25 Pancreatic Pathology Mirko D’Onofrio, Giulia Zamboni, Roberto Malagò, Enrico Martone, Massimo Falconi, Paola Capelli, and

25 Pancreatic Pathology

Mirko D’Onofrio, Giulia Zamboni, Roberto Malagò, Enrico Martone, Massimo Falconi, Paola Capelli, and Giancarlo Mansueto

This chapter is dedicated to Professor Carlo Procacci

M. D’Onofrio, MD; G. Zamboni, MD; R. Malagò, MD;

E. Martone, MD; G. Mansueto, MD; M. Falconi, MD P. Capelli, MD

Department of Radiology, Hospital G. B. Rossi, University of Verona, Piazza L.A. Scuro, 34134 Verona, Italy

the enhancement of the gland begins almost together with the aortic enhancement.

In the pancreas the enhancement reaches its peak between 15 and 20 s after microbubble injec- tion (Fig. 25.1). Pancreatic parenchymography is therefore earlier and shorter than that of the liver, for the absence of a venous blood supply like the portal one (Takeda et al. 2003). Afterwards there is a progressive washout of microbubbles with loss of gland echogenicity (Fig. 25.1). For these reasons, it is difficult to obtain a correct characterization of pan- creatic lesions for the brief duration of both contrast enhancement (wash-in) and contrast release (wash- out), even though contrast-enhanced US allows the continuous assessment of perfusion of pancreatic lesions (D’Onofrio et al. 2003).

25.3

Pancreatitis

Contrast-enhanced US improves the diagnosis of pancreatic inflammatory diseases (Koito et al.

1997). The identification and differential diagnosis of pancreatic inflammation and its complications, such as pseudocysts, are more reliable at contrast- enhanced US than at baseline US.

25.3.1

Acute Pancreatitis

Acute pancreatitis is an inflammatory process which involves the pancreas and the peri-pancreatic retro- peritoneal regions (Klöppel and Schlüter 1999).

Acute focal pancreatitis, even when supported by clinical data, frequently needs to be differentiated from pancreatic heteroplastic lesions (Lorén et al.

1999), and may present a mild or severe form. In mild acute pancreatitis, the gland presents edema and hyperemia. At baseline US, acute focal pan- creatitis appears as a segmental volume increase of

25.1 Introduction 335 25.2 Pancreatic Perfusion 335 25.3 Pancreatitis 335 25.3.1 Acute Pancreatitis 335 25.3.2 Pseudocysts 336 25.3.3 Chronic Pancreatitis 336 25.4 Exocrine Tumors 339 25.4.1 Ductal Adenocarcinoma 339 25.4.2 Serous Cystic Tumors 340

25.4.3 Mucin-Producing Cystic Tumors 342 25.5 Endocrine Tumors 343

25.6 Metastases 344 References 346

25.1

Introduction

The innovative use of contrast-enhanced ultrasound (US) in the study of pancreatic pathology creates the necessity of a semiologic definition. A description of the features of pancreatic pathology, diffuse and focal, solid and cystic, tumoral and pseudotumoral, after microbubble-based contrast agents injection, is therefore mandatory.

25.2

Pancreatic Perfusion

The perfusion of the pancreas justifies the semiology

of the gland parenchymography at contrast-enhanced

US. The differences in semiology between pancreas

and liver at contrast-enhanced US (Chap. 11) assess-

ment are substantial. In particular, considering that

the blood supply of the pancreas is entirely arterial,

intensity curve of the pancreas, obtained with a region of interest (R0) placed at the pancreatic tail, shows the peak of contrast enhancement (A1) at about 15 s after injection (T0);

afterwards a progressive washout of microbubbles occurs

Fig. 25.2a,b. Acute focal pancreatitis. a Baseline US. A hypoechoic focal lesion is identifi ed at the pancreatic head (arrows). b Contrast-enhanced US. The lesion appears hypovascular after microbubble injection with a slight parenchymographic contrast enhancement (arrows) in the pancreatic phase

a b

the pancreas (Fig. 25.2), appearing homogeneously hypoechoic (Lorén et al. 1999). At contrast-enhanced US the pancreatic segment affected by inflammation shows diffuse contrast-enhancement (Fig. 25.2).

Severe acute pancreatitis is characterized by the presence of large confluent necrotic areas, the iden- tification of which is important for patient progno- sis (Casas et al. 2004). Contrast-enhanced US may improve identification and depiction of regional parenchymal necrosis, which appears as non-vascu- lar areas after microbubble injection.

25.3.2 Pseudocysts

Pseudocysts are the most common cystic lesions of the pancreas (Procacci et al. 2001a). The lesion has

a fibrous wall without an epithelial lining (Procacci et al. 2001a). At imaging, whenever inclusions are present, pseudocysts are difficult to differentiate from cystic tumors of the pancreas, especially muci- nous cystadenoma (Procacci et al. 2001a).

Pseudocysts, although with a corpuscular and heterogeneous content at baseline US, show absence of contrast enhancement after microbubble injection appearing completely and homogeneously anechoic (Fig. 25.3).

25.3.3

Chronic Pancreatitis

According to the classification of Marseille (Singer

et al. 1985), pathological alterations of the pancre-

atic parenchyma due to chronic pancreatitis are

Fig. 25.3a,b. Pancreatic pseudocyst. a Baseline US. A cystic lesion of the pancreatic tail (arrows) with intralesional debris. b Contrast-enhanced US. Contrast enhancement is not observed either in the parietal nodules or in the intratumoral septa after microbubble injection, resulting in completely and homogeneously anechoic appearance (arrows)

a b

represented by irregular tissue sclerosis with focal, segmentary, or diffuse destruction of exocrine parenchyma. These parenchymal alterations may be associated with various degrees of Wirsung duct dila- tion and with alterations of the pancreatic perfusion.

The inflammatory process increases the blood supply (Koito et al. 1997) and in the initial phases of the phlogistic process, glandular hyperemia is respon- sible for the increased gland parenchymography at contrast-enhanced US. However, progression of the chronic inflammatory process induces an increase of the degree of fibrosis with a decrease in hyperemia and, as a consequence, in gland parenchymography (Kim et al. 2001). Contrast-enhanced US is especially useful in the differential diagnosis of mass-forming chronic pancreatitis (Koito et al. 1997).

25.3.3.1

Mass-Forming Chronic Pancreatitis

Mass-forming chronic pancreatitis usually arises in patients with a history of chronic pancreatitis (Kim et al. 2001). Differential diagnosis with a neo- plastic disease may be difficult not only due to the very similar features at baseline US (Koito et al.

1997), but also because mass-forming pancreatitis and pancreatic cancer may present with the same symptoms and signs (van Gulik et al. 1997). The main characteristic feature at pathology is progres- sive interstitial fibrosis with chronic inflammatory infiltrate (Kim et al. 2001). US features of mass-form- ing pancreatitis are very similar to those of ductal

adenocarcinoma (Koito et al. 1997; Kim et al. 2001), presenting in most cases as a hypoechoic mass in a limited region of the gland, usually at the head, often with enlargement of the gland contour (Fig. 25.4).

The presence of small calcifications in the lesion may suggest its inflammatory nature (Remer and Baker 2002), but this sign is poorly specific.

For the final diagnosis, contrast material-enhanced CT and biopsy are mandatory. Contrast-enhanced US can improve the differentiation between mass-form- ing pancreatitis and pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma remains persis- tently hypoechoic after microbubble injection, due to the intense desmoplastic fibrotic reaction present- ing a poor vascular component in the lesion. Mass- forming pancreatitis shows parenchymographic enhancement with isoechoic appearance to the sur- rounding pancreatic parenchyma in the early phases after microbubble injection (Fig. 25.4), while contrast enhancement decreases with a wash-out rate similar to the pancreatic gland in the late phase.

The presence of a parenchymography similar to

the adjacent pancreatic parenchyma after micro-

bubble injection is consistent with an inflammatory

origin. The intensity of this parenchymographic

contrast enhancement is related to the length of

the underlying inflammatory process. It has been

observed that, the more the inflammatory process

is chronic and long-standing, the less intense the

intralesional parenchymography, probably in rela-

tion to the entity of the associated fibrosis (Koito et

al. 1997; Kim et al. 2001). Conversely, in mass-form-

ing pancreatitis of more recent onset the enhance- ment is usually more intense and prolonged.

25.3.3.2

Autoimmune Pancreatitis

Autoimmune chronic pancreatitis is a particular type of chronic pancreatitis, with a very recent pathologi- cal definition (Furukawa et al. 1998). Autoimmune pancreatitis is characterized by periductal phlogo- sis, mainly sustained by lymphocytic infiltration, with evolution to fibrosis (Furukawa et al. 1998). As opposed to the other forms of chronic pancreatitis, the pancreas is increased in volume, usually in a dif- fuse way with the typical sausage look, and the main pancreatic duct appears compressed by glandular parenchyma or string-like (Furukawa et al. 1998).

US features are very similar to those of focal pan- creatitis, even though autoimmune pancreatitis may involve the entire gland more frequently, or present a larger extension and ubiquitous localization. US

findings are characteristic in the diffuse form when the entire gland is involved.

The echogenicity is markedly reduced, the gland volume is increased, and the Wirsung duct is com- pressed by the gland parenchyma (Fig. 25.5). Focal autoimmune pancreatitis at the pancreatic head is often characterized by the sole dilation of the common bile duct (Numata et al. 2004). The paren- chymal vascularization in autoimmune pancreati- tis can be demonstrated at contrast-enhanced US (Fig. 25.5), which shows diffuse contrast enhance- ment (Numata et al. 2004) in the early phase (Fig. 25.5). Contrast enhancement appears heteroge- neous for a small caliper of the glandular vessels due to thick lymphocytic infiltration and fibrosis.

Microbubble washout is usually slow but pro- gressive. Contrast-enhanced US findings may be especially useful in the study of focal forms of auto- immune chronic pancreatitis, in which the differen- tial diagnosis with ductal adenocarcinoma is very important (Koga et al. 2002).

Fig. 25.4a,b. Mass-forming chronic pancreatitis. a Baseline US. A heterogeneous mass (arrows) is identifi ed in the head of pan- creas (p, pancreas body). b Contrast-enhanced US. Diffuse parenchymographic contrast enhancement of the lesion (arrows) which appears isoechoic to the adjacent pancreatic parenchyma

a b

Fig. 25.5a–c. Autoimmune chronic pancreatitis. a Baseline US. The pancreatic gland (arrows) appears diffusely hypoechoic and increased in volume, while the Wirsung duct is compressed and not visible. b Contrast-enhanced US. Diffuse heterogeneous contrast enhancement of the pancreatic gland (arrows). c Baseline US after steroid therapy. The pancreatic gland presents a normal appearance

a b c

25.4

Exocrine Tumors

Pancreatic tumors are classified according to their histological type and grade in the WHO classifica- tion (Klöppel et al. 1996). Ductal adenocarcinoma comprises between 80% and 90% of all tumors of the exocrine pancreas.

25.4.1

Ductal Adenocarcinoma

Ductal adenocarcinoma usually presents as a solid mass with infiltrating growth margins. US typically shows a hypoechoic lesion (Fig. 25.6a), with roughly defined margins, confused with the adjacent paren- chyma, often altering the gland contour or some-

times completely included in the gland parenchyma (Fig. 25.7a). At histology, the pancreatic ductal ade- nocarcinoma is characterized by the marked des- moplasia (Klöppel 1984), which determines the hard consistency (Figs. 25.6b,c). The mean vascular density is low (Fig. 25.6d) and often lower than that of the adjacent pancreatic parenchyma.

At contrast-enhanced US ductal adenocarcinoma shows low-grade contrast enhancement during all phases (Figs. 25.6e and 25.7b) for the marked desmo- plasia (Fig. 25.6b) and the low mean vascular den- sity of the lesion (Fig. 25.6d). At contrast-enhanced US ductal adenocarcinoma appears as a hypovascu- lar area compared to the adjacent pancreatic paren- chyma (Figs. 25.6e and 25.7b) with a clear depiction of tumoral margins and size and a better definition of the relationship with the peri-pancreatic arterial and venous vessels for local staging.

Fig. 25.6a–e. Ductal adenocarcinoma. a Baseline US. Hypoechoic mass (arrows) with irregular margins is identifi ed in the pan- creatic head. b Contrast-enhanced US. No contrast enhancement is identifi ed in the pancreatic mass (arrows) after microbubble injection, with hypovascular appearance if compared to the rest of the pancreatic parenchyma during the venous contrast enhanced phase. c Surgical specimen. Hard tumoral consistency due to the fi brous desmoplastic component (arrow) of the tumor which is identifi ed at hematoxylin-eosin staining (d). e Immunohistochemical analysis of CD34 antigen reveals the low vascular density (arrow)

a b

c d e

25.4.1.1

Differentiation and Microvascular Density

The differentiation degree of the adenocarcinoma influences its microvascular density. Poorly differ- entiated adenocarcinoma presents a low microvas- cular density, high malignancy and regional and distant spread which occur earlier than with ductal adenocarcinoma. Pathology findings are repre- sented by a large soft mass, with central necrotic areas. The appearance of poorly differentiated pan- creatic adenocarcinoma at baseline US is not univo- cal. It appears as a fairly sized hypoechoic lesion (Fig. 25.8a) with central necrotic areas due to the rapid tumoral growth not supported by a sufficient neoangiogenesis. Minute calcifications (Fig. 25.8a) may be present in the intralesional necrotic areas.

The tumor grows in all directions, usually in a con- centric way (Fig. 25.8a). Color and power Doppler studies have proven to not be so accurate in the iden- tification of tumoral vascularization (Figs. 25.8b,c), while vascular infiltration and regional and hepatic diffusion occur early.

Contrast-enhanced US shows the vasculariza- tion of the neoplastic tissue with evidence of con- trast enhancement already in the early phase after microbubble injection (Fig. 25.8d). The contrast enhancement in the viable portion of the tumor appears as a shell of solid tissue lining the intratu- moral necrotic areas which appear as non-vascular regions (Fig. 25.8d). The viable portion of the tumor appears hypoechoic in the late phase due to micro- bubble washout.

25.4.1.2 Staging

US staging of ductal adenocarcinoma is accurate (Minniti et al. 2003). The use of microbubble-based contrast agents may complete the regional staging of pancreatic adenocarcinoma by confirming vascular, arterial, and venous infiltration or involvement by the neoplasm (Fig. 25.9). Contrast-enhanced US also contributes to hepatic staging, increasing sensibil- ity and specificity for liver metastases identification and characterization. After studying the pancreatic lesion in the arterial, pancreatic, and venous phases, liver metastases are sought during the sinusoidal hepatic contrast-enhanced phase (Blomley et al.

1998, 1999; Solbiati et al. 2001).

25.4.2

Serous Cystic Tumors

Serous cystoadenoma usually has a benign nature (Compagno and Oertel 1978a). The typical variety is the microcystic, macroscopically characterized by multiple small cysts (<2 cm) separated by thin septa (Procacci et al. 1999a, 2001a). The margins are well- defined and a central scar may be present (Procacci et al. 1999a). The intralesional septal enhancement at contrast-enhanced US improves identification of the microcystic features of the lesion (Fig. 25.10).

The less common oligocystic or macrocystic types of serous cystadenoma present features indistinguish- able from those of the other macrocystic tumors of

a b

Fig. 25.8a–d. Poorly differentiated pancreatic adenocarcinoma. a Baseline US. A hypoechoic mass with diffuse margins (arrows) is identifi ed at the pancreatic body. b,c Color and power Doppler. No tumoral vessels are identifi ed in the pancreatic mass (arrows). d Contrast-enhanced US. Contrast enhancement is identifi ed in the viable portion of the tumor, with evidence of a thick tumoral enhancing rim (arrows) surrounding a central necrotic area (arrowhead)

a b

c d

Fig. 25.9a,b. Ductal adenocarcinoma. a Baseline US. A hypoechoic mass (arrows) is identifi ed at the uncinate process of the pancreas. b Contrast-enhanced US. The lesion does not show contrast enhancement (arrows) after microbubble injection during the early contrast-enhanced phase. Encasement of the inferior pancreaticoduodenal artery and infi ltration of the superior mesenteric artery was shown during the surgical procedure

a b

the pancreas (Procacci et al. 1997; Carbognin et al. 2003).

25.4.3

Mucin-Producing Cystic Tumors

Mucin-producing tumors of the pancreas may orig- inate either from the peripheral ducts (mucinous cystic tumors) or from the duct of Wirsung and its collateral branches (intraductal papillary mucinous tumors, IPMTs) (Procacci et al. 1996).

25.4.3.1

Mucinous Cystic Tumors

Mucinous cystadenoma is a rare primitive pancreatic tumor, even though it is the most common cystic pancreatic tumor (Hammond et al. 2002). Mucinous cystadenoma is considered a pre-malignant lesion (Compagno and Oertel 1978b; Procacci et al.

1999a; Cohen-Scali et al. 2003) and, consequently, the differentiation of mucinous cystadenoma from other cystic pancreatic lesions is important for a cor- rect therapeutic approach. Mucinous cystadenoma presents as a cystic, multilocular or, less often, uni- locular round mass, with variable size (range: 2–

36 cm) (Fugazzola et al. 1991; Buetow et al. 1998).

The multilocular type is typical, even though it is not pathognomonic (Sperti et al. 1993). The unilocular appearance is less common and less typical and has to be differentiated from the other cystic lesions of the pancreas (Demos et al. 2002), particularly pseu- docysts (Warshaw and Rutledge 1987; Sachs et al. 1989; Fugazzola et al. 1991; Sperti et al. 1993;

Buetow et al. 1998; Kuba et al. 1998; Procacci et al.

1999a; de Lima et al. 1999; Scott et al. 2000; Ham- mond et al. 2002) and the oligocystic variety of serous pancreatic cystadenoma (Cohen-Scali et al. 2003).

Mucinous cystadenoma may present calcifi- cations on the wall or the septa (Procacci et al.

2001b), parietal nodules and papillary vegetations (Fugazzola et al. 1991). The cystic content of the lesion may be heterogeneous for the presence of mucin or intralesional hemorrhage. At baseline US mucinous cystadenoma presents as a lesion with cystic areas, separated by septa, with corpuscular mucinous content. By using tissue harmonic imag- ing it is possible to better visualize the cystic walls, septa, nodules and the papillary vegetations (Ham- mond et al. 2002). The content of the mucinous cystadenoma, however, if very corpuscular, may impair identification of parietal nodules, which is fundamental for a radiological diagnosis. Contrast- enhanced US may identify contrast enhancement in nodules and intracystic septa, due to their tumoral nature, after microbubble injection (Fig. 25.11), and improves the differential diagnosis between muci- nous cystadenoma and pseudocyst by the identifi- cation of contrast enhancement in the inclusions inside the pancreatic cystic masses.

25.4.3.2

Intraductal Papillary-Mucinous Tumors

Intraductal papillary-mucinous tumors are consid- ered rare lesions, but recently they have been reported with increasing frequency (Procacci et al. 1996, 1999b, 2001c, 2003). Intraductal papillary-mucinous tumors are macroscopically characterized by their

a b

25.5

Endocrine Tumors

Endocrine tumors may induce specific clinical effects due to the hormonal production (functioning endocrine tumors) or aspecific symptoms due to the expansive growth (non-functioning endocrine tumors). Endo- crine pancreatic tumors appear hypervascular at con- trast material-enhanced CT (Procacci et al. 2001d).

Differential diagnosis between non-functioning endocrine pancreatic tumors and ductal pancreatic adenocarcinoma is of fundamental importance for therapeutic strategy and prognosis (Procacci et al.

2001d). At color and power Doppler US, a spotted pattern can be demonstrated inside the endocrine tumors (D’Onofrio et al. 2004). However, the hyper- vascular endocrine tumors may reveal no Doppler vascular signal due to the small size of the lesion or the vascular network of the tumor (D’Onofrio et al.

2004).

Fig. 25.11a–d. Mucinous cystoadenoma. a Baseline US. A cystic mass is identifi ed in the pancreatic tail presenting an intral- esional septum and peripheral mural nodules (arrows). b Contrast-enhanced US. Contrast enhancement is identifi ed in the septa and peripheral mural nodules after microbubble injection (arrows). c,d Surgical specimen. Mass (arrows) of the pancreatic tail resected with the spleen (s). Intratumoral septa (arrowheads) are evident when the cystic mass is cut

a b

c d

intraductal origin and growth (Zamboni et al. 2003)

with production of dense mucin filling the Wirsung

duct (ductectatic mucin-hypersecreting variant) or

with endoluminal papillary proliferation (papillary-

villous variant). At baseline US the dilation of the

main pancreatic duct is usually demonstrated, while

the identification of the lesion depends on its size

(Fig. 25.12). Intraductal papillary-mucinous tumors

of adequate dimensions appear at baseline US as het-

erogeneous masses, upstream of the Wirsung dila-

tion (Fig. 25.12). Contrast-enhanced US may allow

the identification of intraductal papillary tumoral

vegetations, especially in the papillary-villous vari-

ant, demonstrating its vascularization after micro-

bubble injection (Fig. 25.12). However, the definite

diagnosis of intraductal papillary-mucinous tumors

by demonstrating the communication between the

tumor and the pancreatic duct is difficult with US

(Procacci et al. 2003).

Fig. 25.12a–c. Intraductal papillary-mucinous tumor. a Base- line US. Huge hypoechoic heterogeneous mass of the pan- creatic head with upstream main duct dilation (asterisk). b Contrast-enhanced US. Intense enhancement of intraductal papillary tumoral vegetations and septa (arrows) inside the dilated main pancreatic duct (asterisk). c Specimen. Vegeta- tions and septa are identifi ed inside the main pancreatic duct (arrows)

a b

c

At contrast-enhanced US different contrast enhancement patterns may be observed accord- ing to the tumoral dimension and tumoral vessels.

Huge endocrine tumors show rapid and diffuse con- trast enhancement after microbubble injection in the early phases, with the exception of the necrotic intratumoral areas (Fig. 25.13) (D’Onofrio et al.

2004). In moderate-sized neuroendocrine pancre- atic tumors a capillary blush enhancement may be identified in the early phase, resembling the most characteristic feature of this tumor at angiography (Rossi et al. 1989), presenting as hypoechoic at late phase (D’Onofrio et al. 2004). Since the character- ization of non-functioning endocrine pancreatic tumors is principally linked to frequent tumoral hypervascularization (Procacci et al. 2001d), a high sensitivity of imaging modalities in the detection of macro- and microtumoral circulation is required.

Non-functioning neuroendocrine tumors may be hypovascularized (D’Onofrio et al. 2004). This is directly related to the amount of stroma inside the lesion which is dense and hyalinized. However, in some pancreatic neuroendocrine tumors appearing hypodense at contrast material-enhanced CT, con-

trast enhancement may be visible after microbubble injection (D’Onofrio et al. 2004). The high capabil- ity of contrast-enhanced US in demonstrating endo- crine tumor vascularization is due to the high sensi- tivity of contrast specific modes to the microbubble signal, improving the identification (D’Onofrio et al. 2003) and characterization of pancreatic endo- crine tumors (D’Onofrio et al. 2004). Moreover, contrast-enhanced US improves loco-regional (Fig. 25.14) and hepatic staging of pancreatic endo- crine tumors (D’Onofrio et al. 2004).

25.6 Metastases

Pancreatic metastases are rare and the most common

are those from renal carcinoma. Pancreatic metasta-

ses from renal carcinoma, being hypervascular, may

show diffuse contrast enhancement after microbub-

ble injection (Fig. 25.15), allowing a characterization

and differential diagnosis with pancreatic ductal ade-

nocarcinoma (Flath et al. 2003; Megibow 2003).

Fig. 25.13a,b. Non-functioning endocrine tumor. a Baseline US. Huge heterogeneous mass in the pancreatic tail (arrows). b Contrast-enhanced US. Diffuse contrast enhancement of the lesion (arrows) in the early contrast enhanced phases with evidence of small hypoechoic intratumoral necrotic areas (arrowhead)

a b

Fig. 25.14a–c. Non-functioning endocrine tumor. a Baseline US. Huge hypoechoic heterogeneous mass of the pancreatic body (arrows) with associated splenic vein thrombosis (asterisk). b Contrast-enhanced US. Diffuse contrast enhancement of the tumor (arrows) and of the thrombus in the splenic vein (asterisk) in the early contrast-enhanced phase. c Surgical specimen.

Neoplastic infi ltration of the splenic vein (asterisk)

a b

c

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