Leopold Auerbach's achievements in the field of vascular system.

The scientific activity of Leopold Auerbach (1828-1897) was associated with Wroclaw (Brelsau) medical school, which was renowned for brilliant descriptors of cardiovascular system, whose world-famous achievements became eponymous in history of medicine. Such terms as plexus myentericus Auerbach and Friedreich-Auerbach disease are still used worldwide. Little is known about the fact that the vascular system was at least as important in his scientific impact as neuromuscular field. Actually, one could realize that ganglion cells, which were previously discovered in cardiac location, were identified by Auerbach at interface between circular and longitudinal layer of intestinal tunica muscularis proporia. Consequently, Auerbach focused closely on vessels after examination of neural and muscular components of selected parts of gastrointestinal tract. Namely, he noticed that tightly grouped cells that formed vessels in the process of vasculogenesis and angiogenesis to constitute the lining of capillaries, possessed nuclei.

Basal Cell Carcinoma among Cutaneous Tumours in "Caricature," Painted by Bartolomeo Passerotti (1529-1592).

A fine and fair depiction of basal cell carcinoma is documented with great fidelity in "Caricature" by Bartolomeo Passerotti (1529-1592). The cancer is pearly white and contains an elevated centre with a sharp and somewhat depressed outline due to ulceration of the lesion. The painting is of essential didactic worth for practicing medical doctors. In addition, the masterpiece contains images of the brown elevated lesions that could turn out to be verrucous melanocytic nevi or pigmented seborrheic keratoses, but it cannot be excluded that these nodules are also basal cell carcinomas covered by a brownish crust. It is standard that microscopic verification is required for all these tumours. However, a pearly white irregular tumour is the most characteristic macroscopic presentation of basal cell carcinoma.

Analysis of mutations of PARP1, RNF213, PAX8, KMT2C, MTRR in malignant mesothelioma of testicular tunica vaginalis testis.

Molecular next gene sequencing was used to evaluate mutations in 409 common mutated cancer-related genes in malignant mesothelioma of tunica vaginalis testis (MMTVT) of 81-year-old man. Multifocal papillary-solid areas contained necrosis among highly cellular fields with multiple mitoses. It was positive for WT1, CKAE1/AE3, calretinin, CK7 with negativity for CK5, PSA, TTF-1. Following mutations were revealed in PARP1 (NM_001618: c.2285TG, p.K135R), MTRR (NM_024010: c.147A>G, p.I49M) and two sorts of mutations in structure of KMT2C gene (NM_170606: c.2447_2448insA (c.2447dupA), p.Y816fs and NM_170606: c.1042G>A, p.D348N) for the first time in MMTVT.

Review on significance of GDNF, PTCH1 and RNF213 in chromophobe renal cell carcinoma illustrated by the case of 71-years-old man.

Here we review the role of GDNF, PTCH1, RNF213 illustrated by a case of renal cell carcinoma, chromophobe type (pT2a 8th pTNM edition) of the left kidney of 71-year-old man. Status of potential hotspots in 409 tumor genes were studied by means of next generation sequencing (NGS) technology (IonTorrent - Thermo Fisher Scientific, USA) using Ion AmpliSeq™ Comprehensive Cancer Panel. Next-generation sequencing (NGS) revealed mutations of GDNF (NM_001190468: c. 328C>T, p.R110W, allelic frequency 46%), PTCH1 (NM_001083607:c. 2969C

Heritage of Stanislaw Ciechanowski (1869-1945)-Discoverer of pathogenesis of prostatic hyperplasia-passionis insignia signis fulgent mirificis .

BACKGROUND: Prostatic enlargement was first correctly recognized as a prostatic hyperplasia by professor of anatomic pathology, Stanislaw Ciechanowski (1869-1945) in Cracow on contrary to Parisian urologist Jean Casimir Félix Guyon's concepts of progressing atherosclerosis as a morphological cause of prostatic overgrowth and mechanical insufficiency of lower urinary tract. METHODS: Primary resources were analyzed about Stanislaw Ciechanowski mainly from depositories of the Section of Special Collection, Stanislaw Konopka Main Medical Library Warsaw and Polish bibliograhy of Estreichers at Jagiellonian University. RESULTS: Professor of anatomic pathology, Stanislaw Ciechanowski (1869-1945) was the first to state that chronic inflammation induced overgrowth of parenchymatous and stromal prostate components in course of benign prostatic hyperplasia. Ciechanowski preformed also pioneer and notable studies in the mechanisms of carcinogenesis and classification of cancer in Poland. As one of the major Polish medical editors and a father of Polish modern medical language he was also very prolific author in the field of congenital pathology, sclerosis of pulmonary arteries, endemic goiter, intestinal emphysema, etc. Due to magnitude of autopsies, he preformed, Stanislaw Ciechanowski was a perfect candidate to complete the first edition of several volumes of main Polish handbook on anatomy of a human body after tragic death of professor Adam Bochenek. CONCLUSIONS: Ciechanowski gained such a high authority, that his opinion was found crucial in prewar Poland in the field of medical publications, but his world-famous achievement was scientific explanation of prostate overgrowth as inflammation induced hyperplasia.

Comparison of E-cadherin with STAT3 and apoptosis regulators: Bak and Bcl-xL in endometrioid adenocarcinomas of different ER-alpha immunoprofile.

E-cadherin is a factor of good prognosis in endometrioid adenocarcinomas, while STAT3 is an oncogenic driver of carcinogenesis. E-cadherin, Bak, Bcl-xL and STAT3 were immunohistochemically detected in 78 human endometrioid adenocarcinomas. E-cadherin correlated with STAT3 (p <. 001, r = 0.537) as well as Bak (p = .005, r = 0.314) and Bcl-xL (p = .002, r = 0.340) in the whole study group. In G2 tumors, E-cadherin associated with Bak (p = .021, r = 0.319), Bcl-xL (p = .026, r = 0.309) and STAT3 (p <.001, r = 0.513) but not in G3 adenocarcinomas. E-cadherin correlated with Bak and Bcl-xL in both G1- and estrogen receptor (ER)-negative tumors with significant relation of E-cadherin and STAT3 in G1- and ER-negative tumors. Antigrowth synergy of expression was preserved for antiapoptotic Bak and proliferation-suppressing E-cadherin in IA adenocarcinomas (p = .031, r = 0.342) with no significance between Bak and E-cadherin or STAT3 and emerging correlation between E-cadherin and Bcl-xL in IB + II tumors instead (p = .003, r = 0.472). E-cadherin correlated with Bak and Bcl-xL in ER-positive adenocarcinomas (p = .002, r = 0.382 and p <.001, r = 0.439, respectively) but not in ER-negative tumors. In conclusion, expression deregulation of studied proteins is reflected in selective loss of correlation between suppressors of tumor growth (E-cadherin and Bak) presumably due to progressing impairment of growth-inhibitory properties of clone of neoplastic cells within higher staging and poorer differentiation.

Review on Retinal Gliosis Illustrated with a Series of Massive Glioses and Focal Nodular Gliosis Cases in Regard to Potential Pitfalls of Ocular Reactive Tumor-like Lesions of this Type.

This paper presents a review on retinal gliosis illustrated by series of three cases of patients (a 39-year-old man and a 35-year-old woman with massive retinal gliosis (MRG) and a 51-year-old man with truly focal nodular gliosis of retina) with intraocular tumor-like masses and loss of vision, who recently suffered from painful inflammation of eyeball and who classically had a history of remote ocular trauma, onset of blindness early in lifetime or gradual but progressive loss of sight. The diagnosis of this pathological entity is given for the lesions that are composed of GFAP strongly positive, elongated, fusiform cells consistent with fibrillary astrocytes. As illustrated in cases from our pathological practice, PAS gave positive patchy disseminated reaction in form of cellular densely purplish granules in minority of cells representing glycogen storing. This feature could be consistent with PAS-positive Müller cells that also constitute retinal gliosis as one of cellular components of normal retina that is induced to reactive proliferation. Thus, the paper presents histological background and differential diagnosis of the entity.

Malignant gastrointestinal neuroectodermal tumor (clear cell sarcoma-like tumor of the gastrointestinal tract) of the small intestine in a 12-year-old boy.

The aim of this paper is a clinical and anatomopathological demonstration of a malignant lesion, a gastrointestinal neuroectodermal tumor (GNET), as an exceedingly rare cause of ileus in the pediatric population. Specifically, we present the case of a 12-year-old boy who showed dramatic weight loss, hypochromic anemia, fever, dehydration, exaggerated granulation of the terminal ileum, and mechanical ileus due to the obstruction by an intramural tumor of the small intestine. A 50cm-long part of the small intestine with pathological stricture was surgically removed, sampled and routinely fixed and stained with hematoxylin and eosin. The additional immunostains that were preformed were: PAS, S-100, HMB-45, NSE, LCA, CK AE1 / AE3, desmin, SMA, vimentin, CD99, NSE, synaptophysin, WT-1, calretinin, and DOG-1. Moreover, fluorescent in situ hybridization (FISH) with the EWSR1 Break Apart FISH Probe was applied. The neoplasm was composed of nests and alveolar patterns of frankly malignant clear cells with immunoreactivity to S-100, vimentin, and CD 99. The FISH technique detected chromosomal breaking at 22q12. The tumor metastasized to both the mesenteric lymph nodes and a number of hepatic segments. With several chemotherapy protocols, repeat laparotomies, and liver thermal ablations, the patient had a 1.5-year-long survival from the moment of diagnosis. The diagnosis of this malignancy requires both histopathological evaluation and molecular analysis, and the follow-up is based on careful clinical imaging of the neoplastic spread in order to apply proper surgical and oncological treatments. In conclusion, the clinical course of GNET was highly aggressive.

Professional interest in dermatopathology of Stanislaw Ostrowski - the only one State Polish President among physicians.

President of prewar Lvov and Polish Republic on Exile, associate professor Stanislaw Ostrowski was a dermatologist with a keen interest in dermatopathology. This study was based on original resources, which - mainly reports of his own authorship - were focused on dermatopathology. Stanislaw Ostrowski provided excellent description of naevus epitheliomatosus sebaceus Wolters-Friboes both in Polish and German to be cited after decades in renowned handbooks of dermatopahtology published by Springer Verlag. His scientific output also includes meticulous presentation of Fox-Fordyce disease (apocrine miliaria) as well as gold-induced skin changes to Polish readership. Thus, this study documents dermatopahtological achievements of Stanislaw Ostrowski - the unifying statesman of society of Lvov and Polish emigration in London.

Review of prognostic and predictive aspects of mutated TP53 in Wilms' tumor biology with morphological report and molecular analysis of 37-year-old man's nephroblastoma.

Here we review prognostic and predictive aspects of mutated TP53 in Wilms' tumor biology on the basis of the morphological report and molecular analysis of adult nephroblastoma (diffuse blastemal pattern) of a 37-year-old man. Among quite different proteins, TP53 affects expression of several genes such as hypoxia inducible proteins GLUT1 and EPO as well as multidrug resistance (MDR) mediated by P-glycoprotein (Pgp/MDR1) and multidrug-resistant related protein (MRP1), with certain clinical implications. TP53 mutation was found both in our primary tumor (c.746G>T p.R249M frequency 92%) and in nodal metastasis (c.746G>T p.R249M frequency 90%), and the common polymorphism p.P72R in the same gene was revealed with frequency of about 97% in both primary tumor and metastatic disease with appliance of NGS technology (IonTorrent - LifeTechnology) using Ion AmpliSeq Cancer Hotspot Panel v2.

Eventual proapoptotic or anti-apoptotic impact of aberrantly expressed Cx43 and Cx26 can depend on ER-alpha overexpression in human endometrioid adenocarcinoma.

Estrogen receptor (ER) and progesterone receptor (PgR) accumulations lead to impairment of gap junctional intercellular communication in endometrial cancer. The task of this study was to explore relationships of Cx26 and Cx43 with anti-apoptotic protein Bcl-xL and proapoptotic agent Bak in ER-alpha and PgR negative or variably positive endometrioid adenocarcinomas. Cx26, Cx43, Bak, Bcl-xL, PgR and ER-alpha were detected in 78 endometrioid adenocarcinomas with immunohistochemistry. There was a remarkable cellular re-distribution of Cx26 and Cx43 from normally membranous location in normal endometrium to aberrantly cytoplasmic expression in endometrioid adenocarcinomas, thus suggesting the decrease of functional membranous gap junctions in the malignancy. Bak failed to correlate with Cx43 regardless of either PgR or ER-alpha status of tumors, while Bcl-xL positively correlated with Cx43 in ER-alpha positive tumors (p = 0.001, r = 0.427) and both PgR positive (p = 0.019, r = 0.312) and negative (p = 0.015, r = 0.509) cancers. Similarly, Bcl-xL significantly associated with Cx26 in ER-alpha positive tumors (p = 0.036, r = 0.267) and both PgR positive (p = 0.026, r = 0.297) and negative (p = 0.046, r = 0.429) cancers. On the contrary, Bak exclusively correlated with Cx26 only in ER-alpha negative tumors (p = 0.027, r = 0.551). ER-alpha status of endometrioid adenocarcinomas could restrict eventual proapoptotic or anti-apoptotic impact of aberrantly expressed Cx43 and Cx26 in these tumors.

Vulvar angiomyofibroblastoma--a case report of rare entity mimicking Bartholin cyst.

Vulvar angiomyofibroblastoma is rare tumor of obscure histological origin. Here a case of 49-year old woman is described with this intriguing benign vulvar entity. The tumor developed at left vulvar labia and clinically imitated Bartholin cyst with clinical complaints of regional discomfort without pain. A macroscopic evaluation revealed well separated, encapsulated tumor of 3,5 cm in diameter. On cut surface the tumor was whitish, flesh, solid with myxoid appearance without any apparent cysts formation. There were alternating hypo- and hypercellular in the neoplasm. Microscopically the tumor comprised proliferation of small thin walled vessels that were surrounded with cuffs and islands of epithelioid, spindle and plasmacytoid cells with occasional vacuolization. Some aggregations of cells were quite dense and in such fields, vessels were compressed and ecstatic enough to mimic a bit haemangiopericytoma pattern. A production of myxoid intercellular matrix was seen in loose, hypocellular areas and was confirmed by positive pas-alcian blue stain that demonstrated prominent myxoid stroma and intracytoplasmatic globules of acid glicoproteins. The immunoprofile was remarkable enough to show strong expression of vimentin and desmin, while there was a lack of pan-keratin (CKAE1/3) and smooth muscle actin (SMA) immunoreactivities. Such an immunofentype is regarded to share some of myofibrolastic origin despite SMA negativity. Tumor cells seemed to sprout from perivascular regions giving an impression of accumulations strictly associated with neighbouring vascular branches. This configuration of cells is very often viewed as pericyte-like proliferation. Thus, our case of angiomyofibroblastoma is an example of tumor that probably derives from perivascular stem cells that acquire some of myoid features.

From morphology of human body to reshaping a morphology of the society: heritage in the field of pathology of infectious diseases of Wilhelm Ebstein and work of councilman Sigismund Asch. A story how to counteract epidemics and to transform feudal system into civil democracy.

Collected, primary resources enabled us to extract data that are scarcely present in medical literature of the two Breslauer morphologists of both the human body and - metaphorically - the society: Wilhelm Ebstein (1836-1912) and Sigismund Asch (1825-1901), particularly the latter, who described morphology of melanosis in his doctoral dissertation in 1846, to switch on reshaping social morphology of Wroclaw (Breslau) in Virchow-like manner. In contrast to the main perspective of Ebstein's anomaly that has been finely described in past biographical papers, a primary aspect of infectious diseases is highlighted here in Ebstein's heritage. In 1869, his habilitation on recurrent typhus provided professional support for Asch. As Ebstein cared for the poor in shelters of Wroclaw, Asch admitted poor patients from early morning hours to gain such a great esteem to be elected alderman. Asch's mentality corresponded to Ferdinand Lassalle's philosophy of the social democratic movement. In front of cholera epidemics, Asch contributed to medical control of meat, development of city canalization, establishment of green areas as well he deeply got involved in charity institutions for widows and orphans and was a model medical doctor to follow for much more famous Janusz Korczak who perished together with children from his orphanage in Nazi Concentration Camp in Treblinka. Asch was immortalized as "Doctor Klaus" in the popular play by Adolf L'Arronge and united people in progress from feudal discrimination to democracy and in fight for civil rights in industrial society to gradually replace aristocracy with meritocracy in the mainstream of development of modern society.

Comparison of primarily diet-modifiable intestinal factors, connexin 43 and E-cadherin with TP53 and TGFB1 in colorectal cancer.

BACKGROUND/AIMS: Primarily, a diet (particularly dietary lipids and vitamins) can reversibly modify intestinal expressions of a few factors like connexin 43 (Cx43), E-cadherin (Cdh1), TP53 and TGFB1 with a special impact on immunity and mutagenesis. Malignant phenotype constitutes a diet-resistant signal streaming with engagement of these molecules which are generated in autonomous ways in colorectal cancer. METHODOLOGY: We aimed to compare adhesion proteins: (Cx43) and Cdh1 with TP53 and TGFB1 in colorectal adenocarcinomas. GJA1P1 and Cdh1 with TP53 and TGFB1 were detected with immunohistochemistry in the study of 106 colorectal adenocarcinomas. RESULTS: There was aberrant cytoplasmic expression instead of membranous one of Cx43 and Cdh1 reflecting constitutive destruction of intercellular ties while TP53 showed nuclear expression and TGFB1 accumulated in the cytoplasm. TP53 did not correlate with Cx43 (r=0.083, p=0.397) but correlated with Cdh1 (r=0.199, p=0.041). Cdh1 associated with TGFB1 reaching almost statistical significance (r=0.188, p=0.054), while TGFB1 correlated with Cx43 (r=0.359, p=0.001). CONCLUSIONS: The consequent and constant impairment of cancer intercellular communication seems to engage correlated with each other expressions of Cx43 and TGFB1 in colorectal cancer cells.

Carl Weigert's pioneer definition of heart infarction as myocardial, coagulative necrosis due to obstruction of atherosclerotic coronary arteries in 1880, overshadowed by subsequent, secondary publications in the field.

In 1880, a German Jewish Professor of Pathology, Carl Weigert (1845-1904) first defined heart infarction as myocardial, coagulative necrosis ("Coagulationsnekrose") due to obliteration of atherosclerotic coronary arteries thanks, at least, partially to his great diligence in vascular staining methods. Histochemical techniques made his name eponymic as Weigert's Hematoxylin or Weigert's and Van Gieson's elastic stains are still used in routine practice to visualize, e.g., the framework of vessels. However, his discovery has been overshadowed by far more frequently cited in recent decades, subsequent but secondary, 214-page-long book dated on 1896 and titled "L'infarctus du myocarde et ses conséquences - ruptures, plaques fibreuses, anévrismes du coeur", in which René Marie repeated Carl Weigert's words that dead cardiomyocytes lost their cellular nuclei. Weigert introduced the term "die Infarcte des Herzmuskels", in 1880, in his paper titled "Über die pathologischen Gerinnungsvorgänge", in Virchows Archiv. According to Weigert, occlusions were caused by white thrombi ("weissen Thromben") on the ground of atheromatous changes of the coronary arteries. In following manner, he gave macroscopic description of heart infarction: "If a blood supply is very roughly (German: brüsk), completely cut off in individual parts of the heart muscle, yellowish dry masses are formed that resemble coagulated fibrin". "If examined microscopically, one usually does not find any fibrinous material exudate, but often a delusively normal tissue (sometimes you can even see cross striation of the muscle fibers): but all muscle fibers (...) are anucleate". Paradoxically, coronary thrombosis was also a cause of Carl Weigert's death.

STAT3 and apoptosis regulators: Bak and Bcl-xL in endometrioid adenocarcinomas of different estrogen receptor-α immunoprofile.

Estrogen receptor (ER) is a major feature of endometrioid adenocarcinoma. It has a significant impact on constitution of estrogen-responsiveness of this endometrial malignancy, in which STAT3 (signal transducer and activator of transcription) becomes hyperactivated. The aim of our study was to detect immunohistochemically and compare expressions of STAT3 with apoptosis regulators (Bak and Bcl-xL) in regard to different pathological features and variably pronounced ER-α immunoprofile in 78 endometrioid adenocarcinomas. STAT3 was abundantly detected in nuclei of cancer cells in 54 cases, thus pointing at its activation as an universal nuclear transcriptional factor. Bcl-xL and Bak were expressed in cytoplasm of malignant cells in 62 and 20 cancers, respectively. STAT3 correlated both with Bcl-xL (p = 0.001, r = 0.365) and Bak (p  < 0.001, r = 0.436) in all of endometrioid adenocarcinomas and variably in different subgroups of these tumours segregated in regard to grading, staging and patients' age. Remarkably, only ER-α positive cancers retained these correlations in opposition to ER-α negative tumours with negativity defined as an immunoreactivity below 10%. ER-α receptor probably enhances interactions between STAT3 and Bcl-xL to be present in statistically significant manner. Presence of ER-α receptor seems to be crucial for relationships among Bcl-xL and STAT3 to occur in endometrioid adenocarcinomas.

Heritage of Leopold Auerbach in the field of morphology of nervous system.

Leopold Auerbach (April 27, 1828-September 30, 1897) belongs to world famous figures in medicine, who were born, spent most of their lifetimes and died in Wroclaw (Breslau). Auerbach reported for the first time in literature about existence of plexus myentericus (plexus Auerbachi) including ganglion cells between circular and longitudinal layers of tunica muscularis propria in intestinal wall, in 1862. With his publication on muscular hypertrophy, dated on 1871, he provided ground for another eponym: "Friedreich-Auerbach disease", that refers to facial hemihypertrophy. He was raised in Jewish family, which lived for generations in Wroclaw. His elaborative scientific work was his struggle for human dignity and safe social status, which was shared with many other members of the community at the time of Jewish emancipation thorough the whole XIXth century in Germany. The great value of Leopold Auerbach for the Wroclaw University - his Alma Mater -, which was founded by an Austrian Emperor Leopold I, is even metaphorically coded by the fact, that "AL" are not only initials for Academia Leopoldina but also curiously for the name and surname of this brilliant scientist, who led rather a calm and unspectacular life. This paper is the last one from the series of our biographical papers, in which we focused on his output in the field of vascular system, morphology of invertebrates and - in only short one page-long note until now - on the topic of nervous system, so we decided to present a full text report on the latter but the most famous area of his activity.

Aberrant distributions and relationships among E-cadherin, beta-catenin, and connexin 26 and 43 in endometrioid adenocarcinomas.

During carcinogenesis, loss of intracellular cohesion is observed among cancer cells with altered expression of such adhesion molecules as E-cadherin and beta-catenin, and aberrant expression and cellular location of intercellular gap junction proteins-connexins. The aim of this study was to evaluate immunohistochemically the expression and relationship between E-cadherin and beta-catenin, and the connexins Cx26 and Cx43 in 86 endometrioid adenocarcinomas. The aberrant cytoplasmic translocation of the studied proteins was a predominant finding, whereas only a minority of cases showed normal, nuclear beta-catenin labeling or membranous distribution of the remaining molecules. E-cadherin was positively and significantly associated with beta-catenin (P=0.001, r=0.366), as was Cx26 with Cx43 (P<0.001, r=0.719), E-cadherin with Cx26 (P<0.001, r=0.413), and E-cadherin and Cx43 (P<0.001, r=0.434) in all cancers. A subgroup of endometrioid adenocarcinomas (FIGO IB+II) exclusively showed a positive significant association between the expression of beta-catenin and Cx26 (P=0.038, r=0.339). In addition, there were significantly more beta-catenin-positive carcinomas among superficially spreading cancers (FIGO IA) than among deeper invading neoplasms (FIGO IB+II) (P=0.056). The altered location of the studied proteins indicates impairment of their physiological functions. In particular, normal membranous distribution of E-cadherin and connexins is lost and replaced by abnormal cytoplasmic accumulation in most cancers, and thus intercellular ties are expected to be weakened and loosened as a consequence. In contrast, the lack of relationship between beta-catenin and connexins, E-cadherin seems to be closely associated with the expression of Cx26 and Cx43 in endometrioid adenocarcinomas.