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Gallbladder
Cholecystitis
Clinical features
Chronic cholecystitis due to gallstones most frequently results in intermittent right upper quadrant visceral pain that follows eating (so-called biliary colic). Acute cholecystitis typically presents with biliary colic that progressively worsens, resulting in sharp pain in the right upper quadrant, accompanied by fever and leukocytosis. Acute cholecystitis is most commonly caused by impaction of gallstones within the cystic duct, effecting obstruction and bile stasis. Most cases are sterile and secondary to mucosal damage from chemical injury; only rarely is infection the primary cause. Acalculous cholecystitis is most frequently seen in debilitated hospitalized patients with multiple medical problems. In this setting, decreased gallbladder motility and mucosal ischemia cause cholecystitis. Cryptosporidium parvum and cytomegalovirus may cause an acute infectious cholecystitis in immunocompromised patients.
Less common forms of cholecystitis may vary somewhat in their presentation. Xanthogranulomatous cholecystitis may be mistaken for an invasive gallbladder malignancy intraoperatively because the gallbladder adheres to and may appear to invade adjacent organs. Eosinophilic cholecystitis is three times more likely to be acalculous than usual cholecystitis and may be seen as a manifestation of eosinophilic gastroenteritis, parasitic infestation, or drug ingestion.
Pathologic features
Gross findings
Cholecystitis causes a diffuse thickening of the normally thin gallbladder wall. In acute cholecystitis, the thickening is primarily due to edema, inflammation, and reactive fibroblastic proliferation. The mucosa may be eroded and erythematous. In chronic cholecystitis, muscular hypertrophy and fibrosis are the main causes of the thickening. In xanthogranulomatous cholecystitis, one may see yellow nodules within the gallbladder wall and adjacent connective tissue ( Fig. 16-1 ). The mural thickening caused by florid cholecystitis may be difficult to distinguish from an early gallbladder carcinoma, so careful gross examination and thorough sampling of such specimens are important.
Microscopic findings
Histologically, acute cholecystitis demonstrates edema, neutrophilic infiltration, and associated reactive epithelial changes that can easily be confused with neoplasia ( Fig. 16-2 ). Inflammatory polyps represent small protrusions of inflamed granulation tissue associated with cholecystitis. After a week or so, the acute inflammation organizes and loose fibroblastic proliferation develops. These latter changes merge with those of chronic cholecystitis.
The classic chronic cholecystitis associated with lithiasis is characterized by dense mural muscular hypertrophy and fibrosis, and only minimal chronic inflammation ( Fig. 16-3 ). Frequently, Rokitansky-Aschoff sinuses are identified; these represent diverticuli of gallbladder mucosa into the muscular layer, associated with mild muscular hypertrophy. Rokitansky-Aschoff sinuses merge morphologically with adenomyomas, which demonstrate greater muscular hypertrophy ( Fig. 16-4 ). Importantly, both conditions result in displacement of benign gallbladder epithelium beyond the muscular layer of the gallbladder, a setting in which it may be confused with carcinoma. Cholecystitis is often associated with secondary papillary mucosal hyperplasia. Therefore, in the typical chronic cholecystitis associated with lithiasis, reactive epithelial changes overshadow the inflammatory ones.
Specific histopathologic variants of chronic cholecystitis are xanthogranulomatous cholecystitis, eosinophilic cholecystitis, and cholecystitis associated with primary sclerosing cholangitis (PSC). Xanthogranulomatous cholecystitis (ceroid granuloma, cholecystic granuloma) results from rupture of Rokitansky-Aschoff sinuses with bile extravasation that incites a florid histiocytic reaction. Macrophages with lightly pigmented lipofuchsin (ceroid) granules are abundant, and reactive fibroblastic cells with a storiform pattern may mimic sarcoma ( Fig. 16-5 ). Specific histologic criteria for the diagnosis of eosinophilic cholecystitis have not been established, but a general rule is that eosinophils are out of proportion to other inflammatory cells ( Fig. 16-6 ). Diffuse lymphoplasmacytic acalculous cholecystitis is predominantly confined to the lamina propria. Although these changes may be associated with PSC, they are not specific in that they may be found in patients with distal bile duct obstruction of any cause (such as neoplasms or choledocholithiasis; Fig. 16-7 and Table 16-1 ).
| Type of Cholecystitis | Histology | Associations |
|---|---|---|
| Usual chronic cholecystitis | Muscular hypertrophy, Rokitanky-Aschoff sinuses, minimal inflammation | Gallstones |
| Xanthogranulomatous cholecystitis | Xanthomatous macrophages and fibroblastic reaction | Simulates malignancy clinically |
| Eosinophilic cholecystitis | Eosinophils out of proportion to other inflammation | Other causes of eosinophilic gastroenteritis |
| Diffuse acalculous lymphoplasmacytic cholecystitis | Superficial lymphoplasmacytic infiltrate, no stones | Obstruction of distal bile ducts (i.e., primary sclerosing cholangitis, distal bile duct tumors) |
Metaplasia of the normal columnar absorptive epithelium of the gallbladder often accompanies cholecystitis and may represent an early, nonobligate precursor to gallbladder carcinoma. Three types of metaplasia are recognized in the gallbladder. Gastric metaplasia is seen in half of patients with cholelithiasis ( Fig. 16-8 ). In gastric metaplasia, the normal absorptive epithelium of the gallbladder is replaced by cuboidal cells with cytoplasm composed predominantly of neutral mucin. Intestinal metaplasia is seen in approximately 50% of patients with cholelithiasis and is thought to pose a greater risk for gallbladder carcinoma. Histologically, one sees goblet cells with acid mucin ( Fig. 16-9 ). Neuroendocrine cells and Paneth cells are also frequently seen. Squamous metaplasia is rare in the gallbladder but, when present, is often associated with squamous dysplasia and carcinoma.
Differential diagnosis
The reactive epithelium of acute cholecystitis may be difficult to distinguish from dysplasia or carcinoma in situ. Compared with carcinoma in situ, reactive epithelial changes consist of a less monotonous, more heterogeneous cell population demonstrating less pleomorphism, more vesicular chromatin, prominent but more rounded nucleoli, and more amphophilic cytoplasm. Displaced gallbladder epithelium of adenomyomas may extend beyond the muscular layer to involve the perimuscular connective tissue or even involve perineural spaces, and thus be confused with invasive carcinoma. The absence of atypia within adenomyoma and absence of desmoplasia assures a benign diagnosis. Tangential sectioning of the papillary hyperplasia that accompanies cholecystitis may give a pseudocribriform, spongioid pattern that may mimic cribriform carcinoma. Again, the absence of significant cytologic atypia militates against neoplasia. On frozen section, the histocytes of xanthogranulomatous cholecystitis may be mistaken for signet ring cell carcinoma, especially given that malignancy is often the clinical impression of this benign disorder.
Prognosis and therapy
The usual acute or chronic cholecystitis associated with gallstones is cured by cholecystectomy. In contrast, approximately 40% of patients with acalculous cholecystitis die. This is likely due to underlying medical conditions that may also result in a delay in diagnosis.
Gallbladder carcinoma
Clinical features
Gallbladder carcinoma is the most frequent malignancy in the biliary tract; approximately 5000 new cases are discovered each year in the United States. There is a female predominance, reflecting the female propensity to the major risk factor, cholelithiasis. The mean age at diagnosis is 72 years. The most common presentations include right upper quadrant pain, weight loss, and anorexia for advanced stage tumors, but symptoms at presentation can mimic chronic cholecystitis in early-stage tumors. Jaundice is not common at presentation because the outflow of bile via the common bile duct is not obstructed until the disease is advanced. Some series report that unsuspected gallbladder carcinoma is found in 2% of cholecystectomies, with higher frequencies in patients older than 65 years.
Risk factors for gallbladder carcinoma include genetics, cholelithiasis, and abnormal junction of the pancreatic and bile ducts (AJPBD). Genetic factors are suggested by the prevalence of the disease in American Indians and Hispanic Americans and probably reflect the tendency to form gallstones. Gallstones are found in 75% of cases of carcinoma and are thought to predispose to carcinoma by causing chronic irritation and epithelial damage, leading to increased proliferation and the opportunity for mutation. However, the low overall incidence of gallbladder carcinoma in all patients with gallstones (0.2%) renders the merits of elective cholecystectomy in patients with gallstones debatable. AJPBD refers to the union of the common bile duct and pancreatic duct outside the duodenal wall, beyond the influence of the sphincter of Oddi. This anatomic variant allows reflux of pancreatic juice into the bile duct. This condition is more common in Japan, where approximately one sixth of gallbladder carcinomas are associated with AJPBD. AJPBD is thought to confer a 10-fold increased risk for gallbladder carcinoma. Compared with those patients with gallbladder carcinoma who do not have AJPBD, patients with gallbladder carcinoma arising in the setting of AJPBD are far less likely to have gallstones and are on average 10 years younger at presentation. Moreover, a higher percentage of their tumors carry K-RAS mutations, implying a different genetic pathogenesis. AJPBD is also associated with choledochal cysts, which are strongly associated with bile duct carcinoma. Other associations for gallbladder carcinoma include familial adenomatous polyposis and diffuse dystrophic calcification of the wall of the gallbladder (porcelain gallbladder). The latter is found in less than 0.5% of cholecystectomies, but approximately 20% of porcelain gallbladders are associated with gallbladder carcinoma.
Definition
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Carcinoma derived from the epithelial lining of the gallbladder
Incidence and location
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Rare: less than 0.5% of all cancers in women in the United States
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5000 new cases per year in the United States
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Endemic in Mexico and Chile
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Risk factors include genetics, gallstones, abnormal choledochopancreatic duct junction, and porcelain gallbladder.
Morbidity and mortality
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Highly lethal: overall 5-year survival rate is 5% to 10%
Gender, race, and age distribution
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Female predominance (M:F = 1:2)
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Incidence highest among American Indians and Hispanic Americans
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Mostly affects adults (mean age = 72 years)
Clinical features
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Symptoms vary but include right upper quadrant pain, weight loss, and anorexia.
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Symptoms may mimic cholecystitis.
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May be asymptomatic (occult)
Prognosis and therapy
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Generally poor
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Rare low-stage tumors have better prognosis
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Among low-stage tumors, vascular invasion and grade may have significance
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Surgical resection is the most effective treatment
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Usually CK7 positive; CK20 and CDX2 variable
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CEA positive
Differential diagnosis
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Cholecystitis with reactive atypia
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Carcinoma in situ colonizing Rokitansky-Aschoff sinuses
Pathologic features
Gross findings
Grossly, gallbladder carcinomas usually (70% of cases) form firm, infiltrative masses or may less frequently (30% of cases) form polyps that protrude into the lumen ( Fig. 16-10 ). Occasional cases form subtle thickenings in the gallbladder wall that are grossly indistinguishable from chronic cholecystitis. The majority arises in the fundus (60%), followed by the body (30%) and the neck (10%), but often the epicenter of an extensive tumor cannot be definitively discerned.
Microscopic findings
The vast majority of invasive gallbladder carcinomas are adenocarcinomas composed of cuboidal or columnar cells resembling normal biliary epithelium ( Fig. 16-11 ). Many cases contain goblet cells. The degree of cytologic atypia is often greater than one would expect for the degree of gland formation. Prominent stromal desmoplasia is characteristic. Papillary (in situ) carcinoma is the most important growth pattern to recognize, because these tumors have a better prognosis. The surface papillary component of such tumors is noninvasive and in theory metastatic incapable; when an underlying invasive component is present, it tends to be superficial. Other specific variants include mucinous (colloid) carcinoma, which is diagnosed if greater than 50% of the tumor is composed of extracellular mucin and signet ring cell carcinoma. Clear cell (glycogen-rich) carcinoma of the gallbladder must be distinguished from metastatic clear cell renal carcinoma. Adenosquamous carcinomas are characterized by dual squamous and glandular differentiation. Undifferentiated carcinomas may be composed of spindled and giant cells (similar to pancreatic anaplastic carcinoma), small signet ring cells (mimicking invasive lobular breast carcinoma), or mononuclear cells in a background of osteoclasts (similar to giant cell tumor of pancreas). Cribriform carcinomas simulate their counterparts in the breast. Small cell neuroendocrine (oat cell) carcinoma comprises 5% of gallbladder primary tumors and is morphologically identical to small cell carcinoma of lung. One may find an associated adenocarcinoma in approximately one third of cases ( Fig. 16-12 ).
