Search

Dr. Ondrej Hes clearly belongs to the first category (“born great”), described by William Shakespeare centuries ago. This tribute has been prepared by a group of close friends of Dr. Hes, who had the honor and privilege to know him both personally and professionally over years. On July 2, 2022, Ondrej passed away, a few days after collapsing while running from home to work (his usual routine exercise) outside the hospital in Pilsen (Plzeň) and in the nature that he loved the most.

No abstract available.

Aims Littoral cell angioma (LCA) is a rare primary splenic tumour that is frequently associated with internal malignancies. Immunohistochemistry can demonstrate a distinct hybrid endothelial–histiocytic phenotype of littoral cells, and is a helpful adjunct for making the correct diagnosis. The aims of this study were to present a series of 25 LCAs, with an emphasis on the frequent association of the neoplasm with visceral malignancies, and to provide a detailed immunohistochemical analysis by employing new markers. Methods and results All 25 cases with available tissue blocks were immunohistochemically stained for endothelial and histiocytic markers. Clinical and follow-up data were retrieved from the respective institutions. The tumours were obtained from 16 males and nine females, whose age ranged from 32 to 86 years (mean 56.2 years). Clinical information was available for 24 of 25 patients, and follow-up for 11 of 25 patients (range 2–19 years; mean 11.6 years). Immunohistochemically, all cases were positive for LYVE-1, factor VIII, FLI-1, vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, claudin-5, ERG, LMO2, CD31, CD163, lysozyme, and CD4, but negative for D2-40, CD8, and factor XIIIa. Fifteen of 25 cases were associated with various malignancies, including epithelial, mesenchymal and haematological tumours. Conclusions The cohort of 25 patients is the largest series of LCAs published to date. By using antibodies against recently introduced endothelial markers, we have expanded the immunoprofile of LCA. We have further highlighted the clinical significance of LCA, as more than half of the patients in this study also harboured a coexisting visceral malignancy. Therefore, we conclude that the finding of splenic LCA mandates a thorough clinical evaluation for a concomitant malignancy.

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) has been recently described as a distinct neoplasm. Twenty-one cases from 12 institutions were analyzed using routine histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization. Tumors were removed from 11 male and 10 female patients, whose age ranged from 53 to 79 years. The size of tumors ranged from 1.5 to 16 cm. Follow-up information was available for 14 patients (range, 1 to 96 mo), and metastatic spread was found in 5 cases. All tumors comprised 2 cell populations arranged in organoid structures: small, low-grade neoplastic cells with scant cytoplasm usually lining the inside of alveolar structures, and larger squamoid cells with more prominent cytoplasm and larger vesicular nuclei arranged in compact nests. In 9/21 tumors there was a visible transition from such solid and alveolar areas into papillary components. Areas composed of large squamoid cells comprised 10% to 80% of total tumor volume. Emperipolesis was present in all (21/21) tumors. Immunohistochemically, all cases were positive for cytokeratin 7, EMA, vimentin, and cyclin D1. aCGH (confirmed by fluorescence in situ hybridization) in 5 analyzable cases revealed multiple numerical chromosomal changes including gains of chromosomes 7 and 17 in all cases. These changes were further disclosed in 6 additional cases, which were unsuitable for aCGH. We conclude that tumors show a morphologic spectrum ranging from RCC with papillary architecture and large squamoid cells to fully developed BSARCC. Emperipolesis in squamoid cells was a constant finding. All BSARCCs expressed CK7, EMA, vimentin, and cyclin D1. Antibody to cyclin D1 showed a unique and previously not recognized pattern of immunohistochemical staining. Multiple chromosomal aberrations were identified in all analyzable cases including gains of chromosomes 7 and 17, indicating that they are akin to papillary RCC. Some BSARCCs were clinically aggressive, but their prognosis could not be predicted from currently available data. Present microscopic, immunohistochemical, and molecular genetic data strongly support the view that BSARCC is a distinctive and peculiar morphologic variant of papillary RCC.

Background Trastuzumab emtansine (T-DM1), a novel drug-antibody conjugate, has shown promising activity in HER2-positive breast cancer and is the recommended agent of choice for second line therapy for advanced HER 2-positive breast cancer. Elevations in transaminase levels have been reported in up to 40% of patients treated with T-DM1 on phase I-III clinical studies. More serious hepatotoxicity can also result from this drug-antibody conjugate, but has been infrequently described in the literature. Case Presentation Here we report a 73 year old female with previously untreated metastatic HER 2-positive breast cancer who developed nodular regenerative hyperplasia and noncirrhotic portal hypertension while on treatment with single agent T-DM1. Liver biopsy demonstrated nodular regenerative hyperplasia, bile duct injury, and portal fibrosis. Conclusion A high index of suspicion for liver injury and NRH must be maintained for patients who develop liver test abnormalities and/or signs of portal hypertension during treatment with T-DM1. Abdominal imaging, liver biopsy, and prompt discontinuation of T-DM1 is recommended for patients with signs or symptoms of liver injury.

The advent of human pluripotent stem cells, with the first derivation of human embryonic stem cells in 1998, and of human induced pluripotent stem cells in 2007, has ushered in an era of considerable excitement about the prospects of using these cells to develop new opportunities for healthcare, from their potential for regenerative medicine to their use as tools for studying the cellular basis of many diseases and the discovery of new drugs. But as with the flowering of many new areas in science, the biology of human pluripotent stem cells has its roots in a long history of, sometimes, less fêted research. In a period when research funding is frequently driven by a desire to meet specific clinical or economic goals, it is salutary to remember that the opportunities offered by human pluripotent stem cells have their origins in curiosity driven research without any of those goals in mind. In this case, that research focused on the relatively rare gonadal cancers known as teratomas, tumors that have fascinated people since antiquity because their sometime grotesque manifestations with haphazard collections of tissues and sometimes recognizable body parts. Although well known to clinical pathologists it was the pioneering work of Leroy Stevens, who first discovered that teratomas occur at a significant rate in the 129 strain of the laboratory mouse and could be produced experimentally, that laid the foundations for our understanding of the biology of these tumors and the central role of the embryonal carcinoma cell, one of the archetypal tumor stem cells.

Histopathologic examination of surgically removed tissues and organs is an important aspect of modern hospital quality health care. Most surgical specimens deserve to be submitted for pathologic examination, which may yield valuable new information relevant for the future treatment of the patient. A small number of specimens, recognized as providing limited or no valuable clinical data during pathologic examination, may be placed on the list of specimens “exempt from submission” or those that are labeled as “for gross examination only.” Guidelines written by the committees of the national regulatory organizations provide general orientation on how to deal with various specimens, but the final decision on which type of specimen to eliminate and which ones to include for pathologic examination rests on local governing and advisory bodies of each institution. Particular lists of specimens exempt from pathologic examination are best generated through a consensus agreement of clinical and laboratory physicians. Even though there is general nationwide and even international consensus on which types of specimens deserve pathologic examination and which do not, there are still discussions about the necessity of some pathologic examinations.

Gordon Barry Pierce, my great mentor and long-time friend died in November 2015 at the age of 90 years. We will all miss him. What we are left with, however, are reminiscences of moments we spent with him, his jokes and stories to be retold and passed along, titbits of advice, and pearls of his common-sense Canadian wisdom. A vision of a better world to which he contributed so much. Scientific contributions too numerous to list, many of which had major impact on us who were interested in the same problems as he was. Seminal discoveries that impacted the progress in several fields of scientific endeavor. Major new concepts of oncology and developmental biology that opened new vistas and revolutionized our thinking about the crucial problems of biology and medicine. Unforgettable seminars and lectures. Unquenchable love for science. And much more that, nevertheless, can be summarized in two wondrous exclamations: What a man! What a life!

Emperipolesis has recently been described as a constant feature of "biphasic squamoid" papillary renal cell carcinoma (BPRCC). We also noticed this in some high-grade (HG) RCC, which promoted the present study to estimate the incidence of emperipolesis in RCCs and to describe them in further detail. 14 cases of HGRCC showing emperipolesis were retrieved from our registry. Microscopic examination of filed slides was supplemented with immunohistochemical and molecular-genetic analyses using paraffin embedded tissue. 12 of 14 patients were males with a mean age of 58.6 years (range 41-72 years). Tumor size ranged from 6-16.5 cm (mean of 8.8 cm). Follow up data were available for 8/14 patients (range 0.5-10 years). Metastases were documented in 6 cases. All tumors showed solid-alveolar growth patterns with focal pseudopapillary features, and were composed of large cells with bizarre nuclei and eosinophilic rhabdoid-like cytoplasm. Emperipolesis was a constant and prominent feature in large bizarre cells. All cases were positive for OSCAR, CANH 9, vimentin, cyclin D1, INI-1, and myoD1, while negative for melanocytic markers, CK 7, myoglobin, cathepsin K, and TFE3. VHL gene abnormalities were found in 6/9 analyzable cases, of which 2 demonstrated polysomy of chromosomes 7, 17. Emperipolesis is a rare histomorphologic feature which can be seen not only in BPRCCs but also in highgrade CCRCCs. All RCC cases with prominent emperipolesis fulfilled both morphologic and immunohistochemical diagnostic criteria of high-grade CCRCC. The majority of patients with available follow up information developed metastases.

The terminology of testicular, ovarian, and extragonadal germ cell tumors has been marred historically by histogenetic and diagnostic controversies and a lack of uniform approach to classification of these neoplasms. Even though some inconsistencies and controversies persist, the terminology has in general become less contentious. Furthermore, the usage of diagnostic categories in daily practice of pathology has become less uneven, enabling better clinical-pathologic correlations and a more standardized approach to the treatment of these neoplasms. The advances in experimental pathology of teratomas and human embryonic stem cells have improved our understanding of the histogenesis and cellular/molecular biology of germ cell tumors in general. However, the terminology used in experimental laboratory studies and in clinics still shows some discordances which remain to be reconciled and unified into a universally acceptable nomenclature.

This atlas illustrates the microscopic features of tumors produced from human pluripotent stem cells (hPSCs) xenografted into immunosuppressed mice, according to the generally accepted protocols for performing this teratoma assay of stem cell pluripotency. Microphotographs depict various hematoxylin and eosin (H&E) stained tissues derived from all three embryonic germ layers (ectoderm, mesoderm and endoderm). The appearance of persistent hPSC in teratomas is also described with special emphasis on the morphogenesis of embryoid bodies and yolk sac components surrounding them. The use of immunohistochemistry for analyzing hPSC-derived teratomas is also illustrated.

Diffuse large B cell lymphoma (DLBCL) may present rarely as a spindle cell tumor. Only one previous case of spindle cell DLBCL involving the liver has been reported. We present a case of primary hepatic DLBCL with spindle cell features in a 67-year-old man who initially presented with elevated liver enzymes and an indistinct liver mass identified by computed tomography. The lesion was diagnosed by needle biopsy as an inflammatory pseudotumor at an outside hospital and repeat imaging suggested that the lesion had decreased in size. Thus, no treatment was given. Seven months later, he presented with jaundice and additional porta hepatic mass and lymphadenopathy. A surgical resection was performed. Microscopically, the liver mass, bile duct mass, and lymph nodes demonstrated a spindle cell infiltration interspersed with small and large lymphocytes, and eosinophils in a fibrotic background. One lymph node showed focal architectural effacement by large atypical lymphoid cells. Immunohistochemical staining of the lymph node and liver mass revealed that the tumor cells were positive for CD20, BCL-6, CD79a, and PAX-5. Proliferation index (Ki-67) ranged from 70 to 90 %. We concluded that both the liver and lymph nodes were involved by spindle cell DLBCL. This case is presented to underscore the importance of including DLBCL in the differential diagnosis of spindle cell lesions, especially those found in unusual locations such as the liver.

Only a few cases of sarcomatoid renal cell carcinomas (RCCs) with squamous differentiation have been published. We present 2 RCCs exhibiting a hitherto not reported biphasic neoplastic cell population exhibiting a predominantly alveolar architecture where squamoid differentiation was identified in one of the neoplastic cell populations. None of the tumors showed chromophobe features or any evidence of sarcomatoid transformation. The tumors arose in 2 adult patients and were characterized by routine histology, immunohistochemistry, ultrastructure, array comparative genomic hybridization, confirmatory fluorescent in situ hybridization, and loss of heterozygosity analysis. Tumors measured 3 and 4 cm and were located within the renal parenchyma and had no pelvicalyceal connection. Both tumors were composed of a distinctly dual-cell population. The larger tumor cells displayed squamoid features and formed round well-demarcated solid alveolated islands that, in large parts, were surrounded by a smaller neoplastic cell component. The squamoid cells were immunoreactive for cytokeratins (CKs) (AE1-AE3, Cam 5.2, CK5/6, CK7, and CK20), epithelial membrane antigen, racemase/AMACR, and carboanhydrase IX (in 1 case focally). The small cell population was positive for CK7, epithelial membrane antigen, and racemase/AMACR, whereas CK20, AE1-3, and carboanhydrase IX were negative. CD10 was focally positive in the large squamoid cells in 1 case. Cathepsin K, E-cadherin, and CD117 displayed focal positivity in 1 case. Vimentin, RCC marker, parvalbumin, S100 protein, S100 A1, p63, p53, CDX2, uroplakin III, HMB45, TFE3, WT1, synaptophysin, chromogranin A, thyroglobulin, and TTF1 were negative. The proliferative activity (Ki-67) was low (1%) in the small cell component in both cases, whereas the large neoplastic tumor cells displayed a significantly higher proliferation (20%-35%). Ultrastructurally, desmosomes and tonofilaments were identified in the large tumor cells, confirming squamoid differentiation in a subset of tumor cells. Array comparative genomic hybridization of 1 analyzable case (confirmed with fluorescent in situ hybridization and loss of heterozygosity analysis) revealed partial or complete losses of chromosomes 2, 5, 6, 9, 12, 15, 16, 17, 18 and 22, (including biallelic loss of CDKN2A locus) and partial gains of chromosomes 1, 5, 11, 12 and 13. Follow-up at 6 years showed no recurrence or metastasis in 1 patient. The other (male) patients had a subcutaneous metastasis at presentation, but during a 1-year follow-up no evidence of recurrence or further metastatic events have been documented. Our data indicate that biphasic alveolosquamoid renal carcinoma is a unique and distinctive tumor. The large squamoid and small tumor cells have overlapping but still distinctive immunohistochemical patterns of protein expression. Multiple chromosomal aberrations were identified, some of them located in regions with known tumor suppressor genes and oncogenes.

Mammary analogue secretory carcinoma (MASC) is a recently described low-grade malignant tumor of the salivary glands, biologically and morphologically equivalent to secretory breast carcinoma. We give a brief overview of this new entity, including morphological, immunohistochemical, molecular-genetic, clinical, epidemiologic features, differential diagnosis, and outcome results.

Prior studies have suggested that the type of breast cancer influences the location of distant metastases ("organotropism") and that there may be discordance of estrogen receptor and human epidermal growth factor receptor 2 (Her2) expression between primaries and metastases. Our aims were to investigate the relationship between tumor type and metastatic site and to compare biomarker expression between primary and metastatic tumors. We retrospectively reviewed 102 biopsy-proven cases of breast cancer metastatic to distant sites from 2000 to 2010 and 34 corresponding primaries for histologic subtype, grade, lymphovascular invasion, lymph node metastasis, and expression of estrogen receptor and Her2. Most metastases were of ductal (88) and lobular (11) histologic types. Available data on primaries indicated that the majority were grade III with positive lymph node metastasis and lymphovascular invasion. Biomarkers on 73 metastases showed 37 estrogen receptor positive/Her2-, 6 estrogen receptor positive/Her2+, 8 estrogen receptor negative/Her2+, and 22 estrogen receptor negative/Her2-. The most common metastatic sites were the lung (26%), bone (32%), and liver (21%). We found no association between estrogen receptor/Her2 profile and metastatic site (P = .16). When compared with ductal carcinoma, lobular carcinoma showed a unique metastatic pattern to gastrointestinal tract/gynecologic sites (P = .014). Of 34 cases with paired prognostic markers for primary and metastatic sites, 7 (20%) demonstrated discordance in estrogen receptor-positive/Her2 profile between the primary and the metastasis. Because the estrogen receptor-positive/Her2 profile of metastatic breast cancer did not always match that of the primary tumor, it is important to repeat the prognostic markers of metastasis.

Bladder cancer is a common form of neoplasia which most often presents histologically as urothelial (transitional cell) carcinoma. In this article we review recent publications dealing with the less common variants of urothelial carcinoma such as tumours that show unusual forms of differentiation or the well know squamous, glandular, or sarcomatoid differentiation. Urothelial tumours may also show several distinct growth variants characterized by a nested, micropapillary, lymphoepithelioma-like, or plasmacytoid and giant cell growth pattern. The clinical course of bladder cancer varies depending on the histological type of neoplasia, grade and stage of the tumour. High-grade muscle-invasive urothelial cancers and tumours showing variant microscopic morphology have in general high mortality and poor prognosis.

The pregnane X receptor (PXR) is a nuclear receptor transcription factor regulating drug-metabolizing enzymes and transporters that facilitate xenobiotic and endobiotic detoxification. Recent studies show that PXR is important in abrogating intestinal tissue damage. This study examines the role of PXR in lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced acute liver injury using wild-type and PXR-null mice. LPS/GalN-treated PXR-null mice had greater increases of alanine transaminase (ALT), hepatocyte apoptosis, necrosis, and hemorrhagic liver injury than wild-type mice. LPS/GalN-mediated phosphorylation of JNK1/2 and ERK1/2 was differentially regulated in wild-type and PXR-null mice. Importantly, LPS/GalN-induced hepatic Stat3 survival signaling was impaired and early activation of Jak2 was delayed in PXR-null mice. Expression levels of pro-survival proteins Bcl-xL and heme oxygenase-1 (HO-1), which are downstream of Stat3, were substantially lower in PXR-null than wild-type mouse livers after LPS/GalN treatment. Autophagy is also involved in LPS/GalN-induced liver injury. Lack of PXR resulted in a significant reduction of LC3B-I, -II as well as Beclin-1 protein levels after LPS/GalN treatment. In addition, PXR is implicated in hepatocytes homeostasis. Taken together, PXR is a critical hepatoprotective factor. Increases of LPS/GalN-induced hepatocyte apoptosis and liver injury in PXR-null mice are due to deregulated mitogen-activated protein (MAP) kinase activation as well as delayed Jak2/Stat3 activation, which lead to a compromise in defense mechanisms that involve Bcl-xL-, HO-1, and autophagy-mediated pathways.

Neoadjuvant treatment has become the standard of care for locally advanced gastrointestinal carcinoma, hence, the pathologist increasingly encounters treated primary and metastatic colorectal tumors. The pathologic assessment of therapeutic response and evaluation of residual disease is important because the histologic response to therapy or tumor response grade (TRG) has been shown to correlate with survival. Therefore, it is important for the pathologist to be familiar with the changes seen in colorectal cancer and metastatic colorectal cancer after neoadjuvant therapy. This review discusses the treatment effects seen in colon, rectal and liver resections including lymph nodes and the evaluation of residual tumor tissue in these specimens.

Malignant and advanced gastrointestinal stromal tumors (GIST) are currently treated with imatinib mesylate, an inhibitor of KIT and PDGFRA receptor tyrosine kinase. Pathologic evaluation of residual disease is the gold standard in these cases, as clinical and radiologic assessments of treatment response do not always correlate with the pathologic response. Phenotypic and genotypic changes may also occur which may have an impact on treatment decisions. This review will focus on the role of the pathologist in ordering appropriate testing for the primary tumor, the morphologic, phenotypic and genotypic changes seen following imatinib therapy in cases of advanced GIST, and essential components of the pathology reports.

Modern chemotherapy combined with surgery can achieve complete cure in over 90% of all patients with malignant testicular germ cell tumors. Even tumors that have already metastasized at the time of orchidectomy are curable by platinum-based multidrug treatment. Chemotherapy related changes can be seen in the residual tumor tissue in metastatic sites. In patients fully responding to chemotherapy these changes include complete necrosis of the tumor cells, and inflammatory-phagocytic response, fibrosis replacing the necrotic tumor tissue, and residual benign somatic tissue tissues in form of teratoma. Epithelial and stromal cells of these teratomas may display nuclear atypia, which is however not a reason for concern and should not be considered an indication for additional chemotherapy. Less commonly the lymph nodes contain cystic trophoblastic tumors. In contrast to metastatic classical biphasic or monophasic choriocarcinoma, cystic trophoblastic tumors portend a favorable clinical outcome. Patients with an incomplete response to chemotherapy and those with recurrences of the malignant tumor contain in metastatic sites foci composed of embryonal carcinoma cells, yolk sac carcinoma, or choriocarcinoma. The latter two subtypes of germ cell neoplasia may recur in several microscopic variant forms. Somatic forms of malignancy (also known as "non-germ cell malignancies") that develop occasionally in some treated patients include most often sarcomas and tumors resembling central primitive neuroectodermal neoplasms. These secondary malignancies are usually resistant to chemotherapy. The broad spectrum of morphologic findings in the lymph nodes of patients with treated metastatic testicular germ cell tumors clearly illustrates the importance of meticulous pathologic analysis of tissue changes related to chemotherapy.

Background Debate exists whether frozen-section analysis of sentinel lymph nodes (SLNs) for melanoma is an accurate method to detect disease that has metastasized to the lymph nodes. The purpose of this study was to evaluate the utility of intraoperative frozen section for SLNs in melanoma. Methods We reviewed 133 patients (271 nodes) who underwent SLN biopsy with frozen section for melanoma between April 2003 and September 2007. Frozen-section diagnosis was compared with final diagnosis to determine concordance between intraoperative and postsurgical diagnosis. Results A total of 11 nodes (8% of patients) were found to have metastatic disease. All patients underwent lymph node dissections at the time of SLN biopsy. No false-positive SLNs were found on frozen section. The false-negative rate for SLN biopsy frozen section was 8% (1 of 133 patients). Conclusions Intraoperative frozen section can be an accurate and reliable tool in the right setting for analysis of sentinel nodes in cutaneous melanoma and deserves further study.

Adenomyoepithelioma of the breast is a rare benign breast neoplasm characterized by biphasic proliferation of epithelial and myoepithelial cells. It occurs in older women and presents as a palpable nodular mass. Mammographic findings are nonspecific and often suspicious for malignancy. A core needle biopsy may be misleading and may be mistaken for invasive ductal carcinoma. Characteristic histologic features include a well-circumscribed multinodular growth pattern, in which the nodules consist of closely intermixed proliferating glands and myoepithelial cells. Both epithelial and myoepithelial components show only mild pleomorphism and a low mitotic rate. The epithelial cells react with antibodies to cytokeratins. The myoepithelial cells show positive staining for smooth muscle actin, smooth muscle myosin, calponin, p63, desmin, and S-100. Incompletely resected tumors or tumors extending to the resection margins tend to recur. Malignant transformation of adenomyoepitheliomas has been described but occurs rarely.

The differences and similarities of the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) were examined. Mice (six/group) received one of four Lieber-Decarli liquid diets for 6 weeks: (1) paired-fed control diet; (2) control diet with ethanol (ethanol); (3) paired-fed methionine/choline deficient (MCD) diet; and (4) MCD plus ethanol (combination). Hepatotoxicity, histology, and gene expression changes were examined. Both MCD and ethanol induced macrovesicular steatosis. However, the combination diet produced massive steatosis with minor necrosis and inflammation. MCD and combination diets, but not ethanol, induced serum ALT levels by 1.6- and 10-fold, respectively. MCD diet, but not ethanol, also induced serum alkaline phosphatase levels suggesting bile duct injury. Ethanol increased liver fatty acid binding protein (L-FABP) mRNA and protein levels. In contrast, the combination diet decreased L-FABP mRNA and protein levels and increased hepatic free fatty acid and lipid peroxide levels. Ethanol, but not MCD, reduced hepatic S-adenosylmethionine (SAM) and GSH levels. Hepatic TNFalpha protein levels were increased in all treatment groups, however, IL-6, a hepatoprotective cytokine which promotes liver regeneration was increased in ethanol-fed mice (2-fold), but decreased in the combination diet-treated mice. In addition, the combination diet reduced phosphorylated STAT3 and Bcl-2 levels. While MCD diet might cause bile duct injury and cholestasis, ethanol preferentially interferes with the SAM-GSH oxidative stress pathway. The exacerbated liver injury induced by the combination diet might be explained by reduced L-FABP, increased free fatty acids, oxidative stress, and decreased IL-6 protein levels. The combination diet is an efficient model of steatohepatitis.

The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.

Pancreatic islet α-cell tumours that overexpress proglucagon are typically associated with the glucagonoma syndrome, a rare disease entity characterised by necrolytic migratory erythema, impaired glucose tolerance, thromboembolic complications and psychiatric disturbances. Paraneoplastic phenomena associated with enteric overexpression of proglucagon-derived peptides are less well recognized and include gastrointestinal dysfunction and hyperinsulinaemic hypoglycaemia. The diverse clinical manifestations associated with glucagon-expressing tumours can be explained, in part, by the repertoire of tumorally secreted peptides liberated through differential post-translational processing of tumour-derived proglucagon. Proglucagon-expressing tumours may be divided into two broad biochemical subtypes defined by either secretion of glucagon or GLP-1, GLP-2 and the glucagon-containing peptides, glicentin and oxyntomodulin, due to an islet α-cell or enteroendocrine L-cell pattern of proglucagon processing, respectively. In the current review we provide an updated overview of the clinical presentation of proglucagon-expressing tumours in relation to known physiological actions of proglucagon-derived peptides and suggest that detailed biochemical characterisation of the peptide repertoire secreted from these tumours may provide new opportunities for diagnosis and clinical management.

Polyomavirus nephropathy is commonly seen in the renal allograft setting but is uncommon in native kidneys. This paper describes polyomavirus nephropathy that developed in the native kidneys of a patient following immunosuppressive therapy for rheumatoid arthritis/Sjögren's syndrome associated lung disease. The patient presented with dyspnoea and a slow steady rise in serum creatinine. Owing to chronic immunosuppression, calcineurin-inhibitor toxicity was suspected. However, renal biopsy revealed polyomavirus nephropathy. The treatment of choice, lowered immunosuppression, was complicated by exacerbation of the patient's lung disease. This case highlights features of polyomavirus nephropathy in the native kidney, as well as the difficulty in its treatment when immunosuppressive treatment is necessary for medical comorbidities.

The embryonic portion of 7-day-old mouse embryos transplanted to extrauterine sites of syngeneic adult animals gives rise to teratoid tumors, which may be either benign [teratomas (T)] or malignant [teratocarcinomas (TC)]. The incidence of embryo-derived TC varies from one mouse strain to another, indicating that some strains are TC-permissive whereas others are relatively TC-nonpermissive. Embryos of a TC-permissive mouse strain (DBA/2J) and a TC-nonpermissive one (C57BL/6J) were transplanted into NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mice to determine their tumorigenic potential in the absence of functional adaptive and innate immune responses in the hosts. C57BL/6J embryos transplanted to NSG mice gave rise to TC in 31% of cases, whereas the incidence of TC produced from DBA/2J transplanted embryos was 71%. The NSG embryos transplanted to syngeneic hosts gave rise to TC in 67% of cases, allowing the classification of NSG as a TC-permissive strain. A previously reported correlation between teratocarcinoma and splenomegaly was also observed in the NSG mice. The capacity of these tumors to differentiate into the cells and tissues of the normal embryo is mapped through a detailed histological analysis. These data suggest that teratocarcinogenesis, in the absence of host innate and adaptive immunity, is largely determined by the genetic background of the embryo.

Background Human induced pluripotent stem (hiPS) cells have the ability to undergo self-renewal and differentiation similarly to human embryonic stem (hES) cells. We have recently shown that hES cells under replication stress fail to activate checkpoint kinase 1 (CHK1). They instead commit to apoptosis, which appears to be a primary defense mechanism against genomic instability. It is not known whether the failure of CHK1 activation and activation of apoptosis under replication stress is solely a feature of hES cells, or if it is a feature that can be extended to hiPS cells. Methods Here we generated integration-free hiPS cell lines by mRNA transfection, and characterised the cell lines. To investigate the mechanism of S phase checkpoint activation, we have induced replication stress by adding excess thymidine to the cell culture medium, and performed DNA content analysis, apoptosis assays and immunoblottings. Results We are showing that hiPS cells similarly to hES cells, fail to activate CHK1 when exposed to DNA replication inhibitors and commit to apoptosis instead. Our findings also suggest the Ataxia Telangiectasia Mutated pathway might be responding to DNA replication stress, resulting in apoptosis. Conclusion Together, these data suggest that the apoptotic response was properly restored during reprogramming with mRNA, and that apoptosis is an important mechanism shared by hiPS and hES cells to maintain their genomic integrity when a replication stress occurs.

Liver response to injury includes a relatively narrow spectrum of morphologic changes, and accordingly there are only several pathologic patterns that can be recognized microscopically. First of all one must determine if the liver biopsy is from a native liver or from a liver transplant. If it is native liver one must decide if the liver was biopsied for a mass lesion requiring a tumor diagnosis or a diffuse liver disease. Relevant patient data provided by the clinician is always welcome and encouraged to provide appropriate contextual review. First, diffue liver disease should be divided into acute and chronic liver disease. Next, the liver is classified according the predominent pattern of injury. Then, after incorporation of clinical information and laboratory data, a differential diagnosis can be rendered.

Common medical disease affecting the liver include acute and chronic viral hepatitis, drug-induced liver injury, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, biliary obstruction, alcohol induced liver disease, non-alcohol fatty liver disease, hereditary hemochromatosis, Wilson disease, and α1-antitrypsin deficiency.

An important part of learning liver pathology and understanding liver pathology reports is knowing the unique vocabulary used to describe the histologic features. This can be challenging due to the inconsistent use of terms among pathologists, the overlap of histologic features among different diseases, and the presence of multiple names for the same histologic feature. This chapter functions as a glossary of terms with illustrative photos for each definition.

Liver tumors are classified as benign or malignant and malignant tumors can be primary or metastatic. Primary liver tumors may originate from hepatocytes, bile duct epithelium or endothelial cells. The most common tumors of liver are hemangiomas and the most common malignant tumors of the liver are hepatocellular carcinomas. Metastases are much more common than primary malignant tumors.