ANATOMIC PATHOLOGY

Tissue Eosinophilia: A Morphologic Marker For Assessing Stromal Invasion In Laryngeal Squamous Neoplasms

Mahmoud Said, Sam Wiseman, Jun Yang et al

 

Background: The assessment of tumor invasion of underlying benign stroma in neoplastic squamous proliferation of the larynx may pose a diagnostic challenge, particularly in small biopsy specimens that are frequently tangentially sectioned. Authors studied whether thresholds of an eosinophilic response to laryngeal squamous neoplasms provides an adjunctive histologic criterion for determining the presence of invasion. 

Methods: Eighty-seven (n = 87) cases of invasive squamous cell carcinoma and preinvasive squamous neoplasia were evaluated. In each case, the number of eosinophils per high power field(eosinophils/hpf), and per 10 hpf in the tissue adjacent to the neoplastic epithelium, were counted and tabulated. For statistical purposes, the elevated eosinophils were defined and categorized as: focally and moderately elevated (5–9 eos/hpf), focally and markedly increased (>10/hpf), diffusely and moderately elevated(5–19 eos/10hpf), and diffusely and markedly increased (>20/10hpf). 

Results: In the invasive carcinoma, eosinophil counts were elevated focally and /or diffusely, more frequently seen than in non-invasive neoplastic lesions. The increased eosinophil counts, specifically >10hpf, and >20/10hpf, were all statistically significantly associated with stromal invasion. Greater than 10 eosinophils/hpf and/or >20 eosinophils/10hpf had highest predictive power, with a sensitivity, specificity and positive predictive value of 82%, 93%, 96% and 80%, 100% and 100%, respectively. Virtually, greater than 20 eosinophils/10 hpf was diagnostic for tumor invasion in our series. 

Conclusion: Authors study suggests for the first time that the elevated eosinophil count in squamous neoplasia of the larynx is a morphologic feature associated with tumor invasion. When the number of infiltrating eosinophils exceeds 10/hpf and or >20/10 hpf in a laryngeal biopsy with squamous neoplasia, it represents an indicator for the possibility of tumor invasion. Similarly, the presence of eosinophils meeting these thresholds in an excisional specimen should prompt a thorough evaluation for invasiveness, when evidence of invasion is absent, or when invasion is suspected by conventional criteria in the initial sections.

 BMC Clinical Pathology 2005, 5:1

doi:10.1186/1472-6890-5-1

 

The Evolving Classification Of Soft Tissue Tumours: An Update Based On The New WHO Classification

[REVIEW]

 Fletcher C D M

Tumour classifications have become an integral part of modern oncology and, for pathologists, they provide guidelines which facilitate diagnostic and prognostic reproducibility. In many organ systems and most especially over the past decade or so, the World Health Organization (WHO) classifications have become pre-eminent, partly enabled by the timely publication of new 'blue books' which now incorporate detailed text and copious illustrations. The new WHO classification of soft tissue tumours was introduced in late 2002 and, because it represents a broad consensus view, it has gained widespread acceptance. This review summarizes the changes, both major and minor, which were introduced and briefly describes the significant number of tumour types which have been first recognized or properly characterized during the past decade. Arguably the four most significant conceptual advances have been: (i) the formal recognition that morphologically benign lesions (such as cutaneous fibrous histiocytoma) may very rarely metastasize; (ii) the general acceptance that most pleomorphic sarcomas can be meaningfully subclassified and that so-called malignant fibrous histiocytoma is not a definable entity, but instead represents a wastebasket of undifferentiated pleomorphic sarcomas, accounting for no more than 5% of adult soft tissue sarcomas; (iii) the acknowledgement that most lesions formerly known as haemangiopericytoma show no evidence of pericytic differentiation and, instead, are fibroblastic in nature and form a morphological continuum with solitary fibrous tumour; and (iv) the increasing appreciation that not only do we not know from which cell type(s) most soft tissue tumours originate (histogenesis) but, for many, we do not recognize their line of differentiation or lineage—hence an increasing number of tumours are placed in the 'uncertain differentiation' category. 

Histopathology, Volume 48 Page 3  - January 2006

  

PEComa: what do we know so far?

[REVIEW]

 Hornick J L & Fletcher C D M

PEComas (tumours showing perivascular epithelioid cell differentiation) are a family of related mesenchymal neoplasms that include angiomyolipoma, lymphangiomyomatosis, clear cell 'sugar' tumour of the lung, and a group of rare, morphologically and immunophenotypically similar lesions arising at a variety of visceral and soft tissue sites. These tumours all share a distinctive cell type, the perivascular epithelioid cell or 'PEC' (which has no known normal tissue counterpart). PEComas show a marked female predominance and are composed of nests and sheets of usually epithelioid but occasionally spindled cells with clear to granular eosinophilic cytoplasm and a focal association with blood vessel walls. PEComas appear to arise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and abdominopelvic sites, with a subset occurring in somatic soft tissue and skin. Nearly all PEComas show immunoreactivity for both melanocytic (HMB-45 and/or melan-A) and smooth muscle (actin and/or desmin) markers. A subset of PEComas behave in a malignant fashion. This review examines the members of the PEComa family, with an emphasis on lesions arising outside of the kidney, lung and liver, and discusses preliminary evidence for pathological features that might predict malignant behaviour.

 Histopathology,Volume 48 Page 75  - January 2006
doi:10.1111/j.1365-2559.2005.02316.x

  

The Frozen Section: Pathology in the Trenches

 Juan Lechago

This year marks the 100th anniversary of the seminal publication in JAMA of a report on a successful frozen section preparation technique by Louis B. Wilson from the Mayo Clinic. Indeed, this was not the first time a frozen section was performed and documented: this had happened in Europe for decades during the 19th century on a more or less sporadic manner. It was also not the first time that a frozen section was performed in North America. In 1889, John C. Warren, a surgeon from Massachusetts General Hospital, made reference to examining skin biopsy specimens with the freezing microtome, albeit without detailing the technique. In 1895, James H. Wright, Jr, from McGill Hospital, described a technique for boiling tissues in formalin for a few minutes before freezing them. In 1891, the eminent pathologist from Johns Hopkins Hospital, William H. Welch, performed a frozen section examination of a breast lesion removed by Dr William H. Halsted. Unfortunately, by the time the microscopic diagnosis was rendered, the surgeon had made up his mind regarding the nature of the lesion and completed the operation, which is not an unheard of experience for pathologists, even in modern times. However, the technical quality of most frozen sections during these early years was clearly suboptimal by modern standards. Surgeons such as J. C. Bloodgood, although supporting the concept of the frozen section examination, admitted, in 1908, to not depending on a frozen section to guide the surgical procedure. By the early and mid-1920s, however, a consensus spearheaded by surgeons such as J. C. Bloodgood and W. J. Mayo was taking shape, accepting that intraoperative frozen section diagnosis was a valuable and necessary adjunct to the conduction of surgical operations. In modern times, even though a number of special and histochemical techniques have been proposed on a frozen section basis, most such diagnoses are still rendered on the basis of hematoxylin-eosin–stained tissues.

Although the first users of intraoperative frozen section diagnoses were largely surgeons and obstetricians, it soon became obvious that the experience and knowledge of a trained pathologist were necessities in such settings. Nowadays, a close interaction between pathologist and surgeon is required for the successful conduction of many surgical operations, and such interaction takes place on a daily basis in large and small hospitals. This aspect of the practice of pathology constitutes a veritable “in the trenches” scenario in which clear and prompt communication between surgeon and pathologist is a requisite. In this setting, no opportunity exists for extensive collegial consultation or leisurely perusal of the literature. Assets such as keen eye, deep fund of knowledge, and experience are, indeed, most valuable. However, perhaps the most valuable of such assets is a combination of common sense (the least common of senses, according to an unnamed wag), a clear understanding of the value and limitations of the frozen section, and firmness of character so as not to cave in to occasional excessive, sometimes unrealistic, expectations of the surgeon.

Frozen section examination has a number of indications, such as identification of tissue type, benign versus malignant nature of the tissue, type of malignancy, determination of surgical margins, positivity of lymph nodes, and presence of malignant implants and/or metastases in other tissues. The common denominator of this list is clear: the results will determine the further conduction of the surgical procedure. Otherwise, the setting of frozen tissue examination represents a tradeoff in terms of tissue preservation, extent of sampling, and ability to orient tissues, among other aspects, that results in a suboptimal end product. Curiosity on the part of the surgeon or the patient and need to know the results as soon as possible are definitely not indications for frozen tissue examination; modern tissue handling techniques allow for results using permanent tissue sections early the following day and, sometimes, even the same day. Additionally, contraindications to the use of frozen sections exist, such as small lesions that could be destroyed by the freezing and sectioning, leaving no tissue for a definitive diagnosis with optimally processed tissues, or a situation in which the orientation of the tissues could be distorted to the point where a proper staging of the lesion is compromised during the subsequent observation of the permanent sections. A common situation that must be avoided is the understandable propensity that a conscientious pathologist will have to help by trying to produce a diagnosis at all costs. Sometimes a definitive diagnosis is not possible and a judicious deferral should be the outcome. Sometimes, a generic diagnosis (eg, high-grade malignancy) is the preferred route, rather than trying needlessly to pinpoint the exact nature and/or origin of a lesion. The hallowed principle “primum non nocere” applies to the frozen tissue setting as much as to any other medical situation.

In this issue of Archives of Pathology & Laboratory Medicine, a series of review articles are offered that deal with the frozen section aspects of the main organ and systems. These articles are written by experienced pathologists, most of whom practice their specialty in institutions with a high volume of frozen section consultations, such as The Methodist Hospital and Baylor College of Medicine, both in Houston, Tex. The authors have extracted their cumulative experience and present to us, in each of the articles offered, general aspects, indications, pitfalls, and examples of the most common situations encountered in the practice of the intraoperative consultation using frozen section examination. Each article has a somewhat different flavor, because no systematic format was required from the authors, reflecting the different backgrounds of the writers and the approaches that prevail in different subspecialties. Although books and other publications on frozen section diagnosis have appeared in the past, we believe that no modern, moderately comprehensive picture of the subject has been presented recently. This series of articles attempts to fulfill this perceived need to a significant degree. Clearly, not all subspecialties are represented, and there will be room for expansion in the future. The common approach in this series of articles is to present ideas and methods that may apply to a community practice setting of a general nature, rather than within the ambit of a highly specialized laboratory dealing with a narrow spectrum of disease, such as is found in specialized pediatric, transplantation, or oncologic medical centers. Although clearly of magnificent performance in each of their subspecialties, such medical centers often resort to technology and background knowledge not available in the everyday community or general academic practice.

A parting word regarding the future of the frozen section examination is in order. Much has been said regarding the possible obsolescence of the histologic examination of tissues, as we know it today, with the advent of molecular biology technology. Indeed, such technology represents a marvelous advance that will enable physicians to diagnose and treat patients in a more focused and effective manner and, in general, take medicine to new and wonderful heights. Nonetheless, such histologic examination of tissues still will be necessary to determine that the appropriate material for morphologic and molecular diagnosis is collected. Patients still will need surgery, be it endoscopic, laparoscopic, or thoracoscopic, as the use of minimally invasive and robotic surgery expands daily. During such surgery, the assistance of a “traditional” pathologist to perform an intraoperative consultation will be needed, perhaps more than ever before.

In closing, and on a moderately optimistic note, the author does not believe that the time has arrived to hang the “for sale” sign on our cryostat microtomes.

Archives of Pathology and Laboratory Medicine: Vol. 129,  pp. 1529–1531 ,2005

  

Intraoperative Consultation, Cytologic Preparations, and Frozen Section in the Central Nervous System 

Suzanne Z. Powell, MD

Context: Intraoperative evaluation of lesions in the central nervous system requires the correlation of clinical, radiologic, and histologic data and knowledge of clinicopathologic entities and their common locations. Advances in neuroimaging during the last 20 years have revolutionized the diagnosis and treatment of central nervous system diseases. The diagnosis and treatment of patients have improved because of these changes and have allowed access to regions that were previously inaccessible. These new approaches have placed the pathologist in a key role in the diagnosis and treatment of patients with central nervous system lesions. Assessment of the adequacy of the material, particularly for stereotactic biopsies, is necessary, and a combination of cytologic imprint preparations and frozen sections are often used. This review discusses many of the issues involved in intraoperative consultation and provides a simplified approach to the differential diagnosis of a variety of central nervous system lesions that may be encountered intraoperatively.

Objective: To provide guidelines for and address potential pitfalls in the intraoperative management of the central nervous system.

Data Sources: Author's experience and pertinent literature. 

Conclusions: Careful assessment of the gross specimen coupled with prudent use of frozen sections and cytologic imprint preparations is pivotal to reducing intraoperative error rates and preventing needless anxiety for the patient.

 Archives of Pathology and Laboratory Medicine: Vol. 129, No. 12, pp. 1635–1652, 2005. 

 

 

Clinical Application Of Dynamic Telepathology In Mohs Surgery
Sukal SA, Busam KJ, Nehal KS.

Background: Telepathology is an expanding technology in multiple fields for remote pathology diagnosis and consultation. The use of telepathology in Mohs surgery has been very limited. 

Objective: To describe the clinical experience of using a telepathology system for intraoperative consultations on difficult frozen sections during Mohs surgery.  

Materials and Methods: Intraoperative consultation with a dermatopathologist was obtained using a dynamic telepathology system for all questions arising on frozen sections during Mohs surgery for nonmelanoma skin cancers during a 2-year period.

 Results: The most common reason for consultation was to distinguish basal cell carcinoma from a benign histologic simulant on Mohs frozen sections. Other uses included determining tumor histology and distinguishing inflammation from residual tumor. conclusion: Dynamic telepathology is a useful and convenient adjunct in the Mohs surgery practice for intraoperative consultations on difficult frozen sections.

About Mohs Surgery

Mohs surgery has been shown to be a highly effective treatment for certain types of skin cancer, with a cure rate of up to 99% for certain tumors. Due to the fact that the Mohs procedure is micrographically controlled, it provides the most precise method for removal of the cancerous tissue, while sparing the greatest amount of healthy tissue. For this reason, Mohs surgery may result in a significantly smaller surgical defect and less noticeable scarring, as compared to other methods of skin cancer treatment. The Mohs procedure is recommended for skin cancer removal in anatomic areas where maximum preservation of healthy tissue is desirable for cosmetic and functional purposes. It may also be indicated for lesions that have recurred following prior treatment, or for lesions which have the greatest likelihood of recurrence

 Dermatol Surg. 2005 Dec 1;31(12):1700-1703.

  

Peripheral Frozen Sections: A Treatise on Mohs Surgery

[Review]

Davis, Daniel A, Pellowski, Donna M.

Skin cancer cure rates of 99% can be promised to the patient if the entire peripheral margin of a cutaneous excision is verified to be free of that cancer. Preparing frozen sections to examine only the peripheral margin may seem esoteric to the surgical pathologist. This technique was historically named Mohs' micrographic surgery and is typically performed by a dermatologist in an outpatient clinic, away from the observation of other medical specialists. This treatise provides detailed specifics on how to prepare tissue for peripheral margin evaluation. Along the way, it also provides a brief history of Frederic Mohs' discoveries of the 1930s and how several generations of skin cancer surgeons have refined Mohs' techniques to offer the cutting-edge advantages of the highest cure rates and normal skin sparing.

 Pathology Case Reviews,Volume 10(6), November/December 2005, pp 271-276

 

 

MEDICAL MICROBIOLOGY 

Serological Test Useful for Diagnosis of Latent Visceral Leishmaniasis

DELHI (Reuters Health) Dec 02 - The rapid, low-cost direct agglutination test (DAT) can be used to detect subclinical leishmaniasis in primary care settings, researchers from India report. They hope greater use of the test could contribute to the elimination of visceral leishmaniasis in the country.

Not all those infected with Leishmania donovani go on to develop the disease, Dr. S Bimal and colleagues write in the December issue of Annals of Tropical Medicine and Parasitology.

The paucity of reports on the natural course and diagnosis of latent leishmania infections prompted Dr. S. Bimal from the Rajendra Memorial Research Institute of Medical Sciences from Bihar, in North India, and colleagues to evaluate the role of a direct agglutination test in the early detection of leishmaniasis. The DAT antigen was prepared locally according to established guidelines and used to detect IgM antibodies to Leishmania donovani.

The direct agglutination test was carried out on serum samples from 156 healthy subjects from endemic areas who were close contacts of patients with leishmaniasis, seventy-eight residents of the endemic area not in contact with cases of leishmaniasis, 108 patients with confirmed leishmaniasis and in over 600 controls. The test was repeated again after 6 and 9 months.

Dr. Bimal and colleagues observed that 20 (12.8%) contacts and 29 (37.2%) non-contacts from endemic areas were seropositive for leishmaniasis with titers of over 1:800. None of the controls were seropositive, while over 90% of cases of leishmaniasis were positive, they add.

During follow-up, nine contacts and eight non-contacts remained seropositive after six months, with the numbers declining to seven and one, respectively, after nine months. Among these, seven seropositive contacts and one seropositive non-contact went on to develop leishmaniasis within six months of follow-up, the researchers note.

In endemic areas, the infected population is large in comparison to cases of leishmaniasis, Dr. Bimal and colleagues point out. DAT can be useful in these settings because it is relatively easy to perform in primary care situations, results are available within 24 hours, and because it detects the specific IgM antibodies that are produced early in the course of infection, they explain.

DAT could facilitate early identification of populations at risk and foci of transmission of visceral leishmaniasis in endemic areas, Dr. Bimal and colleagues conclude.

Ann Trop Med Parasitol 2005;99:743-749.

 

Japanese Encephalitis Outbreak Kills 1300 Children In India

Ganapati Mudur

New Delhi

An outbreak of Japanese encephalitis in the northern Indian state of Uttar Pradesh has killed more than 1300 children over the past four months. It has rekindled calls from public health specialists for more intensive efforts to prevent future outbreaks.

Since the first cases in the current outbreak were reported in August, Indian authorities have reported 6171 cases nation-wide, including 5700 cases and 1315 deaths in Uttar Pradesh alone.

"The outbreak in Uttar Pradesh is the longest and most severe in decades," India's health secretary, Prasanna Hota, said last week. "It has not burned itself out yet. But it's going away."

Government officials said early and persistent rain through the monsoon season this year flooded rice fields and provided a breeding environment conducive for Culex tritaeniorhynchus, the species of mosquito that carries the Japanese encephalitis virus from pigs and infects humans through bites.

Although Japanese encephalitis has progressively expanded into new territories in India over the past decade, government figures show that over the past five years the annual number of cases had not exceeded 3000, and annual mortality had always remained below 500.

Uttar Pradesh has seen a steady increase in the number of cases of Japanese encephalitis in recent years. Public health experts believe that fresh outbreaks in areas that have long been classed as high risk zones show a failure in public health measures.

"After an outbreak we typically see just fire fighting," said Pradeep Das, director of the Vector Control Research Centre in Pondicherry. "What we need is a sustained and concentrated effort to prevent future outbreaks," Dr Das said.

Relatively simple steps, such as promoting the use of bed nets, excluding pigs from human habitations, and educating people to avoid going outdoors during the hours when the mosquitoes are most active, have not received adequate investment or resources, Dr Das said.

A government doctor looking into the outbreak said the high numbers of cases and rapid progression to death in some villages seemed to have overwhelmed the medical infrastructure in parts of Uttar Pradesh. In the district of Saharanpur alone 97 villages have been affected.

BMJ  2005;331:1288 (3 December), doi:10.1136/bmj.331.7528.1288-a 

 

BOTTOM LINE                                     

 Nobel Prize in Medicine,  2005  for  H. pylori 

Julie Parsonnet, M.D.

Barry Marshall — the cowinner with Robin Warren of this year's Nobel Prize in Physiology or Medicine for their discovery of Helicobacter pylori — edited a book entitled Helicobacter Pioneers. In it, he collected papers by and about the many physicians who had seen spiral bacteria in the stomach but whose work had languished or been erased from scientific memory. Indeed, the century preceding the publication of Marshall and Warren's first article on H. pylori was peppered with reports from investigators who described seeing helicobacters in human and mammalian gastric mucosa and even curing peptic ulcer disease with antibiotics. The work of these investigators — from France, Poland, Germany, the United Kingdom, the United States, Greece, China, and the Soviet Union — was neither synthesized nor promulgated and was occasionally maligned. One can imagine what Marshall was thinking as he put this book together: "H. pylori was so obvious — how is it that two doctors in Western Australia ended up making this discovery?"

The Nobel committee, in issuing their press release regarding the prize, answered this question succinctly. In delineating the significance of H. pylori, they acknowledged the "prepared mind[s]" and "tenacity" of the new laureates as keys to their success. Unlike Louis Pasteur, who famously said that chance favors only the prepared mind ("Dans les champs de l'observation, le hasard ne favorise que les esprits préparés"), the committee neglected to mention luck.

In  1983,Warren and Marshall noticed the presence of curved bacilli in a gastric biopsy specimen obtained from patiens with active chonic gastritis. Subsequently,these organisms were grown from antral biopsy material. This came about by chance when the cultered plates were left to incubate longer than the usual period over an Easter holiday, thus providing that  fortune favours a prepared mind.

Chance plays a role in all discovery. In his chapter in Helicobacter Pioneers, Warren acknowledges that it would have been very difficult even one decade earlier to make the observations that he and Marshall made. He mentions, in particular, the advent of fiberoptic endoscopy as a key factor in their success. Before modern endoscopy became available, gastric tissue was obtained only at autopsy or on surgical resection. Collected samples typically autolyzed before pathological examination, prohibiting fine inspection of the mucosal surface. When endoscopic biopsy became widely used in the mid-1970s, systematic examination of fine details of gastric mucosa from a cross-section of patients finally became possible. The usefulness of endoscopic biopsy material was further enhanced by the growing accessibility of electron microscopy, which enabled Warren to define the way in which H. pylori became attached to the gastric epithelium. On seeing the microbes clinging to gastric cells, Warren became convinced that the corkscrews were not secondary colonizers of damaged mucosa but, rather, had primary pathogenic significance.

Marshall and Warren's work was serendipitous in nontechnological ways as well. At the beginning of the 20th century, almost every adult in the world and the great majority of children had been infected with H. pylori. Had investigators looked, on autopsy, at the stomachs of patients with ulcer disease and compared them with stomachs without ulcers, they would have seen a similar presence of spiral bacteria. Indeed, H. pylori was so common early in the century that gastritis and gastric preneoplasia were thought to be natural consequences of aging. But thanks to improvements in sanitation and hygiene over the past 100 years, the prevalence of the bacteria has decreased in industrialized countries at a rate as high as 25 percent per decade. This change, paralleled by decreases in the incidence of ulcer and gastric cancer, has allowed investigators to dissect the role of H. pylori in disease. Without these contemporaneous occurrences in the 1970s — the decline of H. pylori and the advent of endoscopy and electron microscopy — it is unlikely that the bacteria's effects could have been discovered.

Yet, presumably, between 1970 and 1983 (the year of Marshall and Warren's seminal letters to the Lancet), thousands of gastroenterologists and pathologists closely inspected the stomach with endoscopic biopsy and even electron microscopy, and only a scattered few recognized the presence of microorganisms. Thus, serendipity alone cannot explain the duo's success; one must acknowledge the role of the "prepared mind" — a mind not only open to new ideas but also informed about the antecedents and the context of its observations. Marshall and Warren were so prepared. Warren was, and is, an expert in gastric pathology and in bacterial staining in pathological specimens. Marshall — who was not yet a gastroenterologist but a registrar in training — was not yet entrenched in the "no acid, no ulcer" dogma of gastroenterologists. Moreover, both he and Warren are natural sleuths with the capacity for focused, hard work.

After Warren proposed to Marshall the idea of a gastric pathogen, they rushed not to publish, but to the library to read new articles and old books. They consulted with experts in bacteriology and gastroenterology. They went to primary sources and analyzed previously collected biopsy specimens. Together, they tenaciously built a body of knowledge surrounding their findings that created a coherent and complete picture. It is understandable, then, how the two were willing and able to stand their ground against the many naysayers who scoffed. Unlike others who had previously seen H. pylori — and those who had challenged them — they were intellectually prepared and armed with facts.

Since the early controversy that raged within the medical establishment (and was amply and ably chronicled in the popular press), H. pylori has become one of the most studied organisms in medicine: more than 22,000 relevant articles have been listed in PubMed since 1983. The organism has provided a fruitful model for understanding bacterial pathogenesis and the molecular intricacies of microbe–host interactions. The microbe and the host communicate through a complex process involving the injection of bacterial components into the host cell through a miniature syringe — its type IV secretion system. The signals that H. pylori then sends to the cells control the structure of the epithelial junctions and the cytoskeleton and may even affect epithelial differentiation, proliferation, and apoptosis. The adverse outcomes of this cross-talk — duodenal ulcer disease, adenocarcinoma, and lymphoma — are not yet completely understood.

The insights that have already been gleaned, however, are certain to be important for similar diseases in other organ systems. Indeed, the discovery of H. pylori has inspired researchers to examine previous convictions with new skepticism and to pursue more aggressively the possibility of infectious causes of myriad chronic diseases, including cancers, rheumatologic diseases, and atherosclerosis. H. pylori has even been used as a tool for studying human evolution and mapping the course of human migrations throughout history.

In short, the clinical and scientific importance of H. pylori has exceeded everyone's wildest expectations. Yet the most important legacy of Marshall and Warren's award may have less to do with science than with the inspiration it should provide to medical practitioners worldwide. This year's Nobel Prize was a prize for clinicians. At the time of their discovery, Warren and Marshall were physicians doing their daily jobs. They were not in the laboratory chasing after the Nobel Prize. They had no intention of being in the limelight. They had no research grants for studying ulcer disease. Rather, they happened upon something interesting, and driven by curiosity, they investigated and reported it. They proved again that we, as physicians, can make groundbreaking discoveries in the course of our clinical practices if we attend to our work with open eyes, a sense of curiosity, a desire to understand, and a willingness to pursue ideas to their completion.

In other words, these two doctors from Western Australia won the Nobel Prize by being exemplars of the great clinician described millennia ago by Hippocrates: "Many and elegant discoveries have been made . . . and others will yet be found out, if a person possessed of the proper ability, and knowing those discoveries which have been made, should proceed from them to prosecute his investigations." May Marshall and Warren inspire others to do likewise.

The New England Journal of Medicine, Volume 353:2421-2423 December 8, 2005, Number 23