Tityus: a forgotten myth of liver regeneration.

The ancient Greek myth of Tityus is related to liver regeneration in the same way as the well known myth of Prometheus is. Depictions of the punishment of Prometheus are frequently used by lecturers on liver regeneration; however, Tityus remains unknown despite the fact that he received the same punishment and his myth could also be used as a paradigm for the organ's extraordinary ability to regenerate. Nevertheless, there is no convincing evidence that ancient Greeks had any specific knowledge about liver regeneration, a concept introduced in the early 19th century. We describe and analyze the myth of Tityus and compare it to the myth of Prometheus. We also explore artistic and literary links and summarize recent scientific data on the mechanisms of liver regeneration. Finally, we highlight links of the legend of Tityus with other sciences.

Interobserver and intraobserver variability in evaluating vascular invasion in hepatocellular carcinoma.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is unique in that the presence of vascular invasion significantly changes tumor stage. Even though searching for vascular invasion is a common practice in surgical pathology, there appears to be a great variation among pathologists in its recognition. This study was designed to assess whether HCC could be accurately staged using vascular invasion as a staging parameter. METHODS: The interobserver and intraobserver agreement for vascular invasion was analyzed in 126 liver resections for HCC. Selected slides were circulated twice among six pathologists for independent review using their own criteria. One to three representative images from 26 equivocal cases selected by one of the authors were re-evaluated by the pathologists. The presence or absence of vascular invasion on each slide or image was recorded as yes or no. The results were analyzed using unweighted kappa statistic analysis for multiple raters. RESULTS: The interobserver agreement was moderate on two slide circulations with kappa values of 0.50 (95% confidence interval 0.45-0.55) and 0.43 (0.38-0.47), respectively. The kappa value dropped significantly to 0.19 (0.09-0.29) on selected images photographed from controversial cases. The intraobserver agreement was moderate, with kappa values ranging from 0.23 to 0.56 (mean = 0.45). CONCLUSIONS: Pathologists can reproducibly recognize vascular invasion in many HCC cases but may have difficulty in equivocal cases, which may lead to either understaging or overstaging of the tumors. This may have a significant impact on prognostic assessment and therapeutic decision making. Our observations indicate the need for improved definition for vascular invasion in HCC.

Hepatocellular carcinoma in a hepatitis C patient with sustained viral response and no fibrosis.

Hepatitis C poses a substantial global health burden. Three to five percent of individuals with liver cirrhosis secondary to hepatitis C will develop hepatocellular carcinoma. The development of hepatocellular carcinoma is closely associated with cirrhosis in hepatitis C infection, whereas in hepatitis B virus infection, hepatocellular carcinoma may occur in the absence of cirrhosis. Although uncommon, hepatocellular carcinoma has been reported in hepatitis C patients without cirrhosis and, in very rare cases, in the absence of active viral replication. We report the case of a 51-year-old patient with hepatitis C who developed hepatocellular carcinoma in the absence of fibrosis and after having achieved sustained virological response with combination peginterferon and ribavirin therapy seven years prior. The patient successfully underwent surgical resection, and histopathological examination of the resected tissue demonstrated a poorly-differentiated hepatocellular carcinoma in an otherwise unremarkable liver. The patient continues to do well and has no evidence of tumor recurrence 18 months post-operatively. This case raises question regarding the carcinogenesis of hepatocellular carcinoma as a sequela of chronic hepatitis C in noncirrhotic liver and moreover after achieving sustained virological response.

Surgical pathology in the 20th century at the Mount Sinai Hospital, New York.

How did the education of surgical pathology, and pathology in general, differ at Mount Sinai? Passing the examination of the American Board of Pathology was never the focus of the department. Learning criteria or quoting references was de-emphasized, but mastery of macroscopic pathology was required, supported in both word and action by two brilliant surgical pathologists, Otani and Kaneko, and by two extraordinary medical pathologists, Klemperer and Popper. Meticulous microscopy emphasized pattern rather than reliance on lists of discrete features. Otani developed a regular "problem case" meeting for a community of pathologists, made up of alumni and other interested pathologists, as well as active department members. These monthly sessions provided the highest level of "continuing medical education." Otani and Kaneko unequivocally believed in learning from cases, and Mount Sinai residents were fortunate both in the one-to-one teaching and in the wealth of material, in all systems, that came to surgical pathology. Outstanding pathologists who came from Mount Sinai settled throughout the country and provided the highest level of diagnoses, but, with the exception of Bernard Wagner, Emanuel Rubin, Fiorenzo Paronetto, Richard Horowitz, Michael Gerber, Marc Rosenblum, Bruce Wenig, Jaishree Jagirdar, Swan Thung, Cesar Moran, Hideko Kamino, Philip LeBoit, Alberto Marchevsky, and others, there were relatively few academic leaders. Otani and Kaneko did not have national reputations. Klemperer, although world renowned, was relatively unassuming, and his disciples numbered almost as many nonpathologists as pathologists. Popper did establish a major center for liver pathology, with students coming from around the world, but did not particularly promote general surgical pathology. Can the Mount Sinai approach still be applied? The decline in the numbers of autopsies performed, the demands for rapid turnaround time, the de-emphasis of gross pathology as newer technologies (eg, immunohistochemistry, cytogenetics, molecular pathology) gain place, the increasing tendency to select investigators, including basic scientists, as teaching department chairs and the financial constraints requiring increasing use of nonphysician workers all speak to the relegation of the Otani-Kaneko era to history. Is this a loss to Pathology? It is certainly a style of practice that has been lost. However, there is no reason to bemoan the state of Pathology in the beginning years of the 21st century. Pathology practice is outstanding at many medical centers throughout the world, including at Mount Sinai under the very able and creative leadership of Alan Schiller, who has presided over great enhancements of the department in both anatomic and clinical pathology, including significant advances in the study of diseases by molecular methods. Surgical Pathology at Mount Sinai has been led by James Strauchen, a renowned hematopathologist recruited by Schiller's predecessor, Jerome Kleinerman, and is currently directed by Ira Bleiweiss, a student of Kaneko. Other techniques and technologies have, to a degree, compensated for some of the changes since the Otani-Kaneko years and it is almost certain that advances in molecular pathology will allow for increasing sophistication in establishing diagnoses, and likely even grading and staging, probably even on blood, rather than tissue, samples. The science of Pathology will advance, as the art declines. Those who learned at Mount Sinai during the Otani-Kaneko years will, however, very likely tell you that they were privileged to have learned Pathology there and, especially, to have learned a distinct philosophy of Pathology under the guidance of caring, thoughtful, and especially gifted pathologists.

Ulceration of pyoderma gangrenosum treated with negative pressure wound therapy.

Pyoderma gangrenosum is a skin disease characterized by wounds with blue-to-purple undermined borders surrounding purulent necrotic bases. This article reports on a patient with a circumferential, full-thickness, and partially necrotic lower-extremity ulceration of unknown etiology. Results of laboratory tests and arterial and venous imaging studies were found to be within normal limits. The diagnosis of pyoderma gangrenosum was made on the basis of the histologic appearance of the wound tissue after biopsy as a diagnosis of exclusion. Negative pressure wound therapy was undertaken, which saved the patient's leg from amputation. Although negative pressure wound therapy has demonstrated efficacy in the treatment of chronic wounds in a variety of circumstances, this is the first documented use of this technique to treat an ulceration secondary to pyoderma gangrenosum.

Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease.

BACKGROUND: 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease. METHODS: We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy. RESULTS: In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction. CONCLUSIONS: 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.

Hepatitis B and hepatitis C.

Hepatitis B and C are worldwide infectious hepatitides which are distinct in terms of epidemiology and molecular biology, but which may be quite similar in terms of clinical manifestations and histopathology, in both the acute and chronic stages. Hepatitis B virus (HBV), the human prototype of the Hepadnaviridae family of viruses is not directly cytopathic and viral hepatitis is caused by the cellular immune response to HBV. Patients infected with HBV may also have hepatitis D (delta) virus (HDV) infection, either as co-infection or a superinfection. Hepatitis D virus does not infect independently. Better control of HBV has also led to a decline in the incidence of HDV. Hepatitis C virus (HCV) is on of the Flaviviridae family of viruses, and is quite heterogeneous, with six major genotypes and more than 100 subtypes. Hepatitis C virus circulates as quasispecies that result from mutations accumulated over time, which probably enable HCV to replicate efficiently or resist immune mechanisms. Quasispecies have complicated vaccine development. Both HBV and HCV will recur in the transplanted liver. The risk of developing hepatocellular carcinoma is significantly greater in both HBV- and HCV-infected individuals.

Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma.

Distinguishing hepatocellular carcinoma (HCC) from cholangiocarcinoma (CC) and metastatic adenocarcinoma (MA) involving the liver can be problematic, often requiring the use of immunohistochemistry to facilitate diagnosis. Hep Par 1, a monoclonal antibody with expression confined primarily to benign and malignant hepatocytes, has recently become commercially available. We evaluated Hep Par 1 along with other immunohistochemical markers used to differentiate HCC, CC, and MA, including AE1/AE3, CAM 5.2, B72.3, monoclonal carcinoembryonic antigen (mCEA), polyclonal CEA (pCEA), alpha-fetoprotein (AFP), factor XIIIa, inhibin, CD10, villin, MOC-31, cytokeratin (CK) 7, CK 19, and CK 20, to determine the markers most useful in differentiating these entities. Forty-two cases of HCC, 9 cases of CC, and 56 cases of MA (24 colon, 15 pancreas, 8 ovary, 5 breast, and 4 stomach) were studied. Hep Par 1 was sensitive and specific for HCC, with 38 of 42 (90%) cases staining positively, whereas reactivity was observed in only 8 of 56 (14%) MAs and 0 of 9 CCs. Though limited somewhat by poor sensitivity, a bile canalicular pattern of staining with pCEA, CD10, and villin was specific for HCC and was not observed in the other tumors. Lack of mCEA and MOC-31 immunoreactivity was also characteristic of HCCs. CK 19 positivity favored CC over HCC, but was not useful in differentiating CC from MA. Expression of AFP, although observed in only about one third of the cases, favored HCC over CC and MA. CK 7 and CK 20 were also useful in this differential diagnosis, particularly when dealing with MA of colonic origin. AE1/AE3, CAM 5.2, B72.3, inhibin, and factor XIIIa were noncontributory in differentiating these entities.

Cartilaginous metaplasia in calcified diabetic peripheral vascular disease: morphologic evidence of enchondral ossification.

The mechanism of arterial calcification is not clear. We examined histological sections of major arteries from lower extremities of two patients with longstanding type II (or non-insulin-dependent) diabetes mellitus, and found morphological evidence of cartilaginous metaplasia and ectopic ossification with associated severe medial arterial calcification and atherosclerosis. Hematoxylin and eosin, alcian blue, and toluidine blue stains were applied for the demonstration of cartilage cells and their specific matrix proteins, and immunohistochemical studies for type II collagen. To our knowledge, cartilaginous metaplasia has not previously been described in medium-sized human muscular arteries. This observation supports the hypothesis that active enchondral ossification may be a pathway leading to arterial calcification in diabetic obstructive peripheral vascular disease.

Determination of HER-2 status and chromosome 17 polysomy in breast carcinomas comparing HercepTest and PathVysion FISH assay.

We evaluated and compared 2 HER-2 tests (immunohistochemical analysis [HercepTest, DAKO, Carpinteria, CA] and fluorescence in situ hybridization [FISH]) and assessed chromosome 17 polysomy status in relation to these tests. HER-2 status was obtained in 690 cases. The rinse step in the HercepTest before and after addition of the visualization reagent was 2 minutes in 188 cases and was increased to 5 minutes in 600 cases. HercepTest with both rinse steps was performed on duplicate slides in 98 cases. Chromosome 17 ploidy status based on FISH results was determined in 687 cases. Weak overexpression (2+) of HER-2 protein was not due to gene amplification in a majority of cases (67/76 [88%]). A small subset of breast carcinomas (19/687 [2.8%]) strongly overexpressed (3+) HER-2 protein without gene amplification. The aneuploidy rate was similar in negative and 2+ cases (60/141 [42.5%] and 12/26 [46%]), compared with 86% (18/21) in 3+ cases. The incidence of polysomy 17 in 2+ nonamplified cases (3/67 [4%]) was similar to that seen in negative cases (5.5%), in contrast with 47% (9/19) of 3+ nonamplified cases. Adding a longer rinse step to the HercepTest converted a subset (3/10 [30%]) of weakly positive cases to negative cases. Weak overexpression of HER-2 protein in a majority of cases seems to represent an artifactual staining pattern. Chromosome 17 polysomy is a major factor in strong HER-2 protein overexpression in 3+ nonamplified cases.

Liver: tissue handling and evaluation.

Liver diseases remain among the most important causes of morbidity and mortality worldwide. Although the diagnostic tools (e.g., blood studies, imaging, genetic and molecular tests) available to clinicians have greatly expanded in number and increased in sensitivity, the examination of liver tissue by a pathologist skilled and experienced in hepatopathology remains vitally important in the evaluation and care of the patient with liver abnormalities. In some disorders, such as autoimmune hepatitis, liver biopsy is considered mandatory. The indications for performing liver biopsies have changed over the years (e.g., large duct obstruction was a common diagnostic problem 50 years ago and is only uncommonly so currently). Liver samples come to the pathologist as aspiration biopsies for cytologic examination, tissue biopsies (fine needle, core, transjugular, and wedge), resections, and explants. Each demands slightly different approaches for optimal handling and evaluation.

Gross examination.

The examination of organs and tissues macroscopically in order to establish a diagnosis and to select relevant portions for subsequent microscopic examination and special studies is fundamental to the practice of pathology. In the autopsy room, in the surgical pathology laboratory and, very often, in the operating room, gross pathology is the essential, underlying basis of morphologic diagnosis. Diagnoses on the basis of gross examination can be accurately made in as many as 90 % of specimens (Grossman IW, A primer of gross pathology, Charles C Thomas, 1972). In the remaining 10 % the skilled pathologist can be close to the diagnosis or can, at least, construct an accurate differential diagnosis that can provide guidance for subsequent studies. Sadly the numbers of pathologists with skills in macroscopic ("gross") pathology is rapidly declining, with concomitant loss in the quality of gross examinations, lower accuracy and elegance of specimen descriptions, and lack of precision in sample selection for special studies. This clearly impacts the quality of surgical pathology practice and, inevitably, the quality of patient care. The decline of gross pathology is a result of a number of factors, including a marked decrease in the numbers of autopsies which means that there are fewer opportunities for pathologists to hone gross pathology skills and to gain proficiency in handling tissues for appropriate further study. This is compounded by an increasing reliance on pathologists' assistants (PAs) for the handling, description and sampling of gross specimens, by the expanded utilization of biopsies rather than resections prior to initiating therapy and by the reliance on highly sophisticated immunopathology, molecular and genomic methods for diagnosis and even for determination of therapy. Despite these and other changes in medical and pathology practice, careful examination of the gross specimen is still the sine qua non of surgical and autopsy pathology practice.

Infective endocarditis: a history of the development of its understanding.

Inflammation of the inner layer of the heart, especially the valvular endothelium, chordae tendinae and mural endocardium was first recognized almost 350 years ago. Over the years it has had many names, but is now generally designated infective endocarditis (IE) and has an associated infectious agent. A sterile vegetative process can also affect the valves and is usually referred to as Libman-Sacks endocarditis. The developments of medical science that allowed for our understanding of this entity included refinement of the autopsy, medical microscopy, microbiology, and in recent years, molecular studies. Some observations were misleading but clarification particularly followed the reports of Morgagni, Osler and Libman. As understanding of the pathobiology of infective endocarditis grew so did the effectiveness of therapy. This paper provides a detailed history of the development of the concept of Infective endocarditis citing many key morphological observations and concludes with brief comments about current concepts of pathogenesis as well as a few remarks about therapy.

Thomas Hodgkin: the "man" and "his disease": humani nihil a se alienum putabit (nothing human was foreign to him).

Thomas Hodgkin (1798-1865) was one of the leading physicians and scientists of the nineteenth century. A renowned diagnostician, he carried out pioneering work in public health, but devoted the greater part of his career to the study of pathology. His contributions transcend many fields, medical and non-medical, but his most important legacy to medical science was the recognition of the disease that bears his name. The diagnosis of Hodgkin's disease was difficult pending recognition of the "peculiar giant cells" that came to characterize the diagnosis. With identification of the Reed-Sternberg cell, it might have been expected that debate concerning the nature of Hodgkin's disease would be stilled. History proved to the contrary. A fierce controversy ignited with respect to the cellular origin of the Reed-Sternberg cell and the relationship, if any, of Hodgkin's disease to other malignant processes arising in the "absorbent glands and spleen." For a century, arguments ebbed and flowed, reflective of individual opinions and changing concepts, yielding ultimately to new methods for examining and identifying cells.

Primary hepatocellular carcinoma ("hepatoid" carcinoma) of the pancreas: a case report and review of the literature.

KEY CLINICAL MESSAGE: We present a case of hepatocellular carcinoma located within the pancreas. These tumors occur in the body and tail of the pancreas, with a male predominance, and at a younger age. Tumors with pure hepatocellular histopathology have better survival and recurrence rates and should be offered surgical therapy if possible.

Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with multiple endocrine neoplasia type 1.

We report a patient with multiple endocrine neoplasia type 1 presenting with elevation of parathyroid hormone-related protein (PTHrP) from a metastatic pancreatic neuroendocrine tumor (PNET), and parathyroid hormone (PTH) from primary hyperparathyroidism, resulting in severe hypercalcemia. Parathyroid hormone-related protein production by the PNET was confirmed by immunohistochemical analysis. Hypercalcemia and elevated PTHrP improved markedly with hepatic artery chemoembolization of liver metastasis. Thus, in multiple endocrine neoplasia type 1, correct identification of the cause of hypercalcemia as PTHrP production from a PNET or PTH production from a parathyroid tumor has important therapeutic implications.

Deep soft-tissue necrosis of the foot and ankle caused by catfish envenomation: a case report.

Catfish envenomations represent a relatively rare cause of complications in podiatric medicine. We report a case of an unusual event eliciting a severe soft-tissue necrosis in a 21-year-old man and his complicated wound-healing process. This case reviews the potential complications of catfish envenomations.