Liver cancer biopsy – back to the future?!

Potential conflict of interest: Nothing to report. Hepatocellular carcinoma (HCC) is the only major cancer in which diagnosis and subsequent indication for treatment is not regularly established by histology. Current AASLD and EASL guidelines do not require biopsy for tumors that develop in cirrhotic livers and in chronic hepatitis B, if the imaging results show changes interpreted as HCC. This leads to an estimated 60‐70% of nonresectable liver tumors being treated as HCC without tissue confirmation. Originally seen as an achievement, this approach neglects basic oncological principles and has had unforeseen negative consequences for diagnosis and treatment. At a time when oncology is moving towards personalized medicine, the lack of tissue in a large proportion of cases has significantly limited this approach for HCC. The foundation of personalized medicine is an integrative molecular‐morphological subtyping of tumors using predictive molecular testing and targeted therapies. Other tumor entities, such as non‐small‐cell lung cancer, breast cancer, and colorectal carcinoma, have all witnessed improved integrative diagnostics, a flourishing trial scenario, novel predictive tests, innovative therapies, and an active bench‐bedside‐bench research scenario. Not so for HCC. What are the reasons? While there are many, we believe reduced numbers of tumor biopsies has been critical. Correct classification and subtyping of tumors is the foundation for rational therapy and the current WHO classification is based on integrated molecular and morphological data. This smart move has improved overall tumor definition and other organ systems have benefited enormously from this concept by the establishment of defined subtypes that require different approaches in diagnostics, treatment, and trial design. However, the effect for HCC has been limited to date, not because HCC is fundamentally different from other solid tumors, but due to a lack of interdisciplinary coevolution of diagnostics, culminating in a greatly reduced number of diagnostic liver biopsies. HCC is best considered not as a homogenous entity but as a closely related group of morphologically and molecularly distinct cancer subtypes. As one example, fibrolamellar carcinoma is already a well‐accepted morphological and molecular subtype of HCC1; furthermore, approximately 4‐5% of liver cancers show both clear cut hepatocellular and cholangiocellular differentiation and are classified as combined HCC/CC.2 In both cases, subtyping is clinically relevant and only established by histology. The importance of tumor subtyping will certainly increase in the future: even within the category of more typical HCCs, relevant morphological/molecular subtypes can be discerned. 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. For the remaining HCCs, molecular subtypes likely exist.4 Biopsy tissue analyses are key for subclassifying these tumors and future clinical trials should address the potential prognostic and predictive impact and specific biological differences. Tumor heterogeneity will not be fully reflected in all liver biopsies, but many HCCs can be subclassified appropriately. Alternatives for subclassifying tumors, for example by imaging studies or serum markers, should be vigorously pursued, but are most likely to develop based on tissue and molecular subclassification. Clinical issues also need to be considered more carefully. Real world performance of imaging diagnostics for HCC does not always live up to the data which formed the basis for the exiting guidelines, data that was typically generated in carefully controlled and supervised multicenter trials. In this regard, there is insufficient data evaluating the post guideline performance of imaging studies.5 To date, the debate on whether to biopsy has been dominated by voices that emphasize negative attributes of liver biopsy. The literature has placed less emphasis on the important positive aspects of histology, including its superior diagnostic sensitivity and specificity, long‐term availability (e.g. for second opinion and future molecular tests), as well as its cost effectiveness and broad availability. Common arguments against liver tumor biopsy have been risk for bleeding and tumor seeding. The risk of bleeding related mortality for liver biopsies is generally accepted to be around 0.1 to 0.01%, which is nontrivial, but offset by the importance of accurate diagnosis for those who will be undertaking specific therapies, which have their own serious risk factors and expenses. In regards to tumor seeding, this event is rare, appears late, can be well treated locally in most cases, and does not reduce life expectancy.5 Another concern of the current diagnostic approach is that clinical trial design mirrors the clinical diagnostic situation. If biopsies are not taken in the clinical setting, they are less likely to be implemented in clinical trials. Meta‐analyses of clinical trials in NSCLC demonstrated that trials with nonselective enrollment for targeted therapeutic studies were highly likely to fail in contrast to trials using predictive marker testing for enrollment.6 This makes sense: if a tumor is not expressing a specific biomarker, targeting that specific biomarker makes little sense. In fact, this may have contributed to the failure of the last six Phase III clinical trials for nonresectable HCC, as upfront biopsies with biomarker analyses were not included in the trial concepts. More recent HCC trials that use biopsy data for adequate patient selection are likely to increase their chance of success.7 Late trial failures are worrisome and may cause a significant reduction of commercial interest in HCC and may divert it to tumor entities that seem to promise more success. Also of concern, the current guidelines are likely to lead to a cycle of “atrophy by neglect.” Reduced exposure to HCC biopsies lowers the specific diagnostic performance of pathologists. Together with sharply reduced biopsy numbers in other chronic liver diseases, these changes make hepatopathology less interesting to junior pathologists and are likely to lead to deleterious brain drain. But the field of liver pathology is not alone. How will the field of hepatology recruit the best and brightest to advance our understanding of liver disease with greatly reduced samples of human liver tissue to study? By animal models alone? By noninvasive testing? A great many more scientific hypothesis can be studied in a set of 100 liver biopsies than in a set of 100 noninvasive test results. We are at a cross‐road. We believe the path of reduced liver biopsies for HCC is inherently limiting and if taken further, will constrain the field for decades to come. The alternative path of performing liver biopsies to diagnose and subclassify HCC is more likely to realize the full potential of the molecular revolution and personalized medicine for HCC patients. Additional efforts should concentrate on morphological and molecular subtyping of HCC to support clinical decisions for both targeted and nontargeted therapies. In many ways, personalized medicine has partly lifted the separation between regular clinical service and clinical trials, as specialized centers have started to use so‐called umbrella‐concepts, including biopsy based analyses for patient recruitment and allocation to targeted vs. nontargeted trials. We believe that improving tumor diagnosis and treatment is an interdisciplinary approach and should take advantage of the power of new technologies. While liver biopsy is an old technology, it provides important and unique information that currently cannot be duplicated. The lack of biopsy material is hurting progress in understanding, diagnosing, and treating HCC. At this cross‐road, we advocate returning back to the “past,” where diagnostic biopsies were commonly performed. We are not alone. An international group of experts on pediatric liver tumors has recently called for mandatory liver biopsies in all pediatric patients with liver tumors.8 We do not believe all adults with liver tumors need biopsies, but developing clinical and trial protocols in adults with HCC that support the important role of biopsies will improve diagnosis of HCC and increase our chance to provide better patient care in the future.