Diagnostic Cytology


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Mucinous cystic neoplasms typically occur as single or multiloculated, mucinous, epithelial-lined cysts surrounded by ovarian-type stroma. The cyst fluid may be watery or viscous. Diagnostic aspirates likely contain degenerated cuboidal to columnar epithelial cells with bland nuclear features Fig. The neoplastic epithelial cells may be arranged singly, on edge, in sheets, or as small papillary tufts.

The background usually shows mucin with chronic inflammatory cells, histiocytes, and debris. The degree of cellularity varies and tends to increase with higher grades of intraepithelial neoplasia. Stromal components are not usually present. With malignant transformation, features of adenocarcinoma with or without mucin and cellular debris are often evident. The definitive diagnosis requires correlation with clinical information, imaging studies, and histopathologic confirmation of ovarian-type stroma surrounding the cyst. The cyst fluid may be assayed for carcinoembryonic antigen and CA to distinguish neoplastic from non-neoplastic liver cysts Box Degenerated mucin-secreting cuboidal to columnar epithelium with bland nuclear features; arranged singly, on edge, in sheets or as small papillary tufts.

Background usually shows mucin with chronic inflammatory cells, histiocytes, and debris. Biliary intraductal papillary neoplasm is a fusiform or cystic unilocular or multilocular luminal dilation in communication with the biliary tract. The affected intrahepatic bile ducts are typically filled with a noninvasive papillary or villous biliary neoplasm covering delicate fibrovascular stalks, and mucin may be seen.

Aspirates are typically hypercellular, comprising broad and often double-layered sheets of ductal cuboidal or columnar epithelium with a distinctive three-dimensional, complex-branching papillary configuration Fig. The sheets of cells do not form a honeycomb pattern but are crowded. Phenotypes include pancreaticobiliary, intestinal, gastric, and oncocytic forms.

The epithelium shows intracytoplasmic mucin vacuoles and occasional signet ring cells. The nuclei show variable abnormalities. Psammoma bodies may be identified. Intraductal papillary neoplasm with associated invasive carcinoma has the highest degree of cellularity and pleomorphism Box Broad, double-layered sheets of ductal columnar epithelium with three-dimensional, complex-branching papillae. Metastatic papillary carcinomas of the pancreas and ovary can simulate intraductal papillary neoplasms. Smears may contain numerous finger-like fibrovascular stalks lined by cuboidal or columnar epithelium with cytologic atypia.


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Aspirates of non-neoplastic cysts typically reveal an abundant amount of turbid, brown fluid with inflammatory cells, macrophages, fibrin, debris, and bile or hematoidin pigment. The fluid lacks lining epithelial cells but may contain benign cells from surrounding liver parenchyma. Secondary bacterial infection may produce cyst fluid that contains abundant neutrophils and proteinaceous background debris. However, the presence of a neoplastic lining epithelium or background mucin excludes the diagnosis of a non-neoplastic cyst.

Cavernous hemangiomas are usually asymptomatic, and they are usually diagnosed incidentally during the workup for other conditions, such as during the process of staging a malignancy, and they can be difficult to distinguish from metastasis radiologically. Hemorrhagic aspirates are often considered unsatisfactory.

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The nondiagnostic appearance of blood with loose rather than dense fibrous connective tissue and few or no background hepatocytes raises the possibility of a hemangioma in the proper clinical setting Fig Histologic material is crucial in establishing a specific diagnosis Box Smears commonly nondiagnostic; specific diagnosis depends more on cell block pattern. Aspirates of mesenchymal hamartomas are obtained mainly in the pediatric population, with rare exceptions, and usually show clusters of epithelial and mesenchymal or spindle-shaped cells with bland-appearing nuclei admixed with loose connective tissue Fig However, aspiration cytology rarely enables a definitive diagnosis, and because hepatoblastomas or malignant mesenchymal tumors are difficult to exclude confidently, cytology is of limited value Box Solid tumors may undergo central necrosis and cavitation, simulating cysts radiologically.

A necrosis-associated tumor should raise the suspicion of an abscess. Necrosis is more likely to occur in malignant lesions, such as squamous cell carcinomas, neuroendocrine tumors, and metastases from colorectal adenocarcinomas and nonkeratinizing undifferentiated carcinoma in the nasopharynx. The diagnostic cells may be obscured by the process. Although most undifferentiated embryonal sarcomas appear ultrasonographically as solid lesions, CT and MRI imaging may detect a low-attenuation mass with a cystic appearance. Most cystic structures result from liquefactive necrosis and blood clots; however, true cystic spaces may also occur.

Aspirates recapitulate the histologic pattern of the tumor. Smears are usually composed of spindle cells and myxoid tissue, intermixed with pleomorphic cells ranging from small round cells to larger multinucleated giant cells.


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Giant cells have bizarre nuclei and massively deranged chromatin structure. The cytologic differential diagnoses include rhabdomyosarcoma , hepatoblastoma, undifferentiated pleomorphic sarcoma, NOS so-called malignant fibrous histiocytoma , and poorly differentiated HCC Box Large, pleomorphic anaplastic cells with multinucleated giant cells and atypical spindle cells. Benign hepatocellular nodules, which can be non-neoplastic or neoplastic, such as focal fatty changes, large regenerative nodules, dysplastic nodules, focal nodular hyperplasia, and hepatocellular adenomas, are discussed together because they share common cytologic features, including fatty changes Box Unfortunately, it is not always possible to distinguish these entities on the basis of smear cytology alone.

They all can mimic well-differentiated HCC. Hepatocytes arranged in jagged irregular clusters, small clusters, short rows, and singly depending on regenerative, dysplastic, or neoplastic nature. Cytoplasm usually abundant except in small cell change and granular but may show a fatty change, lipofuscin pigment, or iron deposition. Bile ductular epithelium and stromal fragments, indicative of hepatocellular-interface restoration, may be present except in neoplastic aspirates. Reticulin stain shows retention of one- to two-cell-thick hepatic cords on cell block. A focal fatty change may simulate a mass lesion radiologically.

Aspirates are composed of a polymorphous population of enlarged, fat-laden, non-neoplastic hepatocytes intermingled with bile duct epithelial clusters.

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Oil globules may be seen in the background on air-dried smears. Aspirates from large regenerative nodules are similar to those from cirrhosis, in which a polymorphous liver parenchymal population shows evidence of hyperplasia and hepatocellular-interface restoration i. Hyperplastic hepatocytes occur in two-cell-thick cords and exhibit slight polymorphism and binucleated forms. Nuclear disarray may be disconcerting. Ductules can be seen emanating from the jagged edges of sizeable parenchymal fragments Fig.

Stroma may be seen in the background.

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The presence of ductules should raise the diagnostic threshold for a malignant process. Hepatocellular atypia, such as large cell and small cell changes e. The nuclear size is similar to that of normal hepatocytes, but there is less cytoplasm, imparting an impression of nuclear crowding Fig.

Aspirates of low-grade dysplastic nodules show hepatocytes that exhibit large cell changes, whereas those from high-grade dysplastic nodules show hepatocytes with small cell changes. Dysplastic hepatocytes tend to occur singly or in narrow cords, usually one to two cells thick. Transgressing endothelium is not a feature. It is almost impossible to distinguish a small cell change from a well-differentiated or early HCC.

The key to recognizing a large cell change as benign is the sporadic placement of these cells in a background of otherwise reactive-appearing hepatocytes and accompanied by bile ductal or ductular epithelium and stroma. Availability of histologic material for immunohistochemistry is invaluable. Patients with cirrhosis without iron overload can accumulate iron within regenerative or dysplastic nodules, which are called siderotic nodules. Siderotic dysplastic nodules are considered to be premalignant, whereas siderotic regenerative nodules are a marker for severe viral or alcoholic cirrhosis.

Iron-free foci in patients with genetic hemochromatosis are likely to be malignant. Focal nodular hyperplasia is characterized by a proliferation of hepatocytes surrounding a central scar containing blood vessels and bile ducts. A brisk ductular reaction is often seen at the hepatocellular-stromal interface. Aspirates typically contain a polymorphous population of cells, but this varies.

Hyperplastic hepatocytes abound in one- to two-cell-thick cords. Bile duct epithelium is usually evident Fig. The presence of ductular epithelium supports the benign nature of this lesion, but this feature can be mistaken for adenocarcinoma if it is the dominant component of the aspirate. A possible diagnostic pitfall is mistaking reactive stroma for a spindle cell neoplasm. A characteristic geographic immunostaining pattern is seen with the use of glutamine synthetase. Without radiologic demonstration of a central scar, it may not be possible to differentiate focal nodular hyperplasia from large regenerative nodules on smear cytology, because both show features of regeneration.

Aspirates of a hepatocellular adenoma are hypercellular and typically contain well-differentiated hepatocytes occurring in one- to two-cell-thick cords Fig. There is no significant atypia. Transgressing endothelium is common, but peripheral endothelium is lacking.

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