Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features

Abstract

Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts—we designate this variant as ‘chromophobe hepatocellular carcinoma with abrupt anaplasia’. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P = 0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

DNAJB1-PRKACA is specific for fibrolamellar carcinoma

“…In support of this, the recently described chromophobe variant of hepatocellular carcinoma is characterized by an altered lengthening of telomere phenotype together with its distinctive morphology. 11 Other morphologically unique variants of hepatocellular carcinoma, such as clear cell hepatocellular carcinoma, steatohepatitic hepatocellular carcinoma, and scirrhous hepatocellular carcinoma, may be associated with unique genetic changes, allowing for a morphology based subclassification that reflects specific genetic driver events, which in turn may lead to a better understanding of tumor biology and implementation of precisely targeted therapies.…”

Liver cancer biopsy – back to the future?!

“…The very high specificity of the typical radiological appearances in the right setting means that the diagnosis can be made without biopsy. [1][2][3][4] Furthermore, biomarkers also have a high specificity in the presence of a mass in the liver. Biomarkers are not optimally sensitive, but when present in sufficient concentration can be diagnostic of malignancy (either HCC or intrahepatic cholangiocarcinoma [ICC]).…”

“…The American Association for the Study of Liver Diseases (AASLD) guidelines from 2011 6 provide an algorithm that has been validated as having high specificity and sensitivity for the diagnosis of HCC. [1][2][3][4] Other scientific associations and groups have proposed similar guidelines or have endorsed the AASLD guidelines. [6][7][8][9][10][11][12][13] Biopsy has a place in this algorithm, but only in cases where radiology is not diagnostic.…”

“…With these requirements in place, the pattern described has shown an almost 100% specificity in studies from different centers, with a sensitivity of approximately 60%. [1][2][3][4]14 This means that, in 40% of the patients, the diagnosis will be by biopsy. It is important to stress that even biopsy does not have 100% sensitivity, and when done for small nodules in cirrhosis, the specificity is less good and interobserver agreement is suboptimal.…”

“…The new chromophobe subtype shows a distinct morphology as well as a specific molecular mechanism to overcome replicative senescence (alternative lengthening of telomeres), in contrast to telomerase activation seen in most HCCs. 3 The molecular mechanisms behind other subtypes, such as steatohepatitic, scirrhotic, and inflammatory HCCs, await clarification, but these subtypes are likely to be relevant to trial design and clinical care. Although the frequency of each individual subtype may not exceed 5%, an estimated 20-30% of HCCs belong to a recognizable morphological/molecular subtype.…”