Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin (Virchows Arch)

Publications in this journal

• Article: IgG4-related disease of the ureter: report of two cases and review of the literature.

  Alessandro Marando, Gioacchino D'Ambrosio, Francesco Catanzaro, Stefano La Rosa, Fausto Sessa
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  ABSTRACT: IgG4-related disease (IgG4-RD) is a recently recognized multi-organ fibro-inflammatory lesion characterized by elevated IgG4 serum levels and mass-forming lesions. This condition shows similar histological features independently of the site of origin including storiform fibrosis, obliterative phlebitis, and dense lymphoplasmacytic infiltrate with a conspicuous IgG4-positive plasma cell component. Since this disease has only recently been categorized as a single specific nosologic entity, lesions with these typical morphological features have previously been named in different ways, creating some confusion and making it difficult to identify cases published in the literature. Lesions with features suggesting IgG4-RDs have very rarely been reported in the ureter, and they have been named using the terms "inflammatory pseudotumor" and "idiopathic segmental ureteritis." Herein, we describe the clinicopathological features of ureteral IgG4-RD found in two different patients. An 82-year-old female and a 77-year-old male underwent ureteral resection due to severe ureteral wall thickness and lumen stenosis suggestive of urothelial carcinoma. However, histological examinations showed transmural fibro-inflammatory lesions, with abundant IgG4 plasma cells intermixed with histiocytes, lymphocytes, fibroblasts, and scattered eosinophils. We have also accurately reviewed the literature in order to identify, among lesions diagnosed with different names, examples of ureteral IgG4-related lesions to give the reader a comprehensive overview of this relatively rare inflammatory disease. We suggest using the name "ureteral IgG4-RD" for those lesions showing the same morphological features as IgG4-RDs located elsewhere.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 05/2013;
• Article: Letter to Dr. Kounis.

  Hiroki Kajihara
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 05/2013;
• Article: Clonality analysis suggests that STK11 gene mutations are involved in progression of lobular endocervical glandular hyperplasia (LEGH) to minimal deviation adenocarcinoma (MDA).

  Akiko Takatsu, Tsutomu Miyamoto, Chiho Fuseya, Akihisa Suzuki, Hiroyasu Kashima, Akiko Horiuchi, Keiko Ishii, Tanri Shiozawa
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  ABSTRACT: Lobular endocervical glandular hyperplasia (LEGH) is a benign proliferative disease of cervical glands. Although histological resemblance of minimal deviation adenocarcinoma (MDA) to LEGH and frequent association of LEGH with MDA have been reported, it still remains unclear whether LEGH is a precancerous lesion of MDA. The present study was undertaken to examine the pathogenetic relationship between LEGH and MDA using a clonality analysis and mutational analyses of the STK11 gene, of which mutations have been reported in MDA. Of nine cases of LEGH only, four were polyclonal and five were monoclonal in composition. Of six LEGH lesions associated with MDA or adenocarcinoma, two were polyclonal and four were monoclonal. In cases of MDA or adenocarcinoma coexisting with LEGH, the patterns of X chromosome inactivation in malignant lesions were identical to those in coexisting LEGH lesions. A mutation of STK11 was only identified in one MDA, but not in LEGH. These results indicate that a subset of LEGH may be a precursor to malignant tumors including MDA and that a mutation of STK11 may be involved in progression of LEGH to MDA.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 05/2013;
• Article: Retinoid acid receptor expression is helpful to distinguish between adenoma and well-differentiated carcinoma in the thyroid.

  Guillaume Gauchotte, Stéphanie Lacomme, Lydia Brochin, Benjamin Tournier, Virginie Cahn, Nathalie Monhoven, Françoise Piard, Marc Klein, Nadine Martinet, Cécile Rochette-Egly, Jean-Michel Vignaud
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  ABSTRACT: Retinoid receptors (RRs) play a key role in cell proliferation and differentiation. We characterized the expression of RA receptors and retinoid X receptors (RARs and RXRs) in a series of 111 thyroid tumors and investigated the mechanisms responsible for their deregulation: hypermethylation of the RARB2 promoter, loss of heterozygosity (LOH) in the regions of RARB and RXRA, and altered expression of CRBP1 and enzymes involved in RA biosynthesis (RDH10 and RALDH2). Expression of RALDH2 and RDH10 was conserved in 100 % of adenomas and in 90 and 98 %, respectively, of carcinomas, whereas staining for CRBP1 was decreased in 9 % of FAs and 28 % of carcinomas, mainly anaplastic carcinomas (55 %). We found an abnormal expression of RARA, RARB, RXRA, and RXRB in 67, 69, 66, and 73 %, respectively, of thyroid carcinomas (n = 78) and in 9, 9, 9, and 33 % of follicular adenomas (n = 33) (p < 0.001). An abnormal staining pattern of at least two of these markers had 90 % sensitivity and 91 % specificity for a diagnosis of malignancy. Promoter hypermethylation of RARB2 was observed in some anaplastic carcinomas (14 %). LOH was found to be common at the RARB locus (3p24-3p25) and the RXRA locus (9q34), respectively, in 44 and 55 % of carcinomas and in 27 and 43 % of adenomas. In conclusion, immunohistochemical staining for RARs and RXRs may help in the differential diagnosis between well-differentiated carcinoma and follicular adenoma. Further investigation should be carried out to determine whether the characterization of RR expression might identify patients who could benefit from therapy with RA derivatives.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 05/2013;
• Article: Iatrogenic gastric ulceration.

  Rinsey R Kurian, Shaun R Preston, Izhar N Bagwan
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: ALK rearrangement in a pure squamous cell carcinoma: the challenge of detection of ALK rearrangement.

  Hyojin Kim, Eunhyang Park, Yu Jung Kim, Jin-Haeng Chung
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Erratum to: Validation of the BRCA1 antibody MS110 and the utility of BRCA1 as a patient selection biomarker in immunohistochemical analysis of breast and ovarian tumours.

  Roy Milner, Helen Wombwell, Sonia Eckersley, Donna Barnes, Juli Warwicker, Erica Van Dorp, Rachel Rowlinson, Simon Dearden, Glen Hughes, Chris Harbron, Bob Wellings, Darren Hodgson, Chris Womack, Neil Gray, Alan Lau, Mark J O'Connor, Catherine Marsden, Alexander J Kvist
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Ki-67 is a reliable pathological grading marker for neuroendocrine tumors.

  Ashlie Nadler, Moises Cukier, Corwyn Rowsell, Sepideh Kamali, Yael Feinberg, Simron Singh, Calvin H L Law
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  ABSTRACT: In neuroendocrine tumors (NETs), proliferation markers, especially Ki-67, have become increasingly important. This study was designed to examine the reproducibility of Ki-67 for use in the current classification of NETs. A retrospectively assembled integrated database with prospectively collected data of patients undergoing multidisciplinary management for NETs from 2000 to 2009 was analyzed. Original pathology was reviewed to reassess Ki-67 values. Ki-67 was then categorized to grades G1 (≤2 %), G2 (3-20 %), or G3 (>20 %) according to the European Neuroendocrine Tumor Society (ENETS) guidelines and the 2010 World Health Organization (WHO) classification. Original Ki-67 values were compared to reviewed values. All statistical analyses were carried out using SAS 9.1.3. A total of 184 patients were included of which 48 % were male. The most common primary NET site was the small bowel, in 27 %. On pathology review, there was 94 % agreement for G1, with 4 % of cases upgraded at review to G2 and 2 % of cases upgraded to G3. For G2, there was 94 % agreement, with 6 % of cases downgraded to G1 and 0 % upgraded. For G3, there was 90 % agreement, with 10 % of cases downgraded to G2 and none to G1 (kappa = 0.89). Ki-67 is a proliferative marker for NETs that is highly reproducible when used to grade tumors according to ENETS and WHO categories. The high inter-institutional reliability in the determination of tumor grade as assessed by Ki-67 makes it a reliable tool in the assessment of patients with NETs.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Differentiated dysplasia is a frequent precursor or associated lesion in invasive squamous cell carcinoma of the oral cavity and pharynx.

  Ruza Arsenic, Michael O Kurrer
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  ABSTRACT: The source of precursor lesions of squamous cell carcinoma (SCC) of the oral cavity and pharynx, their classification, and grading are controversial. In contrast, vulvar and penile cancer precursor lesions are known to be related to human papillomavirus or chronic inflammation and can be described using the vulvar intraepithelial neoplasia (VIN) classification system (VIN 1-3) or as differentiated vulvar intraepithelial neoplasia (dVIN), respectively. Oral and pharyngeal SCC precursor lesions are more etiologically diverse, and the spectrum of lesions may thus be wider. No international consensus exists regarding the histological types of precursor lesions or the significance of individual types. We therefore reviewed resection specimens and preceding biopsies of 155 patients with SCC of the oral cavity and pharynx (excluding tonsils) and identified five basic patterns of SCC-associated or precursor lesions: (1) pleomorphic (22/155), (2) basaloid (5/155), (3) differentiated (63/155), (4) mixed (42/155), and (5) verrucous (12/155). Keratinization was a common but variable feature in differentiated, mixed, and verrucous dysplasia. In 11/155 patients, no precursor lesion could be identified. Progression of isolated differentiated dysplasia (ranging from months to years) was documented in 13/155 (8 %) of patients. Our data suggest that full-thickness epithelial dysplasia of pleomorphic or basaloid type is present in <20 % of oral and pharyngeal SCC, and differentiated dysplasia is a frequent precursor or associated in situ lesion. Failure to recognize differentiated dysplasia results in the underdiagnosis of many patients at risk for invasive carcinoma. These results indicate a need to refine criteria to distinguish differentiated dysplasia from morphologically related lichenoid lesions.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: High microvessel density in pancreatic ductal adenocarcinoma is associated with high grade.

  Anca Barău, Amparo Ruiz-Sauri, Gerardo Valencia, Maria Del Carmen Gómez-Mateo, Luis Sabater, Antonio Ferrandez, Antonio Llombart-Bosch
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  ABSTRACT: The objectives of this work are to study angiogenesis in pancreatic ductal adenocarcinoma using computerized morphometric and image analysis and to compare the microvascular density in intratumoral and peritumoral areas and normal pancreatic tissue. Microvascular density was analyzed in 60 cases of pancreatic ductal adenocarcinoma and 30 samples of normal pancreatic tissue using an avidin-biotin immunoperoxidase technique with an anti-CD31 antibody. Microvascular density (MVD) was analyzed through digital microimaging and computerized analysis. The blood vessel density in the tumor was significantly higher than in peritumoral areas and in normal pancreatic tissue. Well differentiated pancreatic ductal adenocarcinomas contained higher MVD than poorly differentiated carcinomas. In pancreatic adenocarcinoma, MVD is higher than in peritumoral tissue or normal pancreatic tissue.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Neuroendocrine neoplasms of the jejunum: a heterogeneous group with distinctive proximal and distal subsets.

  Xavier Chopin-Laly, Thomas Walter, Valérie Hervieu, Gilles Poncet, Mustapha Adham, Aymeric Guibal, Jean-Alain Chayvialle, Catherine Lombard-Bohas, Jean-Yves Scoazec
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  ABSTRACT: Neuroendocrine tumors (NETs) of the jejunum are rare and usually grouped with either duodenal or ileal NETs. We aimed at better evaluating their characteristics by studying 116 cases of small-bowel NETs for which a precise anatomical location was available. Thirty-four cases were duodenal. Eighty-two were located after the duodenojejunal ligament, including ten cases in the first 50 cm, four cases between 50 and 100 cm, and six cases between 100 and 250 cm. All tumors located after 50 cm from the duodenojejunal ligament were enterochromaffin neoplasms. In contrast, the ten tumors located before this point formed a heterogeneous group. They included two cases of gastrin-expressing tumors in the first 10 cm and one case of enterochromaffin tumor located at 45 cm. The seven remaining cases were large tumors, located between 10 and 50 cm, of intermediate or high histological grade (four out of seven G2 or G3), locally invasive and usually metastatic (five out of seven with liver metastases); their survival was comparable to that of duodenal NETs. Patients with tumors located in the duodenum or the first 50 cm of the jejunum had longer survivals than those with lower jejunal and ileal tumors (p = 0.024). In conclusion, our study underlines the heterogeneity of jejunal NETs and supports the distinction between "upper" and "lower" jejunal tumors, which, for prognostic purposes, might be grouped with, respectively, duodenal and ileal NETs. Our data suggest that the arbitrary limit between upper and lower jejunal tumors might be fixed at 50 cm from the duodenojejunal ligament.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Eosinophilic coronary periarteritis presenting with vasospastic angina and sudden death: a new cause and manifestation of Kounis syndrome?

  Nicholas G Kounis, Andreas Mazarakis, Grigorios Tsigkas
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Disturbed balance between SOX2 and CDX2 in human vitelline duct anomalies and intestinal duplications.

  Lalini Raghoebir, Katharina Biermann, Marjon Buscop-van Kempen, Rene M Wijnen, Dick Tibboel, Ron Smits, Robbert J Rottier
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  ABSTRACT: Congenital gastric-type heteroplasia is common in intestinal duplications and anomalies, which originate from incomplete resorption of the omphalomesenteric duct during development. Two transcription factors determine the proximodistal specification of the gastrointestinal tract, SOX2, expressed exclusively in the proximal part of the primitive gut, and CDX2, expressed solely in the distal part. Aberrant expression of these factors may result in abnormal development and congenital abnormalities. Therefore, we analyzed the expression of SOX2 and CDX2 in a number of pediatric intestinal anomalies. We investigated the expression pattern of SOX2 and CDX2 in three congenital intestinal anomalies in which ectopic gastric tissue may be present, Meckel's diverticulum (N = 8), persistent ductus omphalomesentericus (N = 14), and intestinal duplications (N = 8). CDX2, but not SOX2, was detected in intestinal epithelial cells in tissue lacking gastric heteroplasia. In gastric-type heteroplasia, a reciprocal expression pattern existed between SOX2 and CDX2 in the gastric and intestinal tissues, respectively. Interestingly, patches of CDX2-positive cells were present within the gastric mucosa in a subset of Meckel's diverticula and intestinal duplications, suggesting that it is not the absence of CDX2, but rather the ectopic expression of SOX2 that leads to gastric tissue in the prospective intestinal tissue. This is in concordance with our previous mouse studies. Collectively, our data indicate that a fine balance between SOX2 and CDX2 expression in the gastrointestinal tract is essential for proper development and that ectopic expression of SOX2 may lead to malformations of the gut.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Dentine matrix protein 1 (DMP-1) is a marker of bone-forming tumours.

  T G Kashima, A Dongre, U Oppermann, N A Athanasou
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  ABSTRACT: Dentin matrix protein 1 (DMP-1) is highly expressed by osteocytes and is a non-collagenous matrix protein found in dentin and bone. In this study, we determined the expression of DMP-1 in mature and immature human bone and examined whether DMP-1 is useful in distinguishing osteoid/bone-forming tumours from other primary and secondary bone tumours. DMP-1 expression was immunohistochemically determined in paraffin sections of a wide range of benign and malignant primary bone tumours and tumour-like lesions (n = 353). DMP-1 mRNA expression was also examined in osteosarcoma and fibrosarcoma cell lines as well as bone tumour specimens (n = 5) using real-time PCR. In lamellar and woven bone, DMP-1 was expressed in the matrix around osteocyte lacunae and canaliculi; osteoblasts and other cell types in the bone were negative. Matrix staining of the osteoid and bone was seen in bone-forming tumours including osteoma, osteoid osteoma, osteoblastoma and osteosarcoma. DMP-1 staining was also seen in fibrous dysplasia, osteofibrous dysplasia and chondroblastoma and in reactive bone in solitary bone cysts and aneurysmal bone cysts. DMP-1 was not expressed in the tumour component of other bone neoplasms including Ewing sarcoma, chondrosarcoma, leiomyosarcoma, fibrosarcoma, giant cell tumour of bone and metastatic carcinoma. DMP-1 mRNA was expressed in osteosarcoma cell lines and tumour samples. DMP-1 is a matrix marker expressed around osteocytes in human woven and lamellar bone and is useful in identifying osteosarcoma and other bone-forming tumours.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Interobserver agreement of proliferation index (Ki-67) outperforms mitotic count in pulmonary carcinoids.

  Arne Warth, Ludger Fink, Annette Fisseler-Eckhoff, Danny Jonigk, Marius Keller, German Ott, Ralf J Rieker, Peter Sinn, Stephan Söder, Alex Soltermann, Klaus Willenbrock, Wilko Weichert
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  ABSTRACT: Evaluation of proliferative activity is a cornerstone in the classification of endocrine tumors; in pulmonary carcinoids, the mitotic count delineates typical carcinoid (TC) from atypical carcinoid (AC). Data on the reproducibility of manual mitotic counting and other methods of proliferation index evaluation in this tumor entity are sparse. Nine experienced pulmonary pathologists evaluated 20 carcinoid tumors for mitotic count (hematoxylin and eosin) and Ki-67 index. In addition, Ki-67 index was automatically evaluated with a software-based algorithm. Results were compared with respect to correlation coefficients (CC) and kappa values for clinically relevant grouping algorithms. Evaluation of mitotic activity resulted in a low interobserver agreement with a median CC of 0.196 and a median kappa of 0.213 for the delineation of TC from AC. The median CC for hotspot (0.658) and overall (0.746) Ki-67 evaluation was considerably higher. However, kappa values for grouped comparisons of overall Ki-67 were only fair (median 0.323). The agreement of manual and automated Ki-67 evaluation was good (median CC 0.851, median kappa 0.805) and was further increased when more than one participant evaluated a given case. Ki-67 staining clearly outperforms mitotic count with respect to interobserver agreement in pulmonary carcinoids, with the latter having an unacceptable low performance status. Manual evaluation of Ki-67 is reliable, and consistency further increases with more than one evaluator per case. Although the prognostic value needs further validation, Ki-67 might perspectively be considered a helpful diagnostic parameter to optimize the separation of TC from AC.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: In memoriam.

  Vincenzo Eusebi, Thomas Krausz
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Complete pathological response is predictive for clinical outcome after tri-modality therapy for carcinomas of the superior pulmonary sulcus.

  Johannes L Blaauwgeers, Ingrid Kappers, Houke M Klomp, José S Belderbos, Lea M Dijksman, Egbert F Smit, Pieter E Postmus, Marinus A Paul, Jan W Oosterhuis, Koen J Hartemink, Cornelis G Vos, Jacobus A Burgers, Max Dahele, Erik C Phernambucq, Birgit I Witte, Erik Thunnissen
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  ABSTRACT: The objective was to define the relationship between histopathological changes after pre-operative chemo-radiotherapy (CRT) and clinical outcome following tri-modality therapy in patients with superior sulcus tumours. A retrospective analysis of tumour material was performed in a series of 46 patients who received tri-modality therapy between 1997 and 2007. Median follow-up was 34 months (5-154). Pathological complete response (pCR) was present in 20/46 tumours (43 %). The most common RECIST score after CRT in patients with pCR was a partial response (PR; 10/17, three unknown), whereas in patients without a pCR, stable disease was the most common (22/26) (p = 0.002). In 26 specimens with residual tumour, this was mainly located in the periphery of the lesion rather than the centre (Spearman's correlation = 0.67, p < 0.001). Prognosis was significantly better after a pCR compared to residual tumour (70 % 5-year overall survival vs. 20 %; p = 0.001) and in patients with fewer than 10 % vital tumour cells as compared to those with >10 % (65 % 5-year overall survival vs. 18 %; p < 0.001). A low mitotic count was associated with a longer disease-free survival (p = 0.02). Complete pathological response and the presence of fewer than 10 % vital tumour cells after pre-operative CRT are both associated with a more favourable prognosis. A modification of the pathological staging system after radiotherapy, incorporating the percentage of vital tumour cells, is proposed.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2013;
• Article: Platelet-derived growth factor-A and vascular endothelial growth factor-C contribute to the development of pulmonary tumor thrombotic microangiopathy in gastric cancer.

  Hiroyuki Abe, Rumi Hino, Masashi Fukayama
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  ABSTRACT: Pulmonary tumor thrombotic microangiopathy is a rare but lethal complication in cancer-bearing patients, particularly those with gastric cancer. It is characterized by cancer cell emboli with marked intimal proliferation. In the present study, we tried to elucidate the pathogenesis of pulmonary tumor thrombotic microangiopathy, notably angiogenic factors specific for cancer cells lodged in pulmonary arteries. An autopsy series of gastric cancer (51 cases) was reviewed for pulmonary tumor thrombotic microangiopathy and pulmonary tumor cell emboli without intimal proliferation. Pathological and immunohistochemical characteristics were compared between two groups. In eight cases in muscular pulmonary arteries, tumor thrombotic microangiopathy was noted, and in three cases pulmonary tumor emboli without intimal proliferation was noted. Histological features of pulmonary tumor thrombotic microangiopathy included small nests or single cancer cells accompanied by intimal proliferation, whereas in pulmonary tumor emboli large cell nests prevailed. By immunohistochemistry, in pulmonary tumor thrombotic microangiopathy, cancer cells expressed platelet-derived growth factor-A (7/8 cases) and vascular endothelial growth factor-C (8/8) more frequently than in pulmonary tumor emboli (0/3 and 1/3; P = 0.02 and P = 0.055, respectively). Expression of tissue factor, vascular endothelial growth factor-A and -D, osteopontin, fibroblast growth factor-2, and platelet-derived growth factor-B was similar in both groups. Platelet-derived growth factor-A and vascular endothelial growth factor-C might induce intimal proliferation in pulmonary arteries and contribute to the development of pulmonary tumor thrombotic microangiopathy.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2013;
• Article: In the non-cirrhotic stage of nonalcoholic steatohepatitis, angioarchitecture of portal veins and lobular architecture are maintained.

  Hiroshi Hano, Satoshi Takasaki, Hirohiko Kobayashi, Tomoki Koyama, Tomoe Lu, Keisuke Nagatsuma
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  ABSTRACT: The morphogenesis of lobular restructuring to liver cirrhosis in nonalcoholic steatohepatitis (NASH) is yet to be clearly understood. Therefore, we observed tissue samples from three biopsies and one autopsy with NASH in the non-cirrhotic stage three-dimensionally to elucidate the evolution of fibrosis and the changes of angioarchitecture. Histologic reconstructions revealed that pericellular fibrosis developed around the central vein in the early stage and gradually progressed to arch-shaped band-like fibrosis connecting the central veins in the neighboring lobules. In contrast, the basic angioarchitecture of the portal vein in the portal tracts tended to be preserved in the non-cirrhotic stage, although the portal vein architecture was slightly altered as the portal tract underwent gradual fibrous expansion. In addition, a striking development of arteries originating from the portal tract was found in the fibrotic area around the central and sublobular veins. In summary, while central-central bridging fibrosis and ectopic arterial development were conspicuous, the lobular architecture was maintained relatively well in the non-cirrhotic stage of NASH because of only mildly damaged angioarchitecture of the portal veins. The process of lobular restructuring in NASH is considered to be different from that in chronic viral hepatitis in the non-cirrhotic stage.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2013;