Perspectives in Pathology - Human Pathology

Perspectives in Pathology Siegfried Oberndorfer: Origins and Perspectives of Carcinoid Tumors IRVIN M. MODLIN, MD, PHD, FACS, MICHAEL D. SHAPIRO, BS, AND MARK KIDD, PHD Carcinoid tumors are rare, indolent neoplasms that, although clinically well defined, are regarded as exotic and are consequently often unrecognized. Although little is known of the lives of the men who defined the tumor, described its distinct histology and cell type, and delineated the clinical hallmarks of the disease even less is known of the pathobiology of the lesion. In the nineteenth century, T. Langhans (1839-1915), O. Lubarsch (1860-1933), and W. B. Ransom (1860-1909) described unusual tumors in the small bowel but each failed to adequately investigate these novel entities. This responsibility fell to Siegfried Oberndorfer (1876-1944), who became the first to adequately characterize the nature of the tumors and refer to them as “benign carcinomas.” During his tenure at the Pathological Institute of the University of Munich, Oberndorfer noted in 1907 that the lesions were distinct clinical entities and named them “karzinoide” (“carcinoma-like”), emphasizing in particular their benign features. In 1929 he amended his classification to include the possibility that these small bowel tumors could be malignant and also metastasize. Although the enterochromaffin cell, the carcinoid cell of origin, had been identified as early as 1897 by N. Kulchitsky (1856-1925), it was not until 1953 that F. Lembeck (1922–) established that such cells synthesized and secreted serotonin—a potent bioactive amine. There-

after the protean clinical effects of serotonin, including “flushing,” were recognized as was the associated relationship of carcinoid heart disease (Bio¨rck in 1952) and fibrosis (Moertel in 1961). As the centennial of the observations of Oberndorfer approaches, it should be noted that the legacy of one of Germany’s most distinguished pathologists, teachers, and scientists (whose career fell victim to the machinations of the Third Reich) has been largely unrecognized. Similarly, the biology and mechanistic analysis of these lesions remain to a large extent unexplored. The present article describes the contributions of the clinical and scientific pioneers in the elucidation of carcinoid disease and traces the evolution of the discovery and understanding of carcinoid tumor biology. It also serves to memorialize the extraordinary accomplishments of Oberndorfer, whose vision exceeded his times. HUM PATHOL 35:1440-1451. © 2004 Elsevier Inc. All rights reserved. Key words: carcinoid, chromogranin A, neuroendocrine, Oberndorfer, serotonin. Abbreviations: 5-HT, 5-hydroxytryptamine; 5-HTP, 5-hydroxytrytophan; APUD, amine precursor uptake and decarboxylation; DNES, diffuse neuroendocrine system; EC, enterochromaffin; ECL, enterochromaffin-like.

Carcinoid tumors are usually relatively slow-growing, indolent neuroendocrine neoplasms that sometimes behave in a highly malignant fashion, exhibiting profuse metastatic behavior, most often to the liver and lungs. They are the most common primary neoplasm of the small bowel. Tumors usually present with flushing, diarrhea, liver metastases, or small bowel obstruction, due usually to peritumoral peritoneal fibrosis. Indeed, the diagnosis of carcinoid lesions is often an incidental finding in patients undergoing laparotomy or small bowel resection for intestinal bleeding, obstruction, or inexplicable perforation. Some patients present with the classical carcinoid syndrome, characterized by flushing, diarrhea, bronchoconstriction, and edema, or exhibit carcinoid heart disease, most commonly presenting as right-sided heart failure caused by subendocardial valvular fibrosis.

Even with ever-increasing recognition and understanding of carcinoid tumors,1 the memory of the pathologist who first described this clinical entity has faded into near obscurity. Siegfried Oberndorfer was a pioneer in the field of carcinoid tumor biology, and his early scientific contributions to the elucidation of carcinoid tumors provided the foundation of the disease process.

From the Gastric Pathobiology Research Group, Department of Surgery, Yale University School of Medicine, New Haven, CT. Accepted for publication September 15, 2004. Address correspondence and reprint requests to Irvin M. Modlin, MD, PHD, FACS, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208062, New Haven, CT 06520-8062. 0046-8177/$—see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2004.09.018

SIEGFRIED OBERNDORFER Siegfried Oberndorfer was born in Munich, Germany on June 24, 1876, the second son of successful real estate buyers in the Altstadt, the older part of Munich. He spent his youth in Munich and obtained his medical degree from the University of Munich in 1900. Oberndorfer initially demonstrated his interest in pathology while spending a term of medical school in Kiel (1898), where he studied with his first pathology mentor, A. Heller (1840-1913). He cultivated this interest by serving as an assistant at the Pathological Institute of the University of Munich from 1902 to 1906, where he was further influenced by his coassistant, Hermann Du¨rck (1869-1941). In 1906, Oberndorfer made his first significant contribution to the field of pathology, a study of chronic appendicitis,2 and was also appointed as Lecturer of Pathological Anatomy at the Munich

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FIGURE 1. Dr. Siegfried Oberndorfer (1876-1944) (bottom left) first presented his observations of multiple “benign carcinomas” of the small intestine at the German Pathological Society meeting of 1907. Whereas he initially asserted that the tumors were benign, he modified this description 22 years later in 1929, and thereafter conceptually embraced the malignant potential of the disease.

Hospital Institute of Pathology under the supervision of H. Albrecht (1866-1922). The subsequent year was spent at the Pathological Institute of Geneva with F. Zahn (1845-1904), and it was during this sojourn in Switzerland that he completed and submitted his seminal manuscript properly describing carcinoid tumors of the small intestine (Fig 1). EARLIER OBSERVATIONS Although Oberndorfer was first to coin the term “carcinoid” and describe the idiosyncratic nature of these tumors, such lesions had in fact been observed and documented earlier, during the nineteenth century, by a number of physicians, including Langhans

(1867),3 Lubarsch (1888),4 and Ransom (1890).5 Theodor Langhans of Usinger, Germany, a former pupil of F. Recklinghausen (1833-1910), was the first to describe a carcinoid tumor.3 The lesion had been identified at autopsy in a 50-year-old woman who had perished of tuberculosis. Langhans described a firm, mushroomshaped submucosal tumor that projected into the lumen of the small intestine, and commented on the very sharp borders without any evidence of peritumoral invasion (Fig 2). In addition, he commented on the histological nature of the tumor cells, which he described as resembling poorly differentiated glandular tissue arranged in “nests” with a rich, thick fibrous stroma. His manuscript, published in 1867, focused chiefly on the histological features of the tumor and did

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FIGURE 2. In 1867, Theodor Langhans (1839-1915) (bottom right), from the University of Bern (background), published the first report of a carcinoid tumor found at autopsy in the small intestine of a 50-year-old woman (frontispiece, above left). Langhans also made significant contributions to the pathology of nephritis, drawing attention to the giant cell, which came to be known as the Langhans cell (lower right multinucleated cell of histological inset).

not address the clinical and growth behavior of this previously undocumented neoplasm. So although Langhans had described the gross and microscopic nature of a novel lesion, another 21 years would pass before this obscure and unexplained entity was revisited by Otto Lubarsch. Lubarsch, of Berlin (Fig 3), studied philosophy and natural sciences in Leipzig and Heidelberg and later studied medicine in Jena, Berlin, Heidelberg, and Strasbourg, where he earned a doctorate in 1883. He began his career as an assistant at the Institute of Physiology in Bern and conducted most of his early research in various institutes of pathology throughout Switzerland. In 1888, the 28-year-old Lubarsch described 2 cases of ileal tumors discovered at autopsy.4 In 1 case (a 49-year-old male), the ileum contained numerous tubercular ulcers and tubercular nodules on the mucous membrane; the second case (a 52-year-old male), which also was tubercular, was marked by 6 scattered small carcinomatous growths in the ileum and a cirrhosed liver. Interestingly, diarrhea had been a prominent symptom in the latter patient, quite possibly as a manifestation of carcinoid syndrome, although Lubarsch

made no mention of metastatic disease in either case. Microscopically, he noted a low-grade penetration of the tumor into the muscularis circularis and hyperplasia of the adjacent muscularis mucosae. To his credit, the prescient Lubarsch was reluctant to identify these lesions as carcinomas! In a careful search of the literature, he evaluated the records of 35 cases of intestinal carcinomas occurring near the ileocecal valve and opined that in his estimation, several of these were not “true” carcinomas. William Bramwell Ransom of Nottingham, England was the third to describe a lesion resembling carcinoid tumors.5 In the November 1890 issue of The Lancet, Ransom described a case involving a 50-year-old woman who initially presented with 2 egg-sized lumps in the lower part of her abdomen, menorrhagia, and severe diarrhea. Her symptomatology was attributed mainly to uterine fibroids, and her symptoms had improved only somewhat by the time she left the hospital several weeks later. The diarrhea persisted for the next 2 years, at which time the patient presented with a large, palpable abdominal mass and distinct cachexia. Of particular interest was the observation of severe

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FIGURE 3. In 1888, Otto Lubarsch (1860-1933) (top right) of the Institute of Physiology in Bern (top background) was among the first to provide a detailed pathological description (bottom left, lower background) of carcinoid tumors, reporting multiple ileal carcinoid tumors at autopsy in 2 male patients (frontispiece, center).

attacks of wheezing and diarrhea on eating, arguably the first reported sign of carcinoid syndrome. After the patient’s death soon thereafter, autopsy revealed several small nodules in the ileum located 6 inches above the ileocecal valve, as well as extensive hepatic tumors (presumably metastases). The nodules were walnutsized, and histologically the tumor demonstrated rounded, polypoid growth patterns without any ulceration or macroscopic changes to the mucosa. Ransom noted that the tumor cells were arranged in small nests that formed small tubes or solid bars, and scarcely any remains of villi or crypts of Lieberku¨hn were visible near the free surfaces of the tumor. As with the 2 cases described by Lubarsch, Ransom also noted hyperplasia of the adjacent muscularis mucosae. In addition, he astutely commented that these tumors resembled carcinomas only histologically and “may remain undetected for a long time. . .these tumors demonstrate very slight, local malignancy or tendency to infiltrate or destroy their surrounding tissues.” In concluding his remarks, Ransom proposed that the tumors’ malignant potential largely depends on local conditions (ie, vas-

cular supply and resistance) of the peritumoral tissues and referred to the lesions as “glandular carcinomas,” although their peculiar appearance, caused by penetrating blood vessels into the tumor, led him to propose a resemblance to cylindromas (uncommon benign adnexal tumors). In fact, he believed this angiogenesis was more consistent with the behavior of sarcomas than with carcinomas. But Ransom could only speculate on the etiology of these tumors, and he drew no definitive conclusions. In 1895, A. Notthafft, an assistant at the Pathological Institute of Wu¨rzburg, described 3 tumors of the upper jejunum found at autopsy in a patient who had died of pneumonia.6 The first pinhead-sized tumor was found approximately 10 cm past the end of the duodenum. The second and third tumors, both pea-sized, were found 10 cm and 15 cm distal to the first tumor, respectively. They had a whitish color and a hard consistency with a smooth surface. Notthafft noted rampant tumor growth in the submucosa, which rose strongly over the level of the adjacent mucous membrane, and small cellular infiltration in much of the

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adjacent mucous membranes and into the muscular layer. The tumors were uncharacteristically identified in the submucosa and histologically were not true carcinomas; Notthafft thus referred to them as “beginning carcinomas.”6 The carcinoid tumor then faded into obscurity once more, and 12 more years passed before Oberndorfer’s initial attempt to characterize and delineate the properties of this enigmatic neoplasm was presented. KARZINOIDE AND OBERNDORFER Oberndorfer first presented his observations on carcinoid tumors at the German Pathological Society convention in Dresden, September 1907. In December of that same year, he published his seminal paper, “Carcinoid Tumors of the Small Intestine,” in the Frankfurt Journal of Pathology.7 This manuscript was the first to describe and characterize the tumor that had previously been referred to as a “benign carcinoma.” Oberndorfer’s first case described a 48-year-old woman who had been presumed to have died from tuberculosis. Autopsy found 4 pea-sized tumors in the ileum; the first 3 of these tumors were separated by approximately 20 cm along the intestine, and the fourth was only 1 cm distal to the third. All the tumors were found in the submucosa. The surrounding intestinal mucosa and neighboring serosa revealed no reactive inflammation. The histological findings were consistent with those described by previous authors, in that the lesions were arranged in nests of small polymorphic cells with large nuclei and scant cytoplasm; there were distinguishable, albeit atrophic, crypts of Lieberku¨hn; and dense, fibrous connective tissue composed of the surrounding stroma and rampant epithelial vascular growth was adjacent to the tumor. The mucosa and muscularis mucosae were completely intact, and no cellular infiltration of the tumor into the surrounding stroma could be observed. In addition, noticeable changes of the liver, kidney, and spleen were observed; these organs all exhibited high-grade amyloid degeneration, although whether these findings could be attributed to metastatic carcinoid disease or to tuberculosis was unclear. Oberndorfer’s second case involved a 30-year-old woman who died of typhoid fever soon after giving birth. At autopsy, 3 small (pea-sized) tumors were found in the ileum. The first and second tumors were separated by approximately 30 cm, and the third tumor was about 40 to 50 cm distal to the second tumor. The surrounding stroma of each tumor comprised connective tissue and smooth muscle fibers, and proliferation of glandular epithelium was noted. Oberndorfer reported similar findings in 4 more cases, and noted some general trends. All tumors were located in the submucosa of the ileum, the normal elements of the mucosa (particularly the crypts of Lieberku¨hn) were almost completely absent, and the stromal tissue consisted of smooth muscle fibers and

connective tissue. Oberndorfer remarked that he considered it peculiar to observe multiple primary malignant tumors in the same organ, particularly because he could determine with a relatively high degree of certainty that the multiple lesions were not metastases. As a result of his observations, Oberndorfer ascribed 5 distinct characteristics to these tumors: 1. They are mostly small, with patients commonly demonstrating multiple tumors. 2. The tumor cells are usually surrounded by undifferentiated tissues, possibly demonstrating gland formation. 3. The tumors have not previously been described, and they have the potential to become invasive. 4. They do not metastasize. 5. They apparently grow extremely slowly, achieving no substantial size, and therefore appear to have a harmless nature. Given these tumors’ “aberrant” characteristics, Oberndorfer asserted that such tumors could not be categorized as any other small intestinal neoplasm and represented a novel disease entity. Although 5 of the 6 cases demonstrated undifferentiated tumor cells that would generally be regarded as carcinomas, Oberndorfer recognized that their clinical behavior was inconsistent with that of a “classical” carcinoma and concluded that these lesions were a completely different clinical entity. He argued that large carcinomas of the small intestine were extremely rare and noted that he had never observed multiple large carcinomas of the small intestine. He further asserted that a multiplicity of large identical tumors in the small intestine had not previously been reported, and the considerable distance between the tumors suggested that they were each primaries, because “metastatic hematogenous or lymphatic spread could not account for the observed findings.” He further reasoned that if the tumors were to be considered as multiple primary carcinomas of the intestine, they must adhere to the 3 criteria proposed by Michelsohn8 in that (1) the new formations must differ from each other morphologically and histologically, (2) each carcinoma must be histogenetically derived from the epithelium of the mucosa, and (3) every tumor must have the potential to metastasize. According to Oberndorfer, only the second criterion was fulfilled, and the third criterion was omitted because metastases were not detectable in the cases he had examined. Furthermore, these tumors’ slow-growing tendency distinguished them from the rapid, highly invasive nature of carcinomas. Of paramount importance to Oberndorfer was the need to determine whether these tumors were actually true cancers. Although their histological appearance was consistent with a malignant process, their clinical features suggested otherwise; they did not demonstrate rapid growth, their borders were sharply circumscribed, and they did not metastasize. Given that the classical understanding of a carcinoma did not appear to encompass the behavior of the processes that he observed in these tumors, Oberndorfer reasoned that perhaps

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the term karzinoide (“carcinoma-like”) more accurately described the lesions. Although Oberndorfer’s early contributions to the understanding of the biology of carcinoid tumors were prescient, his assertion that the tumors were of a benign nature subsequently proved to be incorrect. However, in 1929, 22 years after first characterizing the carcinoid tumor, Oberndorfer described his further experience with 36 carcinoid tumors of the appendix and small intestine.9 He revised his initial characterization of the tumor’s benign behavior and confirmed the possibility that karzinoide might exhibit malignant features and metastasize.9 CELL OF ORIGIN: ENTEROCHROMAFFIN CELL Although progress had been made in elucidating the pathological nature of this “odd” tumor of the small intestine, there was a paucity of information available regarding this tumor’s origin. W. M. Bayliss (18601924) and E. H. Starling (1866-1927) provided the first scientific evidence that the gut was an endocrine organ in 1902.10 But much earlier, in 1868, R. P. Heidenhain (1834-1897) of Breslau, Prussia found enterochromaffin (EC) cells in the gastric mucosa, and in 1870 he first noted the existence of enterochromaffin-like (ECL) cells, although he was not able to define their role.11 He noted that such cells, distinguishable by their deepyellow stain from bichromate solutions, were simply morphologically different to other intestinal mucosal epithelial cells. In 1897, Russian Nikolai Kulchitsky noted similar cells in the crypts of Lieberkuhn in the intestinal mucosa. Similar observations were made by A. Nicolas (1891),12 H. Kull (1924),13 and M. C. Ciaccio,14 who introduced the term “enterochromaffin” in 1906. In 1914, A. Gosset (1872-1944) and P. Masson (18801959), using silver impregnation techniques, demonstrated the argentaffin-staining properties of carcinoid tumors15 (Fig 4) and suggested that these neoplasms might arise from EC cells. Subsequent studies demonstrated that carcinoid tumor cells indeed displayed characteristic light microscopy and histochemical features in their reactions with silver salts (eg, argentaffinity and argyrophilia). In 1938, Friederich Feyrter (1895-1973), Professor of Pathology at the Medical Academy of Danzig, Poland, proposed that carcinoid tumors were derived from the diffuse endocrine system.16 He based this proposal on the observation of argentaffin-positive and argyrophilic “clear cells” (helle zellen) throughout the gut and pancreas that failed to take up conventional stains.17 By 1948, A. B. Dawson had developed a technique by which EC and ECL cells of the gastrointestinal tract could be stained with silver nitrate.18 Serotonin, or 5-hydroxytryptamine (5-HT), was described and isolated by M. Rapport in 1948.19 In 1952 V. Erspamer and B. Asero of Milan, both working in the Department of Pharmacology at the University of Bari, isolated 5-HT in the EC tissues of Octopus and Discoglossus and suggested

that serotonin (“enteramine”) was the specific hormone of the EC cell system.20 The Octopus vulgaris, a common native polyp, and the Discoglossus pictus, an amphibian of Sicily and Sardinia, were both readily available and particularly useful because their tissues and organs were especially rich in enteramine. In 1953, F. Lembeck (1922- ) of Graz biochemically confirmed the presence of 5-HT in an ileal carcinoid tumor,21 corroborating the assumption that human EC cells contained this bioactive amine. In 1963, E. D. Williams and M. Sandler proposed the original classification of carcinoid tumors based on their putative embryologic origin (ie, foregut, midgut, or hindgut).22 In 1971, J. Soga and Y. Yakuwa introduced a histological classification based purely on morphological characteristics, describing carcinoid tumors according to their dominant growth pattern: insular, trabecular, glandular, mixed, or undifferentiated.23 Although carcinoid tumors have historically been classified according to the foregut, midgut, or hindgut derivation, this stratification was developed before the elucidation of the different NE cell types and the appreciation that an embryologic classification had little mechanistic or physiological validity.24 Unfortunately, this historical classification predates the understanding of the different cell types responsible for the broad group of tumors generically grouped as carcinoids and has hindered the appreciation of the divergent biological and pathological behavior of the individual tumors and the various secreted peptides and amines. Broadly speaking, it has been accepted that foregut endocrine cells give rise to carcinoid tumors in the respiratory tract, stomach, first part of the duodenum, and pancreas; midgut carcinoid tumors represent lesions of the bowel from the second part of the duodenum through the ascending colon and appendix; and hindgut carcinoids constitute lesions of the transverse and descending colon and rectum. Carcinoid tumors from different segments of the embryologic gut typically vary widely in terms of the character of their bioactive products, and the differences in secreted agents engender diversity in symptoms and immunohistochemical staining patterns. The variations in anatomic location and venous drainage may further alter clinical presentations; thus midgut tumors most commonly produce serotonin and tachykinins, which cause systemic symptoms (diarrhea, flushing, wheezing, right-sided valvular disease, and cutaneous telangiectasia), but usually only after metastasis to the liver or in rare instances after drainage directly into the systemic circulation. In 1966, Anthony Pearse (1916-2003) recognized that the endocrine cells of the gut were linked together by a group of common cytochemical characteristics; in particular, the uptake of 5-hydroxytrytophan (5-HTP) and its decarboxylation to 5-HT was analogous in this distinct population of endocrine cells.25 By 1968, these peptide hormone-producing cells, all of which derived from the neural crest, were collectively known as amine precursor uptake and decarboxylation (APUD) cells.26 Since that time, the definition of these cells has been modified somewhat,

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FIGURE 4. In 1914, Pierre Masson (bottom left) and A. Gosset (top right), using the eponymous trichrome stain (background), demonstrated the argentaffin-staining properties of carcinoid tumors (frontispiece, center). They suggested that the EC cells in the gut (lower left granulated cell in top left image; bottom right cell labeled “a”) formed a diffuse endocrine organ. In 1928, they described these cells as being of neural origin, and proposed that they were the progenitors of neuroendocrine tumors of the gut (carcinoids).

and they are now known as the diffuse neuroendocrine system (DNES) (Fig 5). Although Pearse and others initially suggested that APUD cells were derived from neural crest cells, it is now generally recognized that gastroenteropancreatic APUD cells probably arise from endoderm.27 Indeed, Le Douarin and Dupin28 subsequently demonstrated the multipotency of neural crest cells and proposed that enteric gangliogenesis by neural crest cells reflected the effects of multiple growth factors of the glial-derived neurotrophic factor family, as well as the endothelin-3/endothelin receptor B pathway. More recently, Chalazonitis et al29 reported that differentiation of various types of enteric neurons is also regulated by neurotrophin-3. CARCINOIDS AND CLINICIANS The collection of symptoms including, but not limited to, edema, flushing, and diarrhea, now com-

monly referred to as the “carcinoid syndrome,” was first described in 1931 by A. J. Scholte, a Dutch pathologist who documented at autopsy a 1- cm ileal carcinoid tumor in a 47-year-old male who had suffered from diarrhea, cyanosis, cough, lower extremity edema, and cutaneous telangiectasia before dying from cardiac failure and bronchopneumonia.30 Of particular note was Scholte’s observation of hard thickening of the tricuspid valves and irregular endocardial thickening of the right atrium, likely representing the first documentation of carcinoid heart disease. In the same year, M. A. Cassidy reported a patient who complained of flushing and diarrhea before dying; autopsy revealed the presence of metastatic “adenocarcinoma” and cardiac valvular lesions.31 Although Cassidy did not provide adequate histological descriptions of the tumor tissue to confirm that these lesions were carcinoids, his manuscript included a picture of the patient’s face that clearly illustrates a flushed appearance consistent with

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FIGURE 5. The first description of the DNES was provided in 1938 by Friedrich Feyrter (left), who recognized the presence of argentaffin or argyrophil “clear cells” (helle zellen) in the gut and pancreas, and proposed that such cells were the source of hormones that acted locally (frontispiece, top left). In the 1960s, A. G. Everson Pearse (1916-2003) (bottom right) demonstrated that the cells described by Feyrter shared the ability to metabolize amines and the secretion of peptides and were thus conveniently described by the acronym APUD (amine precursor uptake and decarboxylation) (bottom center).

the carcinoid syndrome (Fig 6). In 1943, S. Millman described a 44-year-old female patient with flushing who on autopsy was found to have multiple ileal carcinoids with metastatic spread to the liver and lymph nodes.32 In 1954, A. Thorson and colleagues33 of Malmo¨, Sweden published the first series of patients presenting with pulmonary stenosis, tricuspid insufficiency, peripheral vasomotor symptoms, bronchoconstriction, and cyanosis in association with malignant carcinoid tumors of the small intestine with metastases to the liver. The initial report of Thorson et al presented 7 “definite” cases, 4 “probable” cases, and 5 cases with partial or not fully verified symptoms were presented, and their symptomatology related to hypersecretion of 5-HT from the carcinoid tumors into the systemic circulation.33 In the same year, B. Pernow and J. Waldenstro¨m, also of Sweden, added paroxysmal flushing as a key component of this syndrome.34 In 1964, J. A. Oates demonstrated that some carcinoid

tumors release kallikrein (which activates bradykinin, a potent vasodilator), and suggested that kallikrein also might play a role in the flushing episodes so characteristic of the disease.35 In 1952, G. Bio¨rck described carcinoid heart disease in a 19-year-old boy suffering from pulmonary stenosis with tricuspid insufficiency and cyanosis.36 The patient was dyspneic at rest and died while undergoing an angiogram, with electrocardiography demonstrating slow contractions of a very broad bundle branch block type. Autopsy revealed a malignant carcinoid in the jejunum with extensive hepatic metastases. This report was among the first to describe both pulmonary stenosis and tricuspid insufficiency in the presence of carcinoid tumors. Carcinoid heart disease is a unique and dangerous component of EC tumors. It represents a serious clinical condition, and 1/3 of all deaths in patients with carcinoid syndrome are related to right ventricular failure second-

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FIGURE 6. The clinical manifestations of carcinoid disease were first described in 1952 by Bio ¨ rck and colleagues (frontispiece, top center), when they characterized by a constellation of symptoms (bottom center) including flushing (top right), diarrhea, edema, wheezing, and right-sided heart failure, the latter of which results from the deposition of fibrotic subendocardial plaques (bottom left; fibrotic plaques stained pink) and is commonly referred to as “carcinoid heart disease.” This syndrome is associated with abnormally high levels of the seratonin metabolite 5-HIAA (center).

ary to cardiac morphological changes (ie, stenosis of the tricuspid and pulmonary valve)37. The lesions, located on the mural and valvular endocardium predominantly in the right side of the heart, consist of fibroblasts or myofibroblasts and a matrix-rich fibrous stroma devoid of elastic fibers covered by endothelium.38 Right-sided valve dysfunction is attributed to the presence of carcinoid plaques, which cause both thickening and retraction of the valve.39 Cardiac surgery for carcinoid heart disease may improve symptoms and longevity, but the scarce data report an early mortality of 35% to 53%.40,41 More recently, the use of hepatic artery embolization to impede the progression of carcinoid heart disease failed to prevent the development of cardiac lesions.42 In 1954, the utility of 5-HT as a plasma marker for carcinoid disease was demonstrated by I. H. Page, based on his observation of elevated urinary excretion of the main 5-HT metabolite, 5-HIAA, in a patient with carcinoid syndrome.43 Subsequently, in 1956 B. J. Haverback and A. Sjoerdsma confirmed this finding in a series of 11 patients with carcinoid syndrome, each of whom displayed markedly elevated levels of urinary 5-HIAA over a 24-hour period.44 In 1957, B. Pernow of

Stockholm conclusively proved this point by measuring serum 5-HT and urinary 5-HIAA levels in 33 patients with abdominal carcinoid tumors.45 Among the patients examined before operation or underwent complete tumor resection, increased serum or urinary 5-HT levels were noted in 17 of 18 cases, and abnormally high 5-HIAA levels were found in 19 of 20 cases. In 1961, C. Moertel et al46 first described the unique relationship between carcinoids and fibrosis. These authors reported that once carcinoid tumors become invasive, they seem to stimulate a considerable fibroblastic reaction within the peritoneum, mesentery, and retroperitoneum, as well as in the lungs and cardiac valves. ANSCHLUSS AND EXODUS Oberndorfer spent 22 years (1911-1933) as Professor of Pathological Anatomy at the Munich-Schwabing Hospital’s Pathological Institute and was recognized as a distinguished teacher and mentor to many generations of young physicians. During this time he enjoyed a most productive career and made several noteworthy

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scientific contributions including in 1918 a recount of his experiences as an army pathologist during the First World War. In 1931, he published an impressive representation of the pathology of the internal male sex organs in the Manual of Pathological Anatomy,47 thereby confirming his oft-repeated avowal that his greatest intellectual interest involved the pathological changes associated with tumor growth. In particular, Oberndorfer documented with meticulous precision the effects of trauma, radium, and radiation on the growth of testicular tumors. In March of 1938, Hitler announced in Linz the legislation underpinning the anschluss (annexation) of Austria into the German Reich and as a consequence all German and Austrian persons of non-Aryan descent were deprived of civil rights and their property expropriated. As a consequence Oberndorfer left Germany and immigrated to Turkey, where he spent 10 extraordinarily productive years as Professor of General and Experimental Pathology in Istanbul. During his exile he wrote a textbook of general pathology (in Turkish), established a fine reputation as teacher, expanded the Institute of Pathology and in 1938 founded the Institute for Cancer Research of Turkey. Thereafter Oberndorfer wrote yet another textbook on tumors, but shortly after its completion died in 1944 and was interred in Istanbul. PERSPECTIVES Although nearly a century has passed since Oberndorfer first recognized the distinctive properties of this class of endocrine tumors and dubbed them karzinoides, the diagnosis and management of such lesions still remains as challenging as the elucidation of their pathogenesis and biology.48 Although carcinoid tumors of certain organs, particularly those of the gastrointestinal tract, have garnered an abundance of interest, identification of the specific cells of origin in each area is uncertain. Indeed, apart from the ECL cell of the stomach and the EC cell of the ileum, there is little certainty regarding the characteristics of the progenitor cell in various organs. Initiation of the lesions particularly in the small bowel is intriguing, because the high incidence of multicentricity implies either exposure to a luminal event or an underlying field defect without clonality. Certainly, gastric carcinoids are gastrindriven, based on increased luminal pH in the atrophic stomach,49 whereas the high incidence of appendiceal carcinoids in an organ with a sequestered lumen argues for a mucosal event as an inciting factor. Although the chimeric nature of the tumor cells has been recognized by the expression of both neural and endocrine markers (chromogranin, neuron-specific enolase), precise determinants of cell lineage and phenotype remain to be identified. Similarly, the fundamental mechanisms of growth regulation of neuroendocrine cells remain for the most part as ill defined as the nature of their diverse bioactive secretory products. Apart from serotonin, various bradykinins and tachykinins, including sub-

stance P, there is little known of the regulatory agents produced by these cells or the precise explanation as to which are responsible for vasoactive events, increased intestinal secretion and motility, or the genesis of the oft-associated local or distant fibroblastic proliferation.50 Similarly, the growth factors responsible for the generation of metachronous or synchronous adenocarcinomas are unknown, although transforming growth factor-␣ and various putative growth regulatory agents, including intrinsic growth factor, have been postulated.51 The mechanistic reason why the growth rate of most carcinoids is indolent and so different from adenocarcinomas is utterly unclear and has been little investigated. Similarly, the nature of metastatic spread in this disease and the ability to determine its likelihood is largely unexplored, although Ki-67 and markers of cell proliferation have been of some utility in this respect.52 Identification of the overexpression of somatostatin subtype 2 receptors by “carcinoid” tumor cells has facilitated identification of the tumors by diagnostic radioisotope imagery, and the subsequent efficacy of receptor-targeted therapy (somatostatin analogues) has provided a method for decreasing the secretion of bioactive products and decreased symptomatology.53 Lacking, however, is the identification of specific growth regulatory targets, such as cell-specific tyrosine kinases, that would facilitate the arrest of neuroendocrine cell proliferation. One suspects that as 2004 passes, Oberndorfer might be disappointed that his original great pathological observation remains to be capitalized on. A slowgrowing lesion with known growth factors and measurable secretory products with both local and distant effects must surely represent the Rosetta stone of neoplasia. The elucidation of the enigma of carcinoid tumors, rather than the pattern recognition of postoperative pathological diagnosis, should become the mantra of the next generation of pathologists. CONCLUSION As a reputable and accomplished German physician in good professional standing, Oberndorfer might have expected that his outstanding contributions to the study of pathology would have earned him international respect and well-deserved recognition as well as laying the foundations for the elucidation of a novel area of tumor biology. Unfortunately, the circumstances of his era and the quixotic nature of his pathological observations resulted in his scientific life being shrouded in the penumbra of the intellectual demise of German medical science and an aura of stasis enveloping the new class of tumors that he had identified. Nor you, ye Proud, impute to these the fault If Memory o’er their tomb no trophies raise . . . .54 Although the unique observation of karzinoide and the introduction of the nomenclature “carcinoid” have stood the test of time, little is known

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about the life of this man, and the lesion that he described remains almost as enigmatic now as when he initially proposed it as a pathological entity. As interest in carcinoid tumors amplifies with the advance of molecular studies and the elucidation of its secreted chemical regulators and growth factors, it is useful to remember the early and erudite observations by Oberndorfer. In his original 1907 manuscript, Oberndorfer presciently noted that carcinoids are “certainly more frequent, as the reports in the literature leave us to assume” and that these tumors are “certainly not so rare. . .I am convinced that if more attention is paid to them in the future, then its number will rapidly increase”. These prophetic observations hold true nearly a century after his pioneering work. If a disease and its elucidation may be considered a living monument to its discoverer, then the contributions of Oberndorfer to medical science have been well served. Acknowledgment. We thank Dr. Walter L. Castrillo´nOberndorfer (Siegfried Oberndorfer’s grandson) and Dr. Ulrike Zuluaga, both of Tu¨bingen, Germany, for their invaluable assistance in providing us with information about Dr. Oberndorfer. We also thank Dr. Axel Bauer of Heidelberg for providing information about Dr. Gosset and Dr. Lembeck, and Dr. Jochen Schaefer for his diligent assistance with translation of German texts.

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