Amedeo Sciarra

Benign hepatocellular nodules of healthy liver: focal nodular hyperplasia and hepatocellular adenoma

Owing to the progress of imaging techniques, benign hepatocellular nodules are increasingly discovered in the clinical practice. This group of lesions mostly arises in the context of a putatively normal healthy liver and includes either pseudotumoral and tumoral nodules. Focal nodular hyperplasia and hepatocellular adenoma are prototypical examples of these two categories of nodules. In this review we aim to report the main pathological criteria of differential diagnosis between focal nodular hyperplasia and hepatocellular adenoma, which mainly rests upon morphological and phenotypical features. We also emphasize that for a correct diagnosis the clinical context such as sex, age, assumption of oral contraceptives, associated metabolic or vascular disturbances is of paramount importance. While focal nodular hyperplasia is a single entity epidemiologically more frequent than adenoma, the latter is representative of a more heterogeneous group which has been recently and extensively characterized from a clinical, morphological, phenotypical and molecular profile. The use of the liver biopsy in addition to imaging and the clinical context are important diagnostic tools of these lesions. In this review we will survey their systematic pathobiology and propose a diagnostic algorithm helpful to increase the diagnostic accuracy of not dedicated liver pathologists. The differential diagnosis between so-called typical and atypical adenoma and well differentiated hepatocellular carcinoma will also be discussed.

TRIP: a pathological score for transarterial chemoembolization resistance individualized prediction in hepatocellular carcinoma

Although potentially very useful in optimizing patient selection and follow‐up, the individual response to transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) is generally unpredictable. The aim of this study was to identify tissue predictors of tumour resistance to TACE for use in clinical practice on pretreatment biopsies.

One-Step Nucleic Acid Amplification in Breast Cancer Sentinel Lymph Node: A Single Institutional Experience and a Short Review

Sentinel lymph node (SLN) examination is a standard in breast cancer patients, with several methods employed along its 20 years history, the last one represented by one-step nucleic acid amplification (OSNA). The latter is a intra-operative molecular assay searching for CK19 mRNA as a surrogate of metastatic cells. Our 3 years experience with OSNA (1122 patients) showed results overlapping those recorded in the same institution with a morphological evaluation (930 patients) of SLN. In detail, the data of OSNA were almost identical to those observed with standard post-operative procedure in terms of patients with positive SLN (30%) and micrometastatic/macrometastatic involvement of SLN (respectively, 38–45 and 62–55%). By contrast, when OSNA was compared to the standard intraoperatory procedure, it was superior in terms of accuracy, prompting the use of this molecular assay as a very valid, and reproducible for intra-operative evaluation of SLN. Further possibilities prompting the use of OSNA range from adhesion to quality control programs, saving of medical time, ability to predict, during surgery, additional nodal metastasis, and molecular bio-banking.

Interferon-Alpha in Cardiac Erdheim-Chester Disease

![Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4] An 80-year-old man, known for years to have chronic renal failure due to retroperitoneal fibrosis, was referred for worsening dyspnea. The cardiac magnetic resonance showed moderate pericardial effusion and a right atrial wall

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers

Targeted therapies against the human epidermal growth factor receptor 2 (HER2) have radically changed the outcome of patients with HER2-positive breast cancers. However, a minority of cases displays a heterogeneous distribution of HER2-positive cells, which generates major clinical challenges. To date, no reliable and standardized protocols for the characterization and quantification of HER2 heterogeneous gene amplification in large cohorts have been proposed. Here, we present a high-throughput methodology to simultaneously assess the HER2 status across different topographic areas of multiple breast cancers. In particular, we illustrate the laboratory procedure to construct enhanced tissue microarrays (TMAs) incorporating a targeted mapping of the tumors. All TMA parameters have been specifically optimized for the silver in situ hybridization (SISH) of formalin-fixed paraffin-embedded (FFPE) breast tissues. Immunohistochemical analysis of the prognostic and predictive biomarkers (i.e., ER, PR, Ki67, and HER2) should be performed using automated procedures. A customized SISH protocol has been implemented to allow a high-quality molecular analysis across multiple tissues that underwent different fixation, processing, and storage procedures. In this study, we provide a proof-of-principle that specific DNA sequences could be localized simultaneously in distinct topographic areas of multiple and heterogeneously processed breast cancers using an efficient and cost-effective method.

Rediscovering secondary tumors of the prostate in the molecular era

Metastatic involvement of the prostate from noncontiguous solid tumors is a rare event occurring by means of vascular dissemination. The reported cases of biopsy and surgical samples with metastatic involvement have increased; however, a comprehensive understanding of secondary tumors of the prostate is currently missing. Metastases to the prostate carry a dismal prognosis and may pose serious diagnostic challenges to both clinicians and pathologists, with crucial therapeutic implications. Secondary tumors of the prostate spread more frequently from the digestive tract, the lung, and the kidney. The integration of clinicoradiologic data with appropriate pathologic and immunohistochemical analyses is essential for the identification and the characterization of secondary tumors of the prostate, whereas molecular analyses could provide additional and complementary information, enabling precise diagnosis and appropriate clinical management. Patients with solitary metastases could benefit from prostatic resection and adjuvant therapy, whereas in cases of disseminated diseases, symptom control may be obtained with palliative procedures. The purpose of this review was to assess the current state of knowledge of secondary tumors involving the prostate gland and to discuss short-term future perspectives, while providing a practical approach to these uncommon conditions for pathologists and oncologists.

Cracking spaces in Hashimoto Thyroiditis are lymphatic and prelymphatic vessels: a gift of immunohistochemistry for the centenary of Hashimoto's description.

A century ago Hashimoto described the histologic hallmarks of struma lymphomatosa: (1) lymphoid follicles, (2) changes in the epithelial cells, (3) formation of connective tissue, and (4) diffuse round cell infiltration. He also showed some cracking spaces close to lymphoid follicles resembling vessels. The aim of this study was to investigate the possible lymphatic nature of these spaces and their prevalence in non-neoplastic thyroid tissue. Ten cases of Hashimoto thyroiditis (HT), 5 of Basedow-Graves disease (BG), and 5 of normal thyroid tissue (NT) were selected. Tissues were stained with hematoxylin and eosin, CD31 (Dako), and D2-40 (Dako) stains. Cracking spaces staining positive for CD31 and D2-40 stains were considered as lymphatic vessels. Site, distribution, intravascular valves and lymphocytes, perivascular lymphoid aggregates, and number and surface of lymphatic vessels were evaluated using a computer-assisted digital videocamera microscope (Nikon digital sigh, DS-2Mv). The number of lymphatic vessels increased from NT [3 (range, 2 to 13)] to BG [8 (range, 5 to 9)] to HT [12.5 (range, 10 to 16)]. A significant statistical difference was observed within the group (P=0.003): HT differed from NT (P=0.016) and BG (P=0.002). The area of lymphatic vessels increased from NT [0.01 mm2 (range, 0.01 to 0.12 mm2)] to BG [0.03 mm2 (range, 0.01 to 0.19 mm2)] to HT [0.03 mm2 (range, 0.01 to 0.6 mm2)]. A significant statistical difference was observed among the groups (P=0.001): NT differed from HT (P<0.001) and from BG (P<0.001). Lymphatic vessels showed valves, perivascular lymphoid aggregates, and intravascular lymphocytes. The cracking spaces shown by Hashimoto are mainly lymphatic vessels and represent a characteristic feature of autoimmune thyroid diseases.

Heterotopic Gastric Mucosa in a Duplication Cyst of the Common Hepatic Duct Mimicking Cholangiocarcinoma

Heterotopic gastric mucosa in biliary tract is a congenital anomaly that can prove significant clinical dilemmas. Here we report the case of a 28-year-old female patient presenting with jaundice, pruritus, and altered liver tests, with predominant cholestasis. Liver biopsy revealed histological changes suggesting large bile duct obstruction with advanced fibrosis. At imaging, common hepatic duct stricture due to an intraluminal enhancing mass was observed. Endoscopic retrograde cholangiopancreatography and upper echoendoscopy revealed a firm mass of the common hepatic duct with a complete obstruction, suspicious for cholangiocarcinoma. Fine-needle aspiration biopsy performed under echoendoscopic guidance revealed fundic type gastric mucosa. Despite histological result, radiological suspicion of malignancy together with advanced fibrosis prompted a segmental resection of biliary tract. At macroscopic examination, the common hepatic duct presented a focal pseudocystic appearance with a firm zone of subtotal stenosis. Histology revealed a duplication cyst lined by heterotopic fundic gastric mucosa. Heterotopic gastric mucosa of the biliary tract should be suspected in young patients without know risk factors for hepatobiliary malignancies. Imaging and careful histological examination are mandatory for optimal management. Liver fibrosis, secondary to chronic biliary obstruction may be a significant late complication.

CYP1A2 is a predictor of HCC recurrence in HCV-related chronic liver disease: A retrospective multicentric validation study

BACKGROUND Although hepatic resection is a potentially curative treatment for hepatocellular carcinoma (HCC), post-operative prognosis remains unsatisfactory due to the high incidence of recurrence. Several clinicopathological markers have been associated with HCC recurrence, but none has been validated. Extratumoral expression of cytochrome P4501A2 (CYP1A2) was recently proposed as predictor of HCC recurrence. AIMS To validate extratumoral CYP1A2 as predictor of HCC recurrence and to determine its applicability to pretreatment liver biopsy. METHODS Surgically resected HCC (n.180) with clinicopathological data and follow up were retrospectively studied (HCV n.54; HBV n.91; NAFLD/NASH n.35). CYP1A2 expression was evaluated using an immunohistochemical assay and semiquantitative analysis. RESULTS Etiology-stratified analysis showed that low CYP1A2 expression was independently associated with recurrence-free survival in HCV patients (HR 2.814, 95% CI 1.300-6.093, p=0.009); this association was lost in the whole cohort. Pretreatment liver biopsy and paired surgical specimens showed concordant CYP1A2 expression in the vast majority of cases (87%), with NPV of 100%, PPV of 81.25%, and a Cohen kappa of 0.72 (substantial agreement). CONCLUSION We validated the extratumoral expression of CYP1A2 as a biomarker of HCC recurrence in HCV patients. CYP1A2 analysis in pretreatment liver biopsy can be of help to stratify HCC patients for personalized treatment.