REVIEW ARTICLE
The History of Sentinel Lymph Node Biopsy Omgo E. Nieweg, MD, PhD,*†‡§ Roger F. Uren, MD, FRACP, DDU,§k and John F. Thompson, MD, FRACS, FACS*†‡§ Abstract: The sentinel node biopsy technique, developed by Drs Donald Morton and Alistair Cochran and reported in 1992, undoubtedly constitutes the most important recent development in surgical oncology. This article describes the evolution of the procedure and its contribution to the evolution of modern multidisciplinary cancer care and discusses its present role in the management of patients with melanoma, breast cancer, and a wide range of other malignancies. Key Words: Sentinel node biopsy, melanoma, history, review (Cancer J 2015;21: 3–6)
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entinel lymph node biopsy is undoubtedly the most important recent development in surgical oncology. Information obtained from sentinel lymph node biopsy has fundamentally changed our views on lymphatic anatomy and tumor spread via lymphatics. Introduction of the technique has also resulted in more accurate staging, better regional disease control, and improved survival of patients with a wide variety of cancer types. Developed by Donald L. Morton (Fig. 1)1 and Alistair J. Cochran (Fig. 2) and colleagues, details of the procedure were first published in 1992. However, several pieces of the puzzle that Drs Morton and Cochran put together had been discovered earlier— some much earlier. So, although one might expect a history of the sentinel node biopsy technique to begin in 1992 with that landmark publication by Morton and Cochran et al, the purpose of this article is to describe the developments that led up to their initial publication and to consider the place of the procedure in the evolution of the multidisciplinary management of patients with cancer.
Early History—Cancer, Lymph Nodes, and Lymphatic Vessels Like many other important developments in medicine, this one begins with Hippocrates. Although there are descriptions of cancer in ancient Egyptian papyri dating back to about 3000 BC, Hippocrates (ca. 460–370 BC) is believed to have been the one who gave cancer its name. He compared the disease to a crab, Karsinos being the Greek word for crab. Some believe the name was chosen because, like a crab, the disease does not let go once it has got its grip on someone. Another opinion is that the crab’s claws and legs represent the protrusions that are observed when the disease invades surrounding tissue. Lymph nodes were also first described in the age of Hippocrates, and he mentioned a disease course that is consistent with metastasis to lymph nodes.2 From the *Melanoma Institute Australia and †The Mater Hospital, North Sydney; ‡Royal Prince Alfred Hospital, Camperdown; §Sydney Medical School, The University of Sydney; kNuclear Medicine and Diagnostic Ultrasound, Newtown, New South Wales, Australia. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. This article is dedicated to Donald L. Morton who, with his pathologist Alistair J. Cochran, developed the modern sentinel node concept. Dr Morton passed away on January 10, 2014, but his legacy to surgical oncology and to cancer patients worldwide will be enduring. Reprints: Omgo E. Nieweg, MD, PhD, Melanoma Institute Australia, 40 Rocklands Rd, North Sydney, New South Wales, Australia 2060. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1528-9117
Working from the school of anatomy in Alexandria and using live animals, it was Herophilus (300 BC) who first noticed lymphatic vessels terminating in glands in the mesentery and Herasistratus (280 BC) who first described the milky contents of such vessels.3 However, they thought that these were blood vessels. In 1622, Gasparo Aselli,4 a professor of anatomy and surgery in Pavia, Italy, operated on a live dog and rediscovered the mesenteric “lacteals.” He also showed the existence of lymphatic vessels in many other animals. He was the first to study the lymphatic system in a systematic and scientific fashion. However, the vessels were still not called “lymphatics” at this time, and he called them the lacteal veins, postulating that they were important in the absorption of chyle. The discovery of these vessels in humans occurred in 1628, when Gassendi and colleagues examined the abdominal contents of a female patient 1 hour after her death.3 Johann Vessling (1634), Caecilius Folius and Nicolaas Tulp (1639), Wallee (1641), and Jean Pecquet (1649) confirmed the existence of such lymphatic vessels as separate entities from arteries and veins.5 The Danish physician, mathematician, and theologian Thomas Bartholin6 (1616–1680) also studied the lymphatic system and made significant contributions. The Danish king, who supported science, donated 2 corpses of executed criminals for Bartholin’s purpose. The king even attended some of the dissections. Bartholin found the thoracic duct and published his finding in 1652. He perceived the lymphatic system to be a circulation separate from the blood circulation. He also postulated that lymph originated from the blood by filtration. He even gave the lymph vessels their name, “vasa lymphatica.” The word lymph comes from the Latin word lympha, which means clear spring water. Other investigators subsequently mapped the lymphatic system. One of them was Anthony Nuck (1650–1692), a professor of anatomy in Leiden, the Netherlands. He injected mercury mixed with tin and lead into lymphatics to make them visible.7 This proved to be a major step forward in unraveling of the anatomy of the lymphatic system.
The 19th Century The German pathologist Rudolf Virchow8 (1821–1902) was one of the founders of modern medicine. He suggested that lymph nodes function as filters in the lymphatic system. It had long been known that lymph nodes could contain cancer, but how this occurred was still a mystery in the mid 19th century. In 1863, Virchow8 proposed that lymph fluid from any given area of the body drains through lymphatics to a specific lymph node and subsequently to other lymph nodes. This astute observation, we believe, indicates that the history of the sentinel node begins with Virchow.9 His proposal was apparently prompted by the observation that carbon pigment from a small skin tattoo on the arm of a sailor was localized to a single lymph node when he performed an autopsy on this man.9 The French anatomist Marie Philibert Constant Sappey7 studied lymphatics using Nuck’s technique, delineating them with mercury. In 1874, he published an anatomical atlas including a detailed study of cutaneous lymphatics that guided surgeons for over a century (Fig. 3). Based on these findings, clinicians began to recommend that local treatment of cancer should be supplemented with regional node therapy to improve the cure rate. One of these clinicians
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FIGURE 3. Sappey7 described lymphatic drainage patterns. Lymphatic mapping demonstrated that certain sites (e.g., near the midline) may drain to multiple nodal regions, that there may be sentinel nodes outside the convention nodal regions, and that there is substantial interindividual variation.
FIGURE 1. Donald L. Morton.
was the prominent British surgeon Herbert Snow,10,11 who worked at the Cancer Hospital (now the Royal Marsden Hospital) in London, the first cancer center in the world. Snow had a particular interest in melanoma; in fact, he may be considered to have been the world’s first melanomologist. In 1892, Snow published an article in which he advocated elective lymph node dissection in patients with melanoma, and in his article, he mentions the work of Virchow.10,11 Virchow’s findings also inspired the renowned American surgeon William S. Halsted12 from Johns Hopkins Hospital in Baltimore (1852–1922) to develop mastectomy with
en bloc axillary clearance for breast cancer in 1894. Halsted had been to Europe repeatedly and had been in touch with Virchow in Berlin. This is how surgery of the lymphatic system became a major element of surgical oncology. Excision of the primary tumor was combined with regional node surgery for a wide variety of malignancies, including head and neck cancer, breast cancer, melanoma, and tumors of the gastrointestinal tract. Meanwhile, techniques used to visualize lymphatic vessels were modernized by the Romanian physician, anatomist, radiologist, and surgeon Dimitrie Gerota13 (1867–1939). Gerota used a blue dye (Prussian blue) and published his technique (Gerota’s method) in 1896.
The Term “Sentinel Lymph Node”
FIGURE 2. Alistair J. Cochran.
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Morton used the term “sentinel” lymph node in the seminal article published in 1992.1 Understandably, the introduction of the term “sentinel node” has often been attributed to him. It soon became evident, however, that others had used the term earlier. Ramon M. Cabañas14 studied lymph node metastases from penile cancer in the late 1960s. He noted that a lymph node located 4.5 cm lateral from the pubic tubercle was often involved first, and he called this node the “sentinel” node.15 Although Cabañas used the term sentinel node for the first node to be involved, his definition was based on the anatomy of the lymphatic system. This is in contrast to Morton’s definition that was based on the physiology of the lymphatic drainage. For penile cancer, Cabañas’ concept may be a reasonable postulation, because penile cancer is almost always located at the same site on the glans. However, this is different from the variable locations of breast cancers and, even more so, of melanomas. As Morton was not the first person to use the term sentinel node, neither was Cabañas.14 In 1966, Sayegh et al16 had used the term sentinel node to describe the primary node receiving discrete lymphatic drainage from the testis. Even earlier, in 1960, Gould et al17 had used the term to describe a lymph node at the junction of the anterior and posterior facial veins. In a study of © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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parotid cancer, they found that this node was the first one to be involved when a parotid tumor spread, and he designated this node the sentinel node.17,18 A radical neck dissection was performed if frozen section examination revealed metastatic disease in this node. Like Cabañas,14 Gould et al suggested that the sentinel node was defined by its constant anatomic position. However, a careful examination of the English-language literature indicates that the first person to use the term “sentinel” node was the British surgeon Leonard R. Braithwaite, who used a blue dye to study lymph drainage from the omentum in cats and in humans.19 In 1923, Braithwaite20 dripped blue dye onto the omentum. He retrieved the node to which the blue lymphatic drained and called this the “gland sentinel” (Fig. 4).
Blue Dye, Lymphoscintigraphy, and the Gamma Ray Detection Probe The first recorded in vivo use of patent blue dye that is nowadays often used to visualize lymphatic vessels appears to have been by Hudack and McMaster,21 who reported this in 1933. In 1950, Walker22 was the first to use radiotracers to map lymphatic drainage. Following this, in 1953, Sherman et al23 demonstrated that colloidal gold could be traced from the point of intradermal injection to the draining lymph nodes. The first imaging of a radioactive node was by Sage and Gozun24 in New York in 1958 following administration of a colloidal protein labeled with gold-198 in a dog. The images were made with a scanner that moved over the body part, as gamma cameras were not introduced until the 1970s. Lymphoscintigraphy was initially used for evaluation of edema and also for visualization of internal mammary lymph nodes to outline the field for parasternal radiation therapy in patients with breast cancer. The first report of the intraoperative use of a gamma ray detection probe in a patient dates back to 1984.25 This patient, who had a rectal carcinoma, was injected with an iodine 131–labeled antibody against carcinoembryonic antigen. The intensity of gamma radiation registered in the tumor slightly exceeded the intensity in
The History of Sentinel Lymph Node Biopsy
surrounding normal tissue. Attempts were subsequently made to use the device to detect lymph node metastases from colon cancer and to localize bone tumors.
Morton and Cochran As already explained, the concept of a tumor initially disseminating to a specific lymph node was discovered more than a century before the landmark article by Morton and Cochran et al was published in 1992. A number of investigators had already used the term sentinel node, blue dyes had been used to visualize lymphatic vessels, lymphoscintigraphy existed, and there was a portable gamma ray detector that could be used in the operating room. What, then, did Morton and Cochran contribute? Contrary to the prevailing understanding of lymphatic metastasis at this time, these 2 men revived Virchow’s concept of selective lymphatic drainage and proposed that metastatic melanoma progresses in an orderly fashion to the sentinel node, then through the chain of second- or third-tier lymph nodes. They reintroduced Gerota’s13 method to visualize lymphatic drainage. They advanced the understanding of lymphatic metastasis beyond the concepts of Cabañas,14 Sayegh et al,16 Gould et al,17 and Braithwaite,20 which were static and anatomically based, assuming a fixed location of the sentinel node. The new concept proposed and validated by Morton and Cochran was dynamic and based on the physiology of lymphatic drainage, which was found to be quite variable from patient to patient. They also showed that there is often a window of opportunity to operate and remove early nodal metastases before these (and their primary tumor) generate the usually fatal blood-borne metastases at distant sites. So, Morton and Cochran fundamentally changed the way of thinking about lymphatic dissemination, emphasizing that in many patients there is an orderly spread of metastasis from the primary site to sentinel lymph nodes first and then elsewhere via the bloodstream. Their concept fits perfectly with the current goal of providing patients with individualized management and the desire to preserve cosmetic aspects and function. In hindsight, it is not surprising that these 2 men developed the concept. In the era of elective lymph node dissection, it was Donald Morton’s team that introduced lymphoscintigraphy in patients with trunk melanomas to determine the draining node field or fields.26 In 1982, Cochran, a pathologist, demonstrated that the S-100 protein is an exquisitely sensitive marker, able to detect minimal volume melanoma metastases in lymph nodes, an essential element of accurate staging.27 Morton and Cochran began their actual sentinel node studies with animal experiments in the mid-1980s and later expanded their investigations to patients. They presented the results of the first 100 patients at the World Health Organization Melanoma Congress in Venice in 1989. Perhaps because the concept they proposed was considered to be fanciful, it was accepted only as a poster. And there was little interest in their findings (the bigger the miracle, the smaller the audience). Undaunted, they persevered and increased the size of their series of patients. It is a little known fact that they had great difficulty getting their revolutionary findings published. The prominent journal to which the authors initially submitted their manuscript refused to publish it; the reviewers simply did not believe them. A second journal turned it down as well, and it took 2 years before a third journal eventually published this now classic and widely cited article.1
The Development of Surgical Oncology FIGURE 4. Braithwaite dripped a blue dye onto the omentum to study lymph drainage. Reprinted from Braithwaite,20 with permission from The British Journal of Surgery.
The era of modern surgery started in the second half of the 19th century with the development of asepsis and the introduction of anesthesia. The subspecialty of surgical oncology was
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subsequently developed and shaped by pioneers such as Virchow, Snow, and Halsted. The first 100 years were characterized by the development of surgical procedures of ever-greater magnitude. These were considered necessary because of the late stage at which most cancer patients presented. This trend began to reverse about 40 years ago. Since then, operations have tended to become less extensive, to preserve function and minimize cosmetic deformity while not jeopardizing the chance of regional control and survival. These reversed trends have occurred in the treatment of many types of solid malignancies. The now well-accepted sentinel node biopsy technique fits in perfectly with this development, and radical lymph node dissections are now reserved for patients who actually have lymph node metastases. In the era of sentinel node biopsy, many patients with breast cancer, melanoma, or vulval or penile cancer are now spared a node dissection that they do not need because they do not have nodal disease. Staging is more accurate, better prognostic information is obtained, local disease control is improved, and there is persuasive evidence that survival is improved in patients with some cancer types, including melanoma and penile cancer.28,29 ACKNOWLEDGMENT The authors thank Kaye Oakley for her expert assistance in the preparation of the manuscript. REFERENCES 1. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392–399. 2. Karpozilos A, Pavlidis N. The treatment of cancer in Greek antiquity. Eur J Cancer. 2004;40:2033–2040. 3. Hewson W. An Inquiry into the Properties of the Blood. In: Gulliver G, ed. The Works of William Hewson FRS. London: Sydenham Society; 1846. 4. Aselli G. De Lactibus sive Lacteis Venis, Quarto Vasorum Mesarai Corum Genere Invento. Milan, Italy: J. B. Bidellius; 1627. 5. Delamere G, Poirier P, Cuneo B. The lymphatics. In: Charpy PP, ed. A Treatise of Human Anatomy. Westminster, UK: Archibald Constable and Co Ltd; 1903. 6. Bartholin T. De Lacteis Thoracis in Homine Brutisque Nuperrime Observatis. Martzan M, ed. Copenhagen: Hafniae; 1652. 7. Sappey PhC. Anatomie, physiologie, pathologie des vaisseaux lymphatiques considérés chez l'homme et les vertébrés. Paris, France: A. Delahaye et E. Lacrosnier; 1874. 8. Virchow R. Die Krankhaften Geschwulste. Berlin, Germany: August Hirschwald; 1863. 9. Virchow RLK. Cellular Pathology 1859. Special Edition. London: John Churchill; 1978:204–207.
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10. Snow H. Melanotic cancerous disease. Lancet. 1892;ii:872–874. 11. Neuhaus SJ, Clark MA, Thomas JM. Dr. Herbert Lumley Snow, MD, MRCS (1847–1930): the original champion of elective lymph node dissection in melanoma. Ann Surg Oncol. 2004;11:875–878. 12. Halsted WS. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June 1889 to January 1894. Johns Hopkins Hosp Bull. 1894;4:297–323. 13. Gerota D, Zur Technik der Lymphgefassinjection. Eine neue injections Masse für Lymphgefass. Polychrom Inject Anat Anzeiger. 1896;12:216–224. 14. Cabañas RM. El tratamiento ganglionar en el cancer del pene [thesis]. New York: 1975. 15. Cabañas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456–466. 16. Sayegh E, Brooks T, Sacher E, et al. Lymphangiography of the retroperitoneal lymph nodes through the inguinal route. J Urol. 1966;95:102–107. 17. Gould EA, Winship T, Philbin PH, et al. Observations on a ‘sentinel node’ in cancer of the parotid. Cancer. 1960;20:77–18. 18. Tanis PJ, Nieweg OE, Valdés Olmos RA, et al. History of sentinel node and validation of the technique. Breast Cancer Res. 2001;3:109–112. 19. Thompson JF, Stretch JR, Uren RF, et al. Sentinel node biopsy for melanoma: where have we been and where are we going? Ann Surg Oncol. 2004;11(3 Suppl):147S–151S. 20. Braithwaite LR. The flow of lymph from the ileocaecal angle, and its possible bearing on the cause of duodenal and gastric ulcer. Br J Surg. 1923; 11:7–26. 21. Hudack SS, McMaster PD. The lymphatic participation in human cutaneous phenomena. J Exp Med. 1933;57:751–775. 22. Walker L. Localization of radioactive colloids in lymph nodes. J Lab Clin Med. 1950;36:440–449. 23. Sherman AI, Ter-Pogossian M, Tocus EC. Lymph node concentration of radioactive colloidal gold following interstitial injection. Cancer. 1953;6: 1238–1240. 24. Sage HH, Gozun BV. Lymphatic scintigrams: a method for studying the functional pattern of lymphatics and lymph nodes. Cancer. 1958;11:200–203. 25. Aitken DR, Hinkle GH, Thurston MO, et al. A gamma-detecting probe for radioimmune detection of CEA-producing tumors. Successful experimental use and clinical case report. Dis Colon Rectum. 1984;27:279–282. 26. Holmes EC, Moseley HS, Morton DL, et al. A rational approach to the surgical management of melanoma. Ann Surg. 1977;186:481–490. 27. Cochran AJ, Wen DR, Herschman HR, et al. Detection of S-100 protein as an aid to the identification of melanocytic tumors. Int J Cancer J Int Cancer. 1982;30:295–297. 28. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinelnode biopsy versus nodal observation in melanoma. N Engl J Med. 2014; 370:599–609. 29. Kroon BK, Horenblas S, Lont AP, et al. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol. 2005;173:816–819.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The History of Sentinel Lymph Node Biopsy Omgo E. Nieweg, MD, PhD,*†‡§ Roger F. Uren, MD, FRACP, DDU,§k and John F. Thompson, MD, FRACS, FACS*†‡§ Abstract: The sentinel node biopsy technique, developed by Drs Donald Morton and Alistair Cochran and reported in 1992, undoubtedly constitutes the most important recent development in surgical oncology. This article describes the evolution of the procedure and its contribution to the evolution of modern multidisciplinary cancer care and discusses its present role in the management of patients with melanoma, breast cancer, and a wide range of other malignancies. Key Words: Sentinel node biopsy, melanoma, history, review (Cancer J 2015;21: 3–6)
S
entinel lymph node biopsy is undoubtedly the most important recent development in surgical oncology. Information obtained from sentinel lymph node biopsy has fundamentally changed our views on lymphatic anatomy and tumor spread via lymphatics. Introduction of the technique has also resulted in more accurate staging, better regional disease control, and improved survival of patients with a wide variety of cancer types. Developed by Donald L. Morton (Fig. 1)1 and Alistair J. Cochran (Fig. 2) and colleagues, details of the procedure were first published in 1992. However, several pieces of the puzzle that Drs Morton and Cochran put together had been discovered earlier— some much earlier. So, although one might expect a history of the sentinel node biopsy technique to begin in 1992 with that landmark publication by Morton and Cochran et al, the purpose of this article is to describe the developments that led up to their initial publication and to consider the place of the procedure in the evolution of the multidisciplinary management of patients with cancer.
Early History—Cancer, Lymph Nodes, and Lymphatic Vessels Like many other important developments in medicine, this one begins with Hippocrates. Although there are descriptions of cancer in ancient Egyptian papyri dating back to about 3000 BC, Hippocrates (ca. 460–370 BC) is believed to have been the one who gave cancer its name. He compared the disease to a crab, Karsinos being the Greek word for crab. Some believe the name was chosen because, like a crab, the disease does not let go once it has got its grip on someone. Another opinion is that the crab’s claws and legs represent the protrusions that are observed when the disease invades surrounding tissue. Lymph nodes were also first described in the age of Hippocrates, and he mentioned a disease course that is consistent with metastasis to lymph nodes.2 From the *Melanoma Institute Australia and †The Mater Hospital, North Sydney; ‡Royal Prince Alfred Hospital, Camperdown; §Sydney Medical School, The University of Sydney; kNuclear Medicine and Diagnostic Ultrasound, Newtown, New South Wales, Australia. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. This article is dedicated to Donald L. Morton who, with his pathologist Alistair J. Cochran, developed the modern sentinel node concept. Dr Morton passed away on January 10, 2014, but his legacy to surgical oncology and to cancer patients worldwide will be enduring. Reprints: Omgo E. Nieweg, MD, PhD, Melanoma Institute Australia, 40 Rocklands Rd, North Sydney, New South Wales, Australia 2060. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1528-9117
Working from the school of anatomy in Alexandria and using live animals, it was Herophilus (300 BC) who first noticed lymphatic vessels terminating in glands in the mesentery and Herasistratus (280 BC) who first described the milky contents of such vessels.3 However, they thought that these were blood vessels. In 1622, Gasparo Aselli,4 a professor of anatomy and surgery in Pavia, Italy, operated on a live dog and rediscovered the mesenteric “lacteals.” He also showed the existence of lymphatic vessels in many other animals. He was the first to study the lymphatic system in a systematic and scientific fashion. However, the vessels were still not called “lymphatics” at this time, and he called them the lacteal veins, postulating that they were important in the absorption of chyle. The discovery of these vessels in humans occurred in 1628, when Gassendi and colleagues examined the abdominal contents of a female patient 1 hour after her death.3 Johann Vessling (1634), Caecilius Folius and Nicolaas Tulp (1639), Wallee (1641), and Jean Pecquet (1649) confirmed the existence of such lymphatic vessels as separate entities from arteries and veins.5 The Danish physician, mathematician, and theologian Thomas Bartholin6 (1616–1680) also studied the lymphatic system and made significant contributions. The Danish king, who supported science, donated 2 corpses of executed criminals for Bartholin’s purpose. The king even attended some of the dissections. Bartholin found the thoracic duct and published his finding in 1652. He perceived the lymphatic system to be a circulation separate from the blood circulation. He also postulated that lymph originated from the blood by filtration. He even gave the lymph vessels their name, “vasa lymphatica.” The word lymph comes from the Latin word lympha, which means clear spring water. Other investigators subsequently mapped the lymphatic system. One of them was Anthony Nuck (1650–1692), a professor of anatomy in Leiden, the Netherlands. He injected mercury mixed with tin and lead into lymphatics to make them visible.7 This proved to be a major step forward in unraveling of the anatomy of the lymphatic system.
The 19th Century The German pathologist Rudolf Virchow8 (1821–1902) was one of the founders of modern medicine. He suggested that lymph nodes function as filters in the lymphatic system. It had long been known that lymph nodes could contain cancer, but how this occurred was still a mystery in the mid 19th century. In 1863, Virchow8 proposed that lymph fluid from any given area of the body drains through lymphatics to a specific lymph node and subsequently to other lymph nodes. This astute observation, we believe, indicates that the history of the sentinel node begins with Virchow.9 His proposal was apparently prompted by the observation that carbon pigment from a small skin tattoo on the arm of a sailor was localized to a single lymph node when he performed an autopsy on this man.9 The French anatomist Marie Philibert Constant Sappey7 studied lymphatics using Nuck’s technique, delineating them with mercury. In 1874, he published an anatomical atlas including a detailed study of cutaneous lymphatics that guided surgeons for over a century (Fig. 3). Based on these findings, clinicians began to recommend that local treatment of cancer should be supplemented with regional node therapy to improve the cure rate. One of these clinicians
The Cancer Journal • Volume 21, Number 1, January/February 2015
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FIGURE 3. Sappey7 described lymphatic drainage patterns. Lymphatic mapping demonstrated that certain sites (e.g., near the midline) may drain to multiple nodal regions, that there may be sentinel nodes outside the convention nodal regions, and that there is substantial interindividual variation.
FIGURE 1. Donald L. Morton.
was the prominent British surgeon Herbert Snow,10,11 who worked at the Cancer Hospital (now the Royal Marsden Hospital) in London, the first cancer center in the world. Snow had a particular interest in melanoma; in fact, he may be considered to have been the world’s first melanomologist. In 1892, Snow published an article in which he advocated elective lymph node dissection in patients with melanoma, and in his article, he mentions the work of Virchow.10,11 Virchow’s findings also inspired the renowned American surgeon William S. Halsted12 from Johns Hopkins Hospital in Baltimore (1852–1922) to develop mastectomy with
en bloc axillary clearance for breast cancer in 1894. Halsted had been to Europe repeatedly and had been in touch with Virchow in Berlin. This is how surgery of the lymphatic system became a major element of surgical oncology. Excision of the primary tumor was combined with regional node surgery for a wide variety of malignancies, including head and neck cancer, breast cancer, melanoma, and tumors of the gastrointestinal tract. Meanwhile, techniques used to visualize lymphatic vessels were modernized by the Romanian physician, anatomist, radiologist, and surgeon Dimitrie Gerota13 (1867–1939). Gerota used a blue dye (Prussian blue) and published his technique (Gerota’s method) in 1896.
The Term “Sentinel Lymph Node”
FIGURE 2. Alistair J. Cochran.
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Morton used the term “sentinel” lymph node in the seminal article published in 1992.1 Understandably, the introduction of the term “sentinel node” has often been attributed to him. It soon became evident, however, that others had used the term earlier. Ramon M. Cabañas14 studied lymph node metastases from penile cancer in the late 1960s. He noted that a lymph node located 4.5 cm lateral from the pubic tubercle was often involved first, and he called this node the “sentinel” node.15 Although Cabañas used the term sentinel node for the first node to be involved, his definition was based on the anatomy of the lymphatic system. This is in contrast to Morton’s definition that was based on the physiology of the lymphatic drainage. For penile cancer, Cabañas’ concept may be a reasonable postulation, because penile cancer is almost always located at the same site on the glans. However, this is different from the variable locations of breast cancers and, even more so, of melanomas. As Morton was not the first person to use the term sentinel node, neither was Cabañas.14 In 1966, Sayegh et al16 had used the term sentinel node to describe the primary node receiving discrete lymphatic drainage from the testis. Even earlier, in 1960, Gould et al17 had used the term to describe a lymph node at the junction of the anterior and posterior facial veins. In a study of © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Cancer Journal • Volume 21, Number 1, January/February 2015
parotid cancer, they found that this node was the first one to be involved when a parotid tumor spread, and he designated this node the sentinel node.17,18 A radical neck dissection was performed if frozen section examination revealed metastatic disease in this node. Like Cabañas,14 Gould et al suggested that the sentinel node was defined by its constant anatomic position. However, a careful examination of the English-language literature indicates that the first person to use the term “sentinel” node was the British surgeon Leonard R. Braithwaite, who used a blue dye to study lymph drainage from the omentum in cats and in humans.19 In 1923, Braithwaite20 dripped blue dye onto the omentum. He retrieved the node to which the blue lymphatic drained and called this the “gland sentinel” (Fig. 4).
Blue Dye, Lymphoscintigraphy, and the Gamma Ray Detection Probe The first recorded in vivo use of patent blue dye that is nowadays often used to visualize lymphatic vessels appears to have been by Hudack and McMaster,21 who reported this in 1933. In 1950, Walker22 was the first to use radiotracers to map lymphatic drainage. Following this, in 1953, Sherman et al23 demonstrated that colloidal gold could be traced from the point of intradermal injection to the draining lymph nodes. The first imaging of a radioactive node was by Sage and Gozun24 in New York in 1958 following administration of a colloidal protein labeled with gold-198 in a dog. The images were made with a scanner that moved over the body part, as gamma cameras were not introduced until the 1970s. Lymphoscintigraphy was initially used for evaluation of edema and also for visualization of internal mammary lymph nodes to outline the field for parasternal radiation therapy in patients with breast cancer. The first report of the intraoperative use of a gamma ray detection probe in a patient dates back to 1984.25 This patient, who had a rectal carcinoma, was injected with an iodine 131–labeled antibody against carcinoembryonic antigen. The intensity of gamma radiation registered in the tumor slightly exceeded the intensity in
The History of Sentinel Lymph Node Biopsy
surrounding normal tissue. Attempts were subsequently made to use the device to detect lymph node metastases from colon cancer and to localize bone tumors.
Morton and Cochran As already explained, the concept of a tumor initially disseminating to a specific lymph node was discovered more than a century before the landmark article by Morton and Cochran et al was published in 1992. A number of investigators had already used the term sentinel node, blue dyes had been used to visualize lymphatic vessels, lymphoscintigraphy existed, and there was a portable gamma ray detector that could be used in the operating room. What, then, did Morton and Cochran contribute? Contrary to the prevailing understanding of lymphatic metastasis at this time, these 2 men revived Virchow’s concept of selective lymphatic drainage and proposed that metastatic melanoma progresses in an orderly fashion to the sentinel node, then through the chain of second- or third-tier lymph nodes. They reintroduced Gerota’s13 method to visualize lymphatic drainage. They advanced the understanding of lymphatic metastasis beyond the concepts of Cabañas,14 Sayegh et al,16 Gould et al,17 and Braithwaite,20 which were static and anatomically based, assuming a fixed location of the sentinel node. The new concept proposed and validated by Morton and Cochran was dynamic and based on the physiology of lymphatic drainage, which was found to be quite variable from patient to patient. They also showed that there is often a window of opportunity to operate and remove early nodal metastases before these (and their primary tumor) generate the usually fatal blood-borne metastases at distant sites. So, Morton and Cochran fundamentally changed the way of thinking about lymphatic dissemination, emphasizing that in many patients there is an orderly spread of metastasis from the primary site to sentinel lymph nodes first and then elsewhere via the bloodstream. Their concept fits perfectly with the current goal of providing patients with individualized management and the desire to preserve cosmetic aspects and function. In hindsight, it is not surprising that these 2 men developed the concept. In the era of elective lymph node dissection, it was Donald Morton’s team that introduced lymphoscintigraphy in patients with trunk melanomas to determine the draining node field or fields.26 In 1982, Cochran, a pathologist, demonstrated that the S-100 protein is an exquisitely sensitive marker, able to detect minimal volume melanoma metastases in lymph nodes, an essential element of accurate staging.27 Morton and Cochran began their actual sentinel node studies with animal experiments in the mid-1980s and later expanded their investigations to patients. They presented the results of the first 100 patients at the World Health Organization Melanoma Congress in Venice in 1989. Perhaps because the concept they proposed was considered to be fanciful, it was accepted only as a poster. And there was little interest in their findings (the bigger the miracle, the smaller the audience). Undaunted, they persevered and increased the size of their series of patients. It is a little known fact that they had great difficulty getting their revolutionary findings published. The prominent journal to which the authors initially submitted their manuscript refused to publish it; the reviewers simply did not believe them. A second journal turned it down as well, and it took 2 years before a third journal eventually published this now classic and widely cited article.1
The Development of Surgical Oncology FIGURE 4. Braithwaite dripped a blue dye onto the omentum to study lymph drainage. Reprinted from Braithwaite,20 with permission from The British Journal of Surgery.
The era of modern surgery started in the second half of the 19th century with the development of asepsis and the introduction of anesthesia. The subspecialty of surgical oncology was
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Nieweg et al
subsequently developed and shaped by pioneers such as Virchow, Snow, and Halsted. The first 100 years were characterized by the development of surgical procedures of ever-greater magnitude. These were considered necessary because of the late stage at which most cancer patients presented. This trend began to reverse about 40 years ago. Since then, operations have tended to become less extensive, to preserve function and minimize cosmetic deformity while not jeopardizing the chance of regional control and survival. These reversed trends have occurred in the treatment of many types of solid malignancies. The now well-accepted sentinel node biopsy technique fits in perfectly with this development, and radical lymph node dissections are now reserved for patients who actually have lymph node metastases. In the era of sentinel node biopsy, many patients with breast cancer, melanoma, or vulval or penile cancer are now spared a node dissection that they do not need because they do not have nodal disease. Staging is more accurate, better prognostic information is obtained, local disease control is improved, and there is persuasive evidence that survival is improved in patients with some cancer types, including melanoma and penile cancer.28,29 ACKNOWLEDGMENT The authors thank Kaye Oakley for her expert assistance in the preparation of the manuscript. REFERENCES 1. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392–399. 2. Karpozilos A, Pavlidis N. The treatment of cancer in Greek antiquity. Eur J Cancer. 2004;40:2033–2040. 3. Hewson W. An Inquiry into the Properties of the Blood. In: Gulliver G, ed. The Works of William Hewson FRS. London: Sydenham Society; 1846. 4. Aselli G. De Lactibus sive Lacteis Venis, Quarto Vasorum Mesarai Corum Genere Invento. Milan, Italy: J. B. Bidellius; 1627. 5. Delamere G, Poirier P, Cuneo B. The lymphatics. In: Charpy PP, ed. A Treatise of Human Anatomy. Westminster, UK: Archibald Constable and Co Ltd; 1903. 6. Bartholin T. De Lacteis Thoracis in Homine Brutisque Nuperrime Observatis. Martzan M, ed. Copenhagen: Hafniae; 1652. 7. Sappey PhC. Anatomie, physiologie, pathologie des vaisseaux lymphatiques considérés chez l'homme et les vertébrés. Paris, France: A. Delahaye et E. Lacrosnier; 1874. 8. Virchow R. Die Krankhaften Geschwulste. Berlin, Germany: August Hirschwald; 1863. 9. Virchow RLK. Cellular Pathology 1859. Special Edition. London: John Churchill; 1978:204–207.
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10. Snow H. Melanotic cancerous disease. Lancet. 1892;ii:872–874. 11. Neuhaus SJ, Clark MA, Thomas JM. Dr. Herbert Lumley Snow, MD, MRCS (1847–1930): the original champion of elective lymph node dissection in melanoma. Ann Surg Oncol. 2004;11:875–878. 12. Halsted WS. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June 1889 to January 1894. Johns Hopkins Hosp Bull. 1894;4:297–323. 13. Gerota D, Zur Technik der Lymphgefassinjection. Eine neue injections Masse für Lymphgefass. Polychrom Inject Anat Anzeiger. 1896;12:216–224. 14. Cabañas RM. El tratamiento ganglionar en el cancer del pene [thesis]. New York: 1975. 15. Cabañas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456–466. 16. Sayegh E, Brooks T, Sacher E, et al. Lymphangiography of the retroperitoneal lymph nodes through the inguinal route. J Urol. 1966;95:102–107. 17. Gould EA, Winship T, Philbin PH, et al. Observations on a ‘sentinel node’ in cancer of the parotid. Cancer. 1960;20:77–18. 18. Tanis PJ, Nieweg OE, Valdés Olmos RA, et al. History of sentinel node and validation of the technique. Breast Cancer Res. 2001;3:109–112. 19. Thompson JF, Stretch JR, Uren RF, et al. Sentinel node biopsy for melanoma: where have we been and where are we going? Ann Surg Oncol. 2004;11(3 Suppl):147S–151S. 20. Braithwaite LR. The flow of lymph from the ileocaecal angle, and its possible bearing on the cause of duodenal and gastric ulcer. Br J Surg. 1923; 11:7–26. 21. Hudack SS, McMaster PD. The lymphatic participation in human cutaneous phenomena. J Exp Med. 1933;57:751–775. 22. Walker L. Localization of radioactive colloids in lymph nodes. J Lab Clin Med. 1950;36:440–449. 23. Sherman AI, Ter-Pogossian M, Tocus EC. Lymph node concentration of radioactive colloidal gold following interstitial injection. Cancer. 1953;6: 1238–1240. 24. Sage HH, Gozun BV. Lymphatic scintigrams: a method for studying the functional pattern of lymphatics and lymph nodes. Cancer. 1958;11:200–203. 25. Aitken DR, Hinkle GH, Thurston MO, et al. A gamma-detecting probe for radioimmune detection of CEA-producing tumors. Successful experimental use and clinical case report. Dis Colon Rectum. 1984;27:279–282. 26. Holmes EC, Moseley HS, Morton DL, et al. A rational approach to the surgical management of melanoma. Ann Surg. 1977;186:481–490. 27. Cochran AJ, Wen DR, Herschman HR, et al. Detection of S-100 protein as an aid to the identification of melanocytic tumors. Int J Cancer J Int Cancer. 1982;30:295–297. 28. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinelnode biopsy versus nodal observation in melanoma. N Engl J Med. 2014; 370:599–609. 29. Kroon BK, Horenblas S, Lont AP, et al. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol. 2005;173:816–819.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
