Cystic hepatobiliary neoplasia

Published on 10/04/2015 by admin

Filed under Surgery

Last modified 10/04/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1376 times

Chapter 79B Cystic hepatobiliary neoplasia

Overview

The vast majority of nonparasitic cystic lesions of the liver are simple cysts. They are unilocular, do not communicate with the biliary tree, have a serous content, and although the epithelium does divide to account for volume expansion, they are not considered a tumor and have no malignant potential. Furthermore, they do not tend to recur following partial resection. These lesions are described in detail elsewhere in this textbook (see Chapter 69A). Although primary or secondary solid hepatic malignancies may become cystic as a result of tumor necrosis, it is extremely rare for them to be totally cystic, although this has been described in case reports for embryonic liver sarcoma, malignant fibrous histiocytoma, or metastases from a variety of primaries, most including neuroendocrine tumors or even colorectal primaries (Yang et al, 2009; Kim et al, 2009; Ding et al, 2006; Sugawara et al, 2000).

Primarily cystic hepatobiliary neoplasms that constitute another group of cystic tumors are extremely rare. They are of biliary origin and comprise both benign (with malignant potential) and malignant tumors that have initially been given the names of cystadenoma and cystadenocarcinoma (Ishak & Kamal, 1994); however, increasing evidence, in particular from Asian authors, suggests that biliary cystic neoplasia comprises a wider group of entities that resemble those described in the pancreas as being either mucinous cystic neoplasms (MCNs) or intraductal papillary mucinous neoplasm (IPMNs) (Zen et al, 2006a, 2006b). The main difference relates to the presence or absence of an ovarian stroma (OS) and whether a luminal communication exists between the tumor and the bile ducts.

No international consensus has been reached, and detailed characteristics of these tumors are not always described in the literature, casting some confusion on previous descriptions and reports of cystadenoma. Although the same confusion has been observed for cystic tumors of the pancreas, the clinical and pathologic differentiations of these two tumors are now accepted worldwide, now that a consensus on the definition of pancreatic MCNs has been reached (Kloppel et al, 2000; Suzuki et al, 2004). A second problem in analyzing the literature is that because of the rarity of the tumor, the number of large series is very limited, and most references are case reports.

Definition

The initial definitions of cystadenoma by Edmondson in 1958 and by Wheeler and Edmondson in 1985 were strict and included three distinctive features: the lesion should be 1) multilocular (composed of multiloculated cysts) 2) lined by a columnar epithelium, and 3) accompanied by a densely cellular ovarian-like stroma.

This definition was revisited in 1994 by Devaney and colleagues following retrospective analysis of a larger series of 70 patients. Although most fulfilled the criteria set out by Edmondson and Wheeler, that definition was considered too restrictive, as the presence of an OS was inconsistently observed. Furthermore, not all cystadenoma-like lesions they saw were multilocular, and the epithelium lining was not exclusively of the columnar type; it was associated in one third with a cuboidal epithelium. This led the authors to suggest that lesions diagnosed as cystadenoma (or cystadenocarcinoma) should include cystic tumors both with and without OS as well as those having a unilocular gross appearance. More precisely, only 14% of the tumors they observed lacked OS, and only a single patient had a unilocular tumor, which actually was a cystadenocarcinoma.

Although being a landmark study by showing that cystadenoma-like lesions encompass different entities, those with OS exclusively observed in women and those without observed in both genders, with potentially different courses, which will be discussed below; this revision might have introduced some confusion, as detailed pathologic description of tumors subsequently reported as being cystadenoma (cystadenocarcinoma) has not always been provided, and some occasionally resemble atypical benign cysts or cystic forms of intrahepatic cholangiocarcinoma, rather than genuine cystadenoma (or cystadenocarcinoma), on the imaging or pathologic pictures illustrating these series and case reports.

Recently it has been suggested that by differentiating biliary cystic tumors based on their stroma and communication between the tumor and the bile duct, two groups of biliary tumors could be identified that are the counterparts of pancreatic cystic neoplasms. The first group has OS, typically does not communicate with the bile duct, and is the biliary counterpart of pancreatic mucinous cystadenoma. The second group lacks OS, communicates with the biliary ducts, and is sometimes referred to as intraductal papillary mucinous neoplasm of the bile duct (IPMN-B), similar to the intraductal papillary neoplasm of the pancreas. A consensus has not been reached yet on a naming convention, but in any case, most agree that only those tumors with OS should be termed cystadenoma.

Hepatobiliary Cystadenoma with Ovarian Stroma

The most classic primary cystic tumors of the liver are hepatobiliary cystadenoma. Being of biliary origin, these tumors may occur anywhere along the biliary tree, including the common hepatic duct, cystic duct, or gallbladder; but the most frequent location, found in 83% to 94% of the patients, is the liver (Devaney et al, 1994; Buetow et al, 1995). These tumors are well known because of their inherent risk of malignant transformation, common to all adenomatous lesions, although this risk has not been precisely quantified.

Incidence

Cystadenomas are exceedingly rare. No accurate incidence estimates are available, but the largest series included 52 patients (Devaney et al, 1994), and most studies since then have comprised fewer than 10 patients; in the early 2000s, it was estimated that fewer than 200 patients had been reported (Duchini, 2001). It is frequently quoted that intrahepatic cystadenomas constitute fewer than 5% of cystic lesions of the liver based on an old report (Ishak et al, 1977), but this figure is likely overestimated; it has since become obvious that the prevalence of simple cysts of the liver in the adult population is higher than previously thought.

Pathology (See Chapter 78)

Cystadenomas are almost always solitary, and they may range in size from less than 1 to 40 cm; they are generally large, with a mean diameter of 15 cm (Buetow et al, 1995). Cystadenomas have been reported to develop equally in the right and left liver or to involve both lobes (approximately 33% each) (Devaney et al, 1994; Akwari et al, 1990); however, a striking feature in our experience, as well as in recent series, is the very high proportion of tumors occurring in the left paramedian section (segment IV) (Daniels et al, 2006; Lewin et al, 2006; Seo et al, 2010). Pictures of cystadenoma provided in the literature also show tumors in this location almost exclusively; an example is shown in Figure 79B.1.

Cystadenomas are grossly lobulated and multiloculated and usually contain clear to mucinous fluid (Buetow et al, 1995). Hemorrhagic fluid may be present (Lewin et al, 2006), but this is very rare and should raise the suspicion of malignancy (Buetow et al, 1995). A bilious content is similarly very unusual (Buetow et al, 1995), as lack of communication with the biliary tree is a distinctive feature; however, fistulization of cystadenoma in the biliary tree has been reported (Hanazaki, 1996; Yi et al, 2009), the same as for pancreatic mucinous cystadenoma, which may explain the bilious content.

The internal lining is generally smooth but may contain microscopic, or more rarely macroscopic, polypoid lesions projecting into the lumen (Fig. 79B.2). This internal lining has three distinct layers: 1) an epithelial layer, 2) a mesenchymal stroma, and 3) an outer layer of collagen connective tissue that separates it from the adjacent parenchyma (Fig. 79B.3).

The epithelial lining, as for pancreatic cystadenoma, consists of glandular, nonciliated cells arranged in a single, flat row with occasional papillary or polypoid projections, pseudostratifications, and cryptlike invaginations. In two thirds of the patients, the epithelium is columnar, but in one third, it consists of a combination of columnar and cuboidal epithelium. The epithelial lining may show denuded areas with chronic inflammation and hemorrhage. The columnar cells contain histologically benign appearing, basally located nuclei and intracellular mucin. The lining epithelium occasionally shows papillary infoldings, and mild epithelial atypia with a slight increase in the size of the basally located nuclei has been reported to be at least focally present in most patients. More severe dysplasia consisting of a multilayer appearance of hyperchromatic cells with loss of polarity appears much less frequently. Foci of intestinal metaplasia are also rare, seen in the form of numerous goblet cells. Atypia and metaplasia are suggestive of a high risk of malignant transformation (Devaney et al, 1994).

Phenotype has been further characterized in a limited number of patients. The epithelium shows strong and diffuse cytoplasmin staining with antibodies against CEA and CA19-9, whereas CA-125 staining is focal or absent (Subramony et al, 1993; Logroño et al, 2002). It also stains positive for CK-7, CK-19, CK-8, and CK-18 (Abdul Al et al, 2007), which supports a biliary origin, and it is negative for inhibin-α (Owono et al, 2001; Abdul Al et al, 2007), vimentin (Owono et al, 2001), and estrogen or progesterone receptors (Daniels, 2006), and CD56 is only expressed focally (Gütgemann et al, 2006).

The stroma consists of a compact arrangement of bland, spindle-shaped cells with round to oval nuclei. This appearance is reminiscent of OS, hence the name given to these tumors; but it has also been found to resemble the primitive mesenchymal elements associated with the developing biliary system in the fetus. This stroma may be abundant in some patients and focal in others, but mitotic activity is not prominent. It expresses estrogen and progesterone receptors, as does the stroma of pancreatic cystadenoma (Daniels et al, 2006; Weihing et al, 1997); α-inhibin, a gonadal protein that has a more limited expression in the sex cord–stromal tissue, is also expressed in both hepatic and pancreatic mucinous cystadenoma (Ridder et al, 1998; Lam et al, 2008) and in sex cord–stromal tumors. They are immunoreactive with α–smooth muscle actin, vimentin, but also desmin. There is no immune reaction with CEA, CA19-9, or CA-125 (Devaney et al, 1994; Logroño et al, 2002).

A densely hyalinized pseudocapsule surrounds the tumor and separates it from the adjacent liver tissue, which explains how these tumors can be enucleated.

Despite the similarities between hepatic and pancreatic mucinous cystadenomas, few studies have compared the phenotypes of both lesions. One reported denser and more abundant stroma, more intense estrogen or progesterone receptors, and more α-inhibin in hepatic than in pancreatic cystadenomas, but the significance of this is unclear (Lam et al, 2008).

Risk Factors and Origin

There are no clearly identified risk factors apart from gender, as cystadenomas with OS are exclusively observed in women. However, a history of previous oral contraceptive use does not appear to be a distinctive feature (Devaney et al, 1994). Several hypotheses have been raised based on some pathologic features of the tumor, most notably the presence of an ovarian-like stroma or the occasional presence of eosinophilic or endocrine cells. It is still unclear whether cystadenomas are of congenital origin or are acquired neoplastic lesions.

The resemblance is striking among cystadenomas with OS located in the liver, pancreas, retroperitoneum, and ovary (Bakker et al, 2007; Nelson et al, 1988; Turbiner et al, 2007). The particular OS common to these locations contains estrogen and progesterone receptors and α-inhibin (Lam et al, 2008). These similarities suggest a common pathway of tumor development, although simultaneous occurrences of hepatic cystadenoma with pancreatic (Brachet et al, 2007) or ovarian cystadenoma (Skopelitou et al, 1996) are exceedingly rare.

One hypothesis is that during embryonic development, ectopic ovarian cells would have migrated to the liver or pancreas, released hormones and growth factors, and caused endodermally derived epithelium to proliferate and finally to form a tumor (Zamboni et al, 1999). The right and left primordial gonads are indeed located directly under the diaphragm prior to their descent, at the level of the dorsocranial side of the liver and the tail of the pancreas respectively. Furthermore, the cells covering the gonads show an activated morphology in contrast to the peritoneal epithelium elsewhere (Erdogan et al, 2006), which suggests that they have the ability to detach from the gonadal surface, cross the peritoneal cleft, and attach to the peritoneal surface of nearby organs. This hypothesis would explain the predominance of cystadenoma in the body or tail of the pancreas, rather than in the head, as well as the apparent predominance of liver cystadenoma in segment IV. Splenogonadal fusion has also been documented (Duncan & Barraza, 2005), and demonstration of endocrine cells in about 50% of cystadenomas is a distinctive feature (Terada et al, 1997) compatible with the hypothesis of these tumors developing from peribiliary glands.

The OS resembles the primitive embryonic mesenchyma of embryonic gallbladder and large bile ducts that contribute to the connective tissue surrounding the bile ducts (Subramony et al, 1993), and it has therefore also been suggested that these tumors could derive from ectopic embryonal tissue destined to form the gallbladder (Subramony et al, 1993) or from ectopic embryonic rests of primitive foregut sequestered within the liver (Wheeler & Edmondson, 1985).

Presentation

Intrahepatic biliary cystadenoma with an OS is exclusively observed in women. Age at diagnosis is highly variable, between 1 (Beasley et al, 1986) and 70 years, but it peaks in the fourth or early fifth decade. In most patients, the tumor is discovered during the workup of epigastric or right upper quadrant pain or vague abdominal complaints that include abdominal discomfort or swelling. Palpation of an abdominal mass that moves freely with respiration is also a classic circumstance of diagnosis. As the tumor may grow to a considerable size, a gradual increase in abdominal girth and/or compression of the stomach or duodenum may also occur; however, because of the slow progression of the neoplasm, the onset of symptoms tends to be insidious and to have evolved for a prolonged period of time before treatment (Akwari et al, 1990; Thomas et al, 2005). This may explain why most reported cystadenomas are large tumors. With the increasingly liberal use of imaging to investigate even the most minor symptoms, cystadenomas are often discovered incidentally, and it is possible that a significant proportion are not identified or are mistaken for simple cysts (Hara et al, 2001).

More acute episodes of pain have been reported in up to 35% of the patients, and most of these are related to biliary obstruction (Akwari et al, 1990; Erdogan et al, 2010). This is biologically witnessed by concomitant cytolysis or cholestasis. Jaundice or itching (Siriwardana & Pathirana, 2009) may also be present, whereas cholangitis is rare. Typically, such episodes are transient, and any jaundice tends to resolve spontaneously, which is compatible with the migration of mucous material or tumor embolus from the cyst into the bile duct (Fig. 79B.4). Such tumor protrusion in the bile duct lumen has been reported even for small cystadenomas less than 4 cm in diameter (Erdogan et al, 2006). An alternative mechanism of obstruction is simple compression of the biliary confluence by the cystadenoma. Other causes of acute presentation have included tumor rupture (Lempinen et al, 2005), superinfection, bleeding (Lewis et al, 1988), and caval compression (Catto et al, 1999), but these are rare.

Diagnosis

Differential Diagnosis

Apart from the other cystic tumors addressed in this chapter, most notably cystadenocarcinoma, the main differential diagnosis of cystadenoma is simple cysts that have become atypical on imaging studies as a result of intracystic bleeding (Kitajima et al, 2003) or previous sclerotherapy (Takayasu et al, 2003; see Chapter 69A). The risk of mistaking a cystadenoma for a benign cyst is that this lesion may be treated by simple unroofing, which is an inappropriate treatment associated with a high risk of recurrence (see Management below); to mistake a simple or atypical cyst for a cystadenoma is to perform an occasionally risky and unwarranted resection, because simple cysts do not require complete resection. Considering the very high incidence of simple cysts, the latter is probably much more common, and it has been shown that a cystadenoma-like lesion is almost as likely to be a simple cyst as to be a cystadenoma (Shimada et al, 1998; Teoh et al, 2006; Koea et al, 2008; Seo et al, 2010). Clinical history is totally unreliable in the diagnosis of hemorrhagic cysts, as intracystic hemorrhage can occur in the absence of any symptoms (Kitajima et al, 2003), and the diagnosis mainly relies on imaging.

Alternative differential diagnosis must include nonsuppurative granulomatous infection of a simple cyst (Kawashita et al, 2006), hepatic abscess (Yamamoto et al, 2009), echinococcal cysts (Ramacciato et al, 2006), mesenchymal hamartoma (Mori et al, 2008), ciliated hepatic foregut cysts, intrahepatic lymphangioma, cystic hemangioma, cystic forms of hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma, mucin-producing metastases from thyroid or colon carcinoma and cystic metastases of the ovary, of melanoma, and of kidney and neuroendocrine tumors (Del Poggio & Buonocore, 2008). They have also been occasionally confused with pancreatic cysts (Logroño et al, 2002).

Imaging

The characteristic ultrasonographic (US) finding for biliary cystadenoma is an anechoic mass with echogenic internal septations (Fig. 79B.5). Papillary projections into the cystic space may also be seen. On CT scans, the lesions appear as multiloculated hypodense masses with a well-defined wall. The content demonstrates fluid attenuation because of the presence of mucin, blood, or bile. Fine septal calcifications may occasionally be seen, and both the wall and the septations enhance following administration of contrast material (see Fig. 79B.1).

With magnetic resonance imaging (MRI), cyastadenoma is typically seen as a fluid-containing multilocular cyst with homogeneous high signal intensity on T2-weighted images and homogeneous low or isosignal intensity on T1-weighted images (Lewin et al, 2006). These signals may vary depending on the content of the cystic fluid. Mucinous fluid will appear with an isosignal, serous fluid with a hyposignal, and hemorrhagic fluid with an hyperintense signal that can only be seen in the lower part of a fluid-fluid level. Thin internal septal structures separate fluid-filled spaces. These, along with the wall of the lesion, are contrast enhanced (Fig. 79B.6).

image

FIGURE 79B.6 Magnetic resonance imaging of a cystadenoma with ovarian-like stroma (AC) and macroscopic view (D). Specimen is the same as in Figure 79B.1. A, The tumor is hyperintense on T2-weighted images. B, Septa are visible on T1-weighted images. C, Tumors enhance after injection of gadolinium.

Contrast US is a promising exploration that allows analysis of the vascularization of the cyst wall and septa, but it has been used infrequently. An intracystic structure of complicated simple cysts corresponds to clots and is not enhanced (Akiyama et al, 2008). Although the periphery of the cyst may show enhancement, this corresponds to compressed adjacent liver, and this should be differentiated from enhancement of the cyst wall of cystadenoma (see Fig. 79B.5).

As for other cystic lesions, CT scan is less reliable and accurate than US or MRI. Cystadenoma in particular may wrongly appear unilocular on CT scan, whereas US (Korobkin et al, 1989) and MRI (Lewin et al, 2006; Williams et al, 2001) will visualize the internal septa. Two additional features besides multilocularity may help in the differential diagnosis of simple cysts: they are frequently multiple (Vuillemin-Bodaghi et al, 1997), whereas cystadenomas are single lesions; and although biliary dilation has been considered uncommon, a mild enlargement upstream of the tumor is probably more frequent than previously thought—using higher resolution imaging, enlargement was observed in one to two thirds of the patients in recent series (Lim et al, 2007; Seo et al, 2010). Along the same line, an increase in serum alkaline phosphatase levels has recently been shown to be a feature distinctive from simple cysts (Seo et al, 2010).

Cytology and Tumor Markers

Tumor Markers

Unlike for the pancreas, measurement of tumor markers in hepatobiliary cystic lesions has been infrequently performed, and results are confusing. Early case reports have pointed to a link between cystadenoma and CA19-9 by showing its expression by epithelial lining and by revealing increased intracystic and serum concentrations (Thomas et al, 1992; Lee et al, 1996). However, CA19-9 is also expressed by normal biliary epithelial cells, and very high levels have occasionally been measured in the bile of patients with various nontumoral conditions (Horsmans et al, 1997; Shimada et al, 1998; Ker et al, 1991). It is also expressed by the epithelium lining simple cysts of the liver (Park et al, 2006) and in the cystic fluid of simple cysts (Park et al, 2006; Choi et al, 2010). An increased serum concentration of CA19-9 in these patients has even been reported and can occasionally be very high, probably as a result of communication of the cyst with the circulation. Three studies have shown that cyst concentration (Choi et al, 2010; Seo et al, 2010) and serum concentration of CA19-9 (Park et al, 2006; Choi et al, 2010) are comparable in patients with cystadenoma and simple cysts. As will be discussed below, CA19-9 is also inaccurate in differentiating cystadenoma from cystadenocarcinoma (Horsmans et al, 1997).

It has also been suggested that a CEA concentration greater than 600 ng/mL in the supernatant of cystic liver lesions could accurately differentiate cystadenoma or cystadenocarcinoma from benign, nonmucinous cysts (Pinto & Kaye, 1989). The epithelial lining of cystadenoma indeed stains positive for CEA (Logroño et al, 2002); however, this has not been confirmed in subsequent studies, in which concentrations in cystadenoma and simple cysts were comparable (Shimada et al, 1998; Choi et al, 2010; Seo et al, 2010).

Complications

Cystadenoma with an OS is considered a precancerous lesion, as will be detailed below. Malignancy arises in most cases from the epithelium lining (cystadenocarcinoma), but sarcomatous transformation of the OS has also been reported (Akwari et al, 1990). No specific feature has been clearly linked to a higher risk of malignancy, apart from the presence of epithelial atypia (dysplasia) or intestinal metaplasia. The odds ratio for their association with malignancy has been calculated to be 8 (95% confidence interval [CI], 2.4 to 27.0) and 2.4 (95% CI, 1.2 to 3.5), respectively (Devaney et al, 1994).

Buy Membership for Surgery Category to continue reading. Learn more here