ANATOMIC PATHOLOGY

 

Anatomical Pathology in The 21st Century—The Great Paradigm Shift

 

EDITORIAL

INTRODUCTION

Anatomical pathology, especially the clinical subdisciplines of surgical and cytopathology, has a distinguished but relatively short history. Prominent in clinical medicine for less than 80 years, these subdisciplines are currently in the midst of significant change. Visions of the future have been discussed in several recent articles. Many if not most of these have emphasized information technology, methods to ameliorate diagnostic errors, and the value of adopting consensus-based guidelines for processing and reporting. Focused in this way, one might view changes in anatomical pathology as a matter of altered methodology. In my view, something much more fundamental is evolving. The changing paradigm can be considered not so much in terms of how we do things but in terms of who we are and what we are becoming. I believe that these issues have received insufficient emphasis and deserve more discussion. This presentation will use selected elements of pathology practice to emphasize the great paradigm shift in which anatomical pathology finds itself. The discussion is divided into 2 parts: technology, and subspecialization.

TECHNOLOGY

We are all aware of the major advances in genetic research and the future potential of the “-omics” (genomics, proteomics, metabolomics, etc). Polymerase chain reactions, single strand conformational polymorphisms, and other such techniques are in current use; but methods that can be adapted to the light microscope, the mainstay of anatomical pathology, are scarce. Immunologic techniques such as immunohistochemistry are widely applied, increasingly through tissue microarrays; and some anatomical pathologists have learned simple cytogenetic-based procedures such as fluorescence in situ hybridization.

The complexities of this new technology are great, and very few pathologists are sufficiently trained in these disciplines to either accurately assess the literature for themselves or to fully understand the clinical appropriateness of the techniques that have been adapted. As a very evident example, most pathologists apparently believe that immunohistochemical reactions are “stains,” such as hematoxylin and eosin (H&E), when in fact they are antigen-antibody interactions that usually only occur at near equilibrium^]. Because we never know the concentration of the antigens in any particular specimen and the concentration of the antibodies tends to be fixed by the manufacturer, achieving an equilibrium point is something of a chance occurrence. Essentially all neoplasms are, in their overall constituents, antigenically deficient compared with their normal tissues of origin; so it is quite possible to have a falsely negative result if too much antibody is applied. Such an occurrence is especially likely in poorly differentiated neoplasms, the type most likely to benefit from immunohistochemical identification. Of course, accuracy can be enhanced by appropriate specimen handling, adequate controls, and titrations of the commercial products; but I suspect that most of us actually treat the application of antibodies to specimens as if the process were a sophisticated H&E stain.

The issue of p53 might serve as another example of the widespread application of techniques without fully understanding the underlying principles. The p53 gene produces a very large protein with multiple binding domains, only a few of which are generally assessed clinically. The function of the gene is complex, depending on the setting. And yet, although the vagaries of p53 continue to be discovered, the literature can be used to justify the application (and charging) of testing for patient care  How do we justify the claim that finding >10%, >20%, or even >50% of nuclei in any urothelial neoplasm “stained” for p53 protein means that the tumor as a whole has such an aberrant cell cycling system that it will be aggressive and should be treated aggressively? Empirical observation, you say; but the literature on the efficacy of p53 remains controversial. If the genetic pathway associated with overexpression of p53 protein were the ruling factor, then (nearly) all patients with a “positive” result should have an adverse outcome, whereas only 20% to 50% seem to.

Anatomical pathology is a discipline built upon the interpretation of changes in tissues and cells. Anatomical pathologists have spent many years studying the various components of the art—gross anatomy, histology, cytology. How many of us have devoted similar efforts to the understanding of the essentials of genetics, proteomics, and their techniques? How many of us understand the biology behind the lines of a gel or the map of the microsatellite instability of a chromosome? Relatively uninformed acceptance of poorly understood techniques alters the role of a pathologist from an expert who can make independent judgments to an information specialist who must rely upon the judgments of others—a fundamental paradigm shift in anatomical pathology.

EXPERTISE AND SUBSPECIALISATION

The great paradigm shift in anatomical pathology has provided us with technology that we use but do not fully understand. It has burdened us with an increasingly complex literature without concomitant guidance on how to deal with it. We must succumb to authority whether or not we have reason to agree with the recommendations, aka rules, being promulgated. This tends to inhibit our ability to treat our patients according to our understanding of the best practice and increasingly makes us act like laboratorians monitoring precalibrated “instruments” (e.g., synoptic reports).

If all of this were not sufficiently daunting, we must seriously entertain the proposition of changing our approach to the practice of surgical and cytopathology. It might be comforting to realize that over the 150 years of its existence, pathology has been changing constantly. Beginning as a way for individual clinicians to enhance the treatment of their particular patients, pathology had evolved as a full-time discipline by the early 20th century. The American Society of Clinical Pathologists was formed to give the fledgling hospital-based doctors a national voice and to distinguish them from research pathologists. After World War II, surgical pathology came into its own so successfully that it nearly eclipsed both autopsy and cytopathology. Surgical pathologists were redefining disease in terms of the appearance of tissues and cells under the light microscope. The notion that diseases manifested their nature in their morphology took a very firm hold. Pathologists were the doctor's doctor. We were the specialists and clinicians were the generalists.

Over the last 25 years, most of these have changed. Clinicians are now the specialists, whereas most pathologists have become general practitioners. Some anatomical pathologists pride themselves with good reason on their vast knowledge of many subdisciplines; but no one can keep up with the pathologic literature, and the impetus to remain generalist is primarily financial. Until a few years ago, only dermatopathologists and cytopathologists could make a living in a subspecialized environment. Currently, gastrointestinal and urologic pathologists have augmented their ranks.

The overriding reason to believe that subspecialization in anatomical pathology is the way of the future is that clinicians demand it. As subspecialists themselves, they are no longer willing to give a generalist pathologist the benefit of the doubt. It makes no difference to them that study after study has documented a very low significant error rate among generalist anatomical pathologists. The issue has become credibility, not competence. Of course, there are benefits to pathologists here:

·        a decreased literature to negotiate;

·        increased credibility and respect;

·        decreased medicolegal exposure.

Splintering of the old discipline is a big negative, and there are disputes over which business model is most beneficial to all concerned. The biggest stumbling block to subspecialization, however, has been the ratio of clinicians to pathologists that is required to make the system financially viable, especially to subspecialties with low volumes.

Subspecialization in anatomical pathology becomes practical when the following factors are satisfactorily addressed.

·        Volume. The number of billable items, usually specimens but sometimes significantly augmented by ancillary tests, is sufficient to support a pathologist and whatever staff is required to produce the consultative report. In nearly all cases, a central pathology facility that receives specimens from several clinical subspecialty practices is required.

·        Pathologist adaptation. The anatomical pathologist, trained in general pathology, must accept the risks associated with subspecialization. These include loss of expertise in other subspecialties (over time), less employability should adverse events occur, travel or relocation to the central pathology facility, and credentialing in all areas where the patients reside, according to the laws in effect.

·        Turnaround time. Using current models, the turnaround time will likely be lengthened because specimens must be transported from various off-site locations.

·        Clinician-pathologist interaction. For those who value and have maintained an “in-person” interaction, perhaps over the microscope, things must change. Other forms of close communication can, of course, be substituted.

All of these factors have already been addressed in the many subspecialty pathology practices now in operation. All assume that the technology used to interpret specimens for the past 150 years, namely, the light microscope, will continue to be required.

If specimens could be processed locally or at a central facility and then quickly digitized, the images could be sent to pathologists anywhere in the world. This technology (virtual microscopy) is available and is currently being perfected^]. The primary conceptual issue is acceptance of a system that would abandon the light microscope in favor of the computer monitor. In addition to the advantages already listed, the pathologist would not be required to travel or move. Potentially, he could acquire images from other countries, thus broadening his practice and increasing his job security. Turnaround time could actually be decreased, depending on where in the world the specimen originated. Control of the “business,” previously in the almost exclusive purview of clinicians and hospital administrators, would have to be at least shared with the owners of the central processing facilities.

Virtual microscopy has disadvantages in addition to a certain amount of retraining from microscope to monitor. These include an increased level of competition, perhaps worldwide, that could drive down reimbursement and put some pathologists out of work. It seems likely, although by no means assured, that the number of specimens will not be sufficient for all the pathologists available. If subspecialization becomes widespread, the various practices may have too little in common to support the discipline of anatomical pathology as we now know it.

The great paradigm shift in anatomical pathology is fundamentally altering not only how we do things but how we are perceived and who we are as a discipline. The changes are far advanced; and it seems unlikely that their direction can be significantly altered, barring a major world economic upheaval. Almost every aspect of our discipline has been affected; and although the general pathologist is unlikely to disappear (it was not that long ago when autopsy was king), his status is unlikely to remain what it is today. Fortunately, changes of the magnitude discussed here take a long time to solidify; and we have time to adjust.

Human Pathology, July 2007 • Volume 38 • Number 7

 

 

So-Called Telangiectatic Focal Nodular Hyperplasia: A Newly Recognized Variant of Hepatic Adenoma

 

Guindi, Maha

Management of hepatic adenoma (HA) and focal nodular hyperplasia (FNH) heavily relies on the distinction between the 2 entities. Most FNH are not resected, whereas HA can be complicated by hemorrhage and malignancy and is generally excised. FNH is composed of benign hepatocytes and contains bile ductules. Historically, there are 2 main subtypes of FNH, classic/solid and telangiectatic (TFNH). Traditional descriptions of HA indicate that it does not contain ducts or ductules. Radiologic and pathologic features of TFNH pose difficulty in the classification of TFNH within the spectrum of benign hepatocellular lesions. TFNH has pathologic features that overlap with HA. Its radiologic features are atypical for classic FNH. Recent evidence from clonality studies, genomics, and proteomics shows the profile of TFNH as being more like that of HA. This review discusses the evolution of our understanding of TFNH, and its recent reclassification as an HA variant. There are conflicting results regarding the clonality of FNH between studies. Using X chromosome inactivation, a majority of TFNH lesions were found to be monoclonal in some series. Gene expression profiling showed the pattern of dysregulation of angiopoietin genes, angiopoietin-1 and -2, in TFNH to be closer to HA, and unlike that of classic FNH. Proteomic profiling of TFNH is closer to HA than classic FNH. It is important for the practicing pathologist to recognize the features of so-called TFNH and its reclassification as an adenoma variant because of management implications. This requires a paradigm shift in that the presence of ductules does not preclude the diagnosis of HA.

Pathology Case Reviews. 12(4): 154-159, July/August 2007

 

Endometrial Intraepithelial Carcinoma (EIC)/Serous (Type 2) Surface Cancer

Bishop, John W. Maksem, John A.

Serous (type 2) endometrial carcinomas are uniformly high grade, estrogen independent, often found in thin, atrophic endometria. This contrasts to the thickened endometrial stripe seen with endometrioid (type 1) carcinomas. In further distinction from type 1 carcinomas, type 2 carcinomas are known to metastasize widely without apparent myometrial invasion and without an identifiable stromal response-hence the difficulty in classifying a lesion as truly "intraepithelial" without data concerning its absence from usual sites of tumor metastasis. Endometrial intraepithelial carcinoma can be diagnosed cytologically by the findings of: marked nuclear atypia with enlarged nucleoli; confluent, strong p53 nuclear reactivity; and a marked increase in Ki-67 reactive nuclei. The very high Ki-67 proliferation index of these lesions exposes neoplastic epithelium that contrasts with surrounding atrophic epithelium. The p53 labeling is uniformly intense and confluent among malignant nuclei, unlike characteristically weak, spotty, or absent p53 labeling of early type 1 carcinoma and atypical hyperplasia.

Pathology Case Reviews. 12(4):166-169, July/August 2007.

 

CYTOPATHOLOGY

Commentary: Liquid Automation Refreshes Dr Papanicolaou

Geoff Watts, Science Editor, BMJ

That the Papanicolaou test has been modified so little during the greater part of its existence is surely a tribute to the insight and inventiveness of the physician scientist from whom it takes its name. When change began to be mooted in the 1980s it was because new levels of computing power were making it realistic to think of automating the microscopic examination of cells from the cervix. But to do so reliably depended on first improving the quality of the smears. This prompted the development of liquid based cytology—and with it a need for realistic comparative assessments: of the performance of the new technique as against conventional methods, and of automated as against manual microscopy for examining cervical cell preparations.

Various liquid based cytology systems are now commercially available. In methods and equipment their details differ from one manufacturer to another, but all dispense with a core feature of the conventional cervical smear test. Instead of smearing the cervical material on to a microscope slide, the tester rinses the brush-like sample collection device in a small pot of preservative fluid. At the cytology lab the floating cells are dispersed and variously centrifuged or filtered to remove blood, mucus, and other debris, and then allowed to form a monolayer on a microscope slide.

In principle this approach confers several advantages. Virtually all the cells collected from the cervix should be present in the suspension, allowing the final sample to be more representative of the original population. The cells themselves, besides being more evenly distributed across the slide, should also be better preserved. Consequently, the proportion of specimens rejected as unsuitable for examination should fall, allowing the productivity of cytology labs to rise. Laboratory staff taking part in a UK Department of Health evaluation study generally approved the system.

Moving on to automation, here too one of the goals is an increase in productivity—coupled, it has been hoped, with improved accuracy. The ThinPrep imaging system used by Davey et al is intended not to replace human judgment, but to facilitate it by drawing the attention of the microscopist to the cells of most relevance. It uses a stain that gives an appearance similar to that used in the conventional smear test, but in which the intensity of colouration is closely correlated with the DNA content of the nucleus. The underpinning biological principle is that "abnormal cells have abnormal DNA content."

The automatic analyser works its way through a cartridge of slides, scanning each for the largest and darkest cells. It records the locations of 20 that are likely to be of interest to the cytologist. It also identifies two more locations based on the cells' clustering characteristics. When the operator comes to examine the slide, the motorised stage of the microscope moves these sites successively into the field of view. If the operator judges any cells to be abnormal, the entire slide is then scanned. The location of suspicious cells can be electronically marked before the slide is passed to the cytologist for further examination. The system aims to focus human attention and expertise where it is most needed.

BMJ 2007; 335:35-36 (7 July), doi:10.1136/bmj.39260.482616.DE

 

Fine-Needle Aspiration: A Powerful Modality in the Preoperative Diagnosis of Solid Pseudopapillary Neoplasm of the Pancreas

Jhala, Nirag; Siegal, Gene P.; Jhala, Darshana

Fine-needle aspirates of the pancreas are increasingly being performed to obtain preoperative diagnoses of pancreatic lesions. This has also led to an increased recognition of nonductal pancreatic malignancies such as solid pseudopapillary neoplasm of the pancreas and pancreatic endocrine tumors. These tumors often show overlapping cytomorphologic features, which could lead to errors in interpretation by unsuspecting pathologists. This report describes the salient cytologic features of various nonductal pancreatic neoplasms that, if followed closely, should help avoid pitfalls in diagnoses. This discussion uses a case of solid pseudopapillary neoplasm of the pancreas diagnosed on endoscopic ultrasound-guided fine-needle aspirate as the model.

Pathology Case Reviews. 12(4):170-176, July/August 2007.

 

CLINICAL PATHOLOGY

Average Blood Glucose Instead of HbA1c? Change Appears to Be Coming for Diabetes Care

 

Michael O'Riordan

July 3, 2007(Chicago, IL) - A small but clinically relevant change appears to be coming to the management of patients with diabetes mellitus. Hemoglobin A1_c (HbA1_c) levels, used to assess long-term glycemic control, might soon be replaced with average blood glucose, a change experts say will add clarity for diabetic patients looking to manage their disease.

Discussing the expected change here at the American Diabetes Association (ADA) 2007 Scientific Sessions last week, Dr David Nathan (Harvard University Medical School, Boston, MA) said that "patients have a glucose problem, not a hemoglobin problem" and that fasting glucose would be a better measure, as this new value "would help them understand their disease better." Reporting glycohemoglobin results as an A1_c-derived average glucose, said Nathan, would have the advantage of reporting chronic glycemia in the same units as the patients' self-monitoring of daily glycemia.

Nathan is the lead investigator of the international ADAGE trial, a study performed to confirm the relationship between average glucose and HbA1_c levels. To date, only a few studies with relatively infrequent glucose monitoring support a strong mathematical relationship between average glucose and HbA1_c, but if a switch is to be made from HbA1_c to average glucose levels, an international study is needed to establish the relationship across diabetes type, races, and ethnicities, said Nathan.

The ADAGE study, conducted at 10 centers in North America, Europe, and Africa, has almost completed recruitment, but Nathan presented preliminary results to the media and later during an ADA plenary session. The results of the first 250 subjects who have completed the study showed a close correlation between HbA1_c values at three months and average blood glucose during the same period. This relationship appeared to be the same for patients with type 1 and type 2 diabetes, said Nathan. The ADAGE investigators expect to present the final results of the study at the European Association for the Study of Diabetes this September.

Dr Richard Kahn, the chief scientific and medical officer of the ADA, said the change is not yet a foregone conclusion, and while there is "always concern when you change the currency," he believes that switching from reporting HbA1_c to average blood glucose levels will help patients better understand their disease and the importance of maintaining a healthy diet and lifestyle. Laboratories will still report the HbA1_c values, in addition to the new average glucose levels, but Kahn said an educational campaign would ensure that patients learn about the switch to average glucose and what these new values mean. The switch to average glucose wouldn't likely occur until sometime in 2008.

In a technical addition, Nathan and Kahn shed some light on a new standardization of the HbA1_c measurement, a process that involves better calibration of the machines to more accurately reflect HbA1_c. However, this recalibration is a "behind-the-scenes" process and won't be observed at the clinical or patient levels, they said.

CALCULATION OF MBG

 

HbA1c is the product of the irreversible condensation of glucose with the N-terminal residue of the ß-chain of hemoglobin A.

 

The HbA1c concentration in blood is directly proportional to the mean concentration of glucose prevailing in the previous 6-8 weeks (MBG), equivalent to the lifetime of the erythrocytes, as a stated in the formulas below.

 

MBG (mg/dL) = 31.7 x %HbA1C – 66.1

 

MBG (mmol/L) = 1.76 x %HbA1C – 3.67

 

from  Heartwire — a professional news service of WebMD

 

Impaired Kidney Function Common in Older Adults With Normal Serum Creatinine

NEW YORK (Reuters Health) Jul 03 - Reliance on serum creatinine level can result in significant underdiagnosis of impaired kidney function in older adults, according to a report in the June Journal of the American Geriatrics Society.

Serum creatinine is the most widely used test to assess renal function in clinical practice, the authors explain, though it is well established that serum creatinine alone may not correlate with glomerular filtration rate (GFR), the best measure of kidney function.

Dr. Sandra V. Giannelli from National Institute on Aging, Bethesda, Maryland, and colleagues evaluated the magnitude of renal function misclassification in 660 community-dwelling elderly men and women, aged 65 to 102 years, with normal serum creatinine values.

When GFR was estimated using the Cockcroft-Gault equation, only 8% of the population aged 65 and older actually had normal renal function, the authors report, and more than a third had moderate renal function impairment (GFR 30-59 mL/min).

Similarly, using 24-hour urine collection to determine creatinine clearance, 27% of older individuals had normal renal function, but 25% had a GFR below 60 mL/min despite having a normal serum creatinine concentration.

With both methods, the proportion of individuals with moderately impaired renal function increased with age.

Misclassification was greatest in normal and underweight persons, the researchers note, and was larger in women than in men.

In multiple logistic regression analyses, older age, female sex, and lower body-mass index (BMI) were associated with greater odds of having a GFR below 60 mL/min.

"Analyses presented here show that depending on normal serum creatinine alone as evidence of normal renal function will result in missing moderate impairment of kidney function in a substantial proportion of the older population," the investigators write.

"This study demonstrates that appropriate methods of assessment can identify an important subset of the older population meeting criteria for chronic kidney disease despite normal serum creatinine," they conclude. "Diagnosing these people may allow clinicians to introduce effective treatments to decrease disease progression, better manage comorbidities and their complications, and appropriately choose medications and adjust drug dosage, all components of high-quality medical care."

J Am Geriatr Soc 2007;55:816-823.

 

BOTTOM LINE

Hansen's Disease

John Launer

Earlier this year, I visited the University of Bergen to give a lecture, and found that the department where I was speaking was in one of Bergen's former leprosy hospitals. Norway is now very wealthy, so it is a shock to discover that it was one of the poorest countries in Europe until well into the twentieth century, and leprosy was endemic there. Bergen still takes pride in G.H. Armauer Hansen (1841–1912), the local physician who first identified Mycobacterium leprae, and whose name became an eponym for the disease.

Hansen's achievements in defeating leprosy were prodigious. He began his career with detailed population research, and used it to show that leprosy was neither a hereditary disease nor due to poor living conditions alone, thus disproving two ideas that were common at the time. He then used Norway's national leprosy register to demonstrate that isolating patients led to a decline in the incidence of the disease, suggesting that leprosy was almost certainly infectious. No one had previously shown that a chronic disease could be caused by bacteria, but Hansen found bacilli lying within the cells of intact leprous nodules. He proposed that these were indeed the cause. Eventually he became Norway's chief medical officer for leprosy, promoting legislation that required the isolation of patients with leprosy, either at home or in hospitals dedicated for that purpose. These days there is controversy about the ethics and the efficacy of such a policy, but Norway's isolation regime was a relatively humane one, with patients largely free to move around as they wished during the day. It also does seem to have contributed to a decline in incidence rates in Norway, from the time of Hansen until the last in-patient in Bergen with leprosy died in the 1970s. Subsequently, the system of registering infectious diseases and the establishment of isolation hospitals served as models throughout the world.

Two difficult episodes stand out in Hansen's life. The first arose from his caution as a scientist, the second from incaution. In 1875, he described his discovery of ‘staff-like bodies’ in leprous specimens, but he did so in tentative and somewhat convoluted terms. ‘Though unable to discover any difference between these bodies and true bacteria’, he wrote, ‘I will not venture to declare them to be actually identical’. Four years after publishing this description, Hansen received a visit from Albert Neisser, a pupil of Koch. Together they tried to stain the bacilli to make them more visible, but failed. Neisser then took some of Hansen's material back home to Germany, where he succeeded in staining M. leprae and claimed precedence as its true discoverer. An unseemly and nationalistic public controversy followed. In time, Hansen's role was acknowledged, while Neisser lent his name to an even less glamorous bacterium. But the fight took its toll on Hansen.

The second episode took place soon afterwards. Hansen knew that the best way to prove conclusively that M. leprae was really the cause of leprosy was to induce the disease in other mammals by inoculating them with leprous material. This proved to be notoriously difficult. (Indeed, it was only achieved in 1960.) Hansen's own father-in-law, D.C. Danielssen, had previously injected leprous nodules into himself, members of his medical staff and patients with other diseases, in order to see what would happen, but with no result. Hansen too injected himself, and made several attempts to inoculate it into human volunteers and rabbits as well. Eventually, after an exchange of letters with Koch, he decided to take tissue from a patient with lepromatous leprosy and inject it into the skin and conjunctivae of two patients with tuberculoid leprosy to see if the different variant of the disease would appear in them.

Nothing serious happened to the patients. However, Hansen was arraigned on a criminal charge of having carried out an operation on one of them without her consent, causing her ‘much anxiety and not inconsiderable pain.’ There was a debate about whether the case should proceed, presumably because Hansen was already a physician of considerable distinction. Nevertheless, the trial took place. In 1880, Hansen was sentenced to lose his hospital post, while being allowed to remain in his role as chief medical officer. He continued his experiments, but only on animals. He did not mention the trial or sentence in his memoirs.

A century and a half later, it is hard to know how harshly to judge Hansen. Looked at in historical terms, he had a precedent for what he did, a credible and humane underlying motive, and possibly the encouragement of the greatest bacteriologist of his time. His crime certainly looks petty by the standards of the twentieth century, when physicians undertook experimentation on psychiatric patients, prisoners and ethnic minorities on a far more horrific scale. Yet at the time, his own countrymen saw him as culpable for what he did. Historians have sustained that verdict since then, by examining the standards of consent that were already current in his home country at the time. Norway seems to have provided the world with a model of medical ethics, as well as public health.

QJM Advance Access published online on June 20, 2007
QJM, doi:10.1093/qjmed/hcm053