, Elghiti J, Henin D. p53 protein expression and DNA ploidy in cystic tumors of the pancreas. Pancreas 1996; 13: 247–52. 33. Hruban RH, Petersen GM, Ha PK, Kern SE. Genetics of pancreatic cancer: from genes to families. Surg Oncol Clin North Am 1998; 7: 1–23.