P- Reviewer: Roncalli M, Xu R S- Editor: Gou SX L- Editor: A E- Editor: Wu HL
Published online Aug 27, 2014. doi: 10.4254/wjh.v6.i8.580
Revised: June 10, 2013
Accepted: August 19, 2013
Published online: August 27, 2014
This practical atlas aims to help liver and non liver pathologists to recognize benign hepatocellular nodules on resected specimen. Macroscopic and microscopic views together with immunohistochemical stains illustrate typical and atypical aspects of focal nodular hyperplasia and of hepatocellular adenoma, including hepatocellular adenomas subtypes with references to clinical and imaging data. Each step is important to make a correct diagnosis. The specimen including the nodule and the non-tumoral liver should be sliced, photographed and all different looking areas adequately sampled for paraffin inclusion. Routine histology includes HE, trichrome and cytokeratin 7. Immunohistochemistry includes glutamine synthase and according to the above results additional markers such as liver fatty acid binding protein, C reactive protein and beta catenin may be realized to differentiate focal nodular hyperplasia from hepatocellular adenoma subtypes. Clues for differential diagnosis and pitfalls are explained and illustrated.
Core tip: In this paper are illustrated macroscopic and microscopic aspects of focal nodular hyperplasia and hepatocellular adenoma. These illustrations represent typical as well as less usual aspects of these two benign hepatocellular tumors. Microscopic pictures are performed using classical routine stains such as HE, trichrome or cytokeratin 7 or less usual markers proven of great interest to identify focal nodular hyperplasia (FNH) such as glutamine synthase or liver fatty acid briding protein, C reactive protein or b catenin to identify hepatocyte nuclear factor 1 alpha mutated hepatocellular adenoma (HCA), inflammatory HCA, β-catenin mutated HCA respectively. These illustrations combined with brief clinical information should be helpful for pathologists for their practice. Indeed if FNH are rather frequent tumor easy to recognize, there are difficulties when key features are lacking or when features such as steatosis or sinusoidal dilatation, features of HCA, are present. The great message of this paper is the possibility to identify HCA subtypes, a key feature for the coming years to better manage patients.
- Citation: Sempoux C, Balabaud C, Bioulac-Sage P. Pictures of focal nodular hyperplasia and hepatocellular adenomas. World J Hepatol 2014; 6(8): 580-595
- URL: https://www.wjgnet.com/1948-5182/full/v6/i8/580.htm
- DOI: https://dx.doi.org/10.4254/wjh.v6.i8.580
In the most recent liver pathology textbooks[1-4], the description of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) taking into account the new classification of HCA allows to better differentiate FNH from HCA and to identify HCA subtypes, but not surprisingly there are few pictures of these 2 entities by lack of space.
The aim of this atlas is to illustrate more extensively than in textbooks[1-4] and journals[5-7] the most frequent pathological aspects of FNH and HCA both macroscopically and microscopically, using traditional routine stainings and more recently described immunohistochemical approach.
It is important to mention that if these new immunohistochemical techniques have allowed the classification of HCA into subtypes by the pathologists, the definite criteria to classify HCA relies on molecular analysis. The strict correlation between the interpretation of the HCA classification based on the phenotype (macroscopy, routine techniques and immunohistochemistry) versus the genotype defined by the molecular analysis has to be strictly performed. In addition, the molecular classification is still in progress; therefore some data presented here should be interpreted cautiously in particular regarding the subgroups of β-catenin mutated HCA (β-HCA) and unclassified HCA (UHCA).
FNH are frequent hepatocellular nodules. Until recently the diagnosis was not always easy. If the diagnosis is certain, resection is not recommended; however, resection is occasionally performed upon pain, organ compression, doubt in differential diagnosis with HCA or with hepatocellular carcinoma. Using routine histopathological techniques [HE, trichrome, cytokeratin 7 (CK7)] the diagnosis is certain in more than 80% of cases. Glutamine synthase (GS) staining has the great advantage to confirm rapidly and with high confidence the diagnosis. When combining all the markers, the accuracy of the diagnosis is close to 100%.
HCA are rare hepatocellular nodules frequently resected when their size exceed 5 cm. HCA are divided into subtypes using molecular markers and immunohistochemistry. The most common HCA: HNF1A mutated HCA (H-HCA, 35%) and inflammatory HCA (IHCA, 50%) can be recognized with some degree of confidence by imaging techniques and by HE[13-15]. GS is a surrogate marker to identify β-catenin mutated HCA (β-HCA, 10% and β-catenin activated inflammatory HCA, β-IHCA, 10% of IHCA)[15,16]. Identification of β-catenin mutated HCA is of major clinical relevance because of the highest risk of malignant transformation[17,18]. The mutation can be confirmed using β-catenin staining. The absence of aberrant nuclear staining is not however an argument to refute the diagnosis, because it is often focal[15,16]. When GS is difficult to interpret, molecular biology is necessary to demonstrate β-catenin mutation in order to confirm the diagnosis. When the diagnosis of H-HCA or IHCA is not self-evident on routine stainings, immunostainings included liver-fatty acid binding protein (L-FABP), C-reactive protein (CRP), markers which are useful to identify H-HCA (absence of LFABP) and IHCA (diffuse positivity of CRP). The absence of the above markers identifies unclassified HCA (less than 10%). The differential diagnosis between FNH and HCA is important as well as the identification of HCA subtypes thought to be of great importance for the present and future management[19-22]. Indeed, in the past there has been a great confusion between FNH and HCA[23,24].
Below are figures of FNH and HCA. For each macroscopic or microscopic pictures, we have given in the legend a minimum of clinical information. In this practical atlas we have not illustrated HCA with malignant transformation.
To increase the chance to make a correct diagnosis, some rules must be respected: the specimen must be carefully sliced; photographs should be taken to illustrate necrosis, hemorrhage and fibrotic bands; all areas of interest must be sampled as well as the non tumoral liver and the junction between the nodule and the non tuomral-liver; routine histology includes HE, trichrome, and CK7; these markers may be sufficient to make a diagnosis of FNH, HCA and eventually HCA subtypes. When needed to differentiate an FNH from an HCA or to identify HCA subtypes, additional immunomarkers may be useful. In some occasions all of them may be useful when there is no indication for a specific diagnosis or HCA subtypes: it includes LFABP, C reactive protein (CRP), GS and β-catenin. Even when all the rules are followed, difficulties in interpretation may occur. First of all to have to check the quality of the technique; it is not necessary to overinterpret doubtful immunohistochemical data. When there is no way to interpret satisfactorily the data, one is forced to rely on the molecular data. This is why it is highly recommended for referral center to freeze material (tumor and non tumoral tissue) when their counterparts are analysed by routine histology.
The macroscopic aspects are presented in Figure 1. Microscopic typical features on Masson’s Trichrome, GS and CK7 immunostainings are presented in Figure 2. Microscopic atypical features on Masson’s trichrome and GS immunostaining are presented in Figure 3. The other microscopic aspects dealing with steatotic, pre-FNH and regressing FNH are presented in Figure 4.
The macroscopic aspects of different subtypes are presented in Figure 5.
UHCA are still poorly understood entities. However, their histological characteristics are worrisome and in many aspects in at least 50% of cases are reminiscent of b catenin HCA. Micrographs are presented in Figures 19 and 20.
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