A Voice From the Past: Rediscovering the Virchow Node With Prostate-specific Membrane Antigen-targeted 18 F-DCFPyL Positron Emission Tomography Imaging (2018)

More than 150 years ago, German pathologist Rudolf Ludwig Karl Virchow (1821-1901) described the finding of the involvement of the left supraclavicular node in gastric cancer.1Virchow R.L.K. Zur diagnose der krebse im unterleibe.Med Reform. 1848; 45: 248Google Scholar It is now known that a number of abdominal and thoracic malignancies have a propensity to metastasize to this anatomic site, which is commonly referred to as Virchow node. Cancers known to spread to Virchow node include malignancies of the lung, pancreas, and esophagus, and adenocarcinoma of the gastric corpus, kidney, ovary, testicle, stomach, corpus uteri, cervix uteri, colon, and rectum.2Viacava E.P. Pack G.T. Significance of supraclavicular signal node in patients with abdominal and thoracic cancer—a study of one hunded and twenty-two cases.Arch Surg. 1944; 48: 109-199Crossref Google Scholar Metastasis to Virchow node has also been reported in men with prostate cancer; however, this has generally been observed at a low frequency of only 0.5%.3Lopez F. Rodrigo J.P. Silver C.E. et al.Cervical lymph node metastases from remote primary tumor sites.Head Neck. 2016; 38: E2374-E2385Crossref PubMed Scopus (53) Google Scholar In recent years, positron emission tomography (PET) radiotracers targeting prostate-specific membrane antigen (PSMA), including 68Ga-PSMA-11 and 18F-DCFPyL, have been increasingly used to image men with prostate cancer.4Rowe S.P. Gorin M.A. Allaf M.E. et al.PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges.Prostate Cancer Prostatic Dis. 2016; 19: 223-230Crossref PubMed Scopus (100) Google Scholar, 5Gorin M.A. Pomper M.G. Rowe S.P. PSMA-targeted imaging of prostate cancer: the best is yet to come.BJU Int. 2016; 117: 715-716Crossref PubMed Scopus (16) Google Scholar PET imaging with these agents offers greatly improved sensitivity over conventional imaging modalities for detecting low volume sites of tumor burden.6Rowe S.P. Macura K.J. Mena E. et al.PSMA-based [(18)F]DCFPyL PET/CT is superior to conventional imaging for lesion detection in patients with metastatic prostate cancer.Mol Imaging Biol. 2016; 18: 411-419Crossref PubMed Scopus (154) Google Scholar, 7Pyka T. Okamoto S. Dahlbender M. et al.Comparison of bone scintigraphy and 68Ga-PSMA PET for skeletal staging in prostate cancer.Eur J Nucl Med Mol Imaging. 2016; 43: 2114-2121Crossref PubMed Scopus (253) Google Scholar Because of the outstanding sensitivity afforded by PSMA-targeted PET, it can be directly visualized that many patients with advanced prostate cancer can harbor disease within Virchow node (Fig. 1).3Lopez F. Rodrigo J.P. Silver C.E. et al.Cervical lymph node metastases from remote primary tumor sites.Head Neck. 2016; 38: E2374-E2385Crossref PubMed Scopus (53) Google Scholar, 7Pyka T. Okamoto S. Dahlbender M. et al.Comparison of bone scintigraphy and 68Ga-PSMA PET for skeletal staging in prostate cancer.Eur J Nucl Med Mol Imaging. 2016; 43: 2114-2121Crossref PubMed Scopus (253) Google Scholar, 8Aggarwal R.R. Cooperberg M.R. Ngyuen H.G. et al.Incidence of intrathoracic (IT) metastases detected by 68Ga-PSMA-11 PET in early stage prostate cancer (PC).J Clin Oncol. 2017; 35: 5056Google Scholar, 9Gorin M.A. Rowe S.P. Patel H.D. et al.Prostate specific membrane antigen targeted 18F-DCFPyL positron emission tomography/computerized tomography for the preoperative staging of high risk prostate cancer: results of a prospective, phase II, single center study.J Urol. 2017; 199: 126-132Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 10Afshar-Oromieh A. Hetzheim H. Kratochwil C. et al.The theranostic PSMA ligand PSMA-617 in the diagnosis of prostate cancer by PET/CT: biodistribution in humans, radiation dosimetry, and first evaluation of tumor lesions.J Nucl Med. 2015; 56: 1697-1705Crossref PubMed Scopus (260) Google Scholar This observation has served as an opportunity to re-explore the exemplary life and career of Rudolf Ludwig Karl Virchow. Remembered as the most influential pathologist in the 19th century, Virchow was also famous as a liberal politician and as one of the leaders of the “Deutsche Fortschrittspartei” (German Progressive Party), the liberal political movement in Germany. In a time of competing political ideologies including nationalism, socialism and conservatism, the “Progressive Party” led the opposition to the constitutional forces of the Prime Minister of Prussia, Otto von Bismarck. However, because of his role in the 1848 “Märzrevolution” (March Revolution), Virchow was finally forced to leave Berlin and was subsequently appointed as the first Chair of Pathological Anatomy at the University of Würzburg in 1849.11Turk J.L. Rudolf Virchow—father of cellular pathology.J R Soc Med. 1993; 86: 688-689PubMed Google Scholar, 12Byers 3rd., J.M. Rudolf Virchow—father of cellular pathology.Am J Clin Pathol. 1989; 92: S2-S8PubMed Google Scholar Five years later, the Charité Berlin reassigned him as the first Chair of Pathological Anatomy and Physiology due to his increasing international popularity and reputation.11Turk J.L. Rudolf Virchow—father of cellular pathology.J R Soc Med. 1993; 86: 688-689PubMed Google Scholar, 13Ackerknecht E.H. Rudolf Virchow: Doctor, Statesman, Anthropologist. The University of Wisconsin Press, Madison1953Google Scholar, 14Silver G.A. Virchow, the heroic model in medicine: health policy by accolade.Am J Public Health. 1987; 77: 82-88Crossref PubMed Scopus (27) Google Scholar Known as the father of cellular pathology, Virchow established the journal “Archiv für pathologische Anatomie und Physiologie und für klinische Medizin” in a close collaboration with his friend Benno Reinhardt (1819-1852). Pursuing the goal of transforming the esoteric medicine in Germany to a scientific discipline, this journal is still with us today and is now known as “Virchows Archiv”, the official journal of the European Society of Pathology.15Newerla J.G. Benno Reinhardt, 1919-1852—a biographical study and a contribution to the early history of Virchows archiv.N Engl J Med. 1939; 221: 419-423Crossref Google Scholar As a broadly influential thinker of his day, Virchow's career in social science remains equally as remarkable as his work in medicine. More specifically, he is credited with founding the newspaper “Die medicinische Reform” (Medical Reform), popularizing the term “social medicine,” and promoting the concept of physicians serving as “attorney(s) of the poor.” One of his most famous contributions in medical literature is the “Report on Typhus Epidemic in Upper Silesia.” Asked by the Education Minister of Prussia, Virchow investigated the 1848 typhus epidemic in Upper Silesia (now within the borders of Poland) and stated that Prussian authorities had failed in preventing the outbreak of this devastating disease. Outlining a revolutionary program, Virchow emphasized the urgent need for improvement of social conditions in this area, which are democratic self-government, disestablishment of the Catholic Church, and agricultural cooperatives.16Azar H.A. Rudolf Virchow, not just a pathologist: a re-examination of the report on the typhus epidemic in Upper Silesia.Ann Diagn Pathol. 1997; 1: 65-71Crossref PubMed Scopus (5) Google Scholar, 17Taylor R. Rieger A. Medicine as social science: Rudolf Virchow on the typhus epidemic in Upper Silesia.Int J Health Serv. 1985; 15: 547-559Crossref PubMed Scopus (70) Google Scholar, 18Brown T.M. Fee E. Rudolf Carl Virchow: medical scientist, social reformer, role model.Am J Public Health. 2006; 96: 2104-2105Crossref PubMed Scopus (73) Google Scholar Another example of his contribution to social medicine is his report “Reinigung und Entwässerung Berlins” in which, through a combination of political power and scientific knowledge, he pushed the construction of the first sewer system of Berlin.19Virchow R.L.K. Reinigung und Entwässerung Berlins: General–Bericht über die Arbeiten der Städtischen Gemischten Deputation für die Untersuchung der auf die Kanalisation und Abfuhr Bezüglichen Fragen.1873Google Scholar With close to 2000 publications, Virchow has made major contributions to the field of cellular pathology and should be remembered for the introduction of certain medical terms that are still used today; Virchow defined the term “embolus” along with its thrombosis mechanism, the word “amyloid” and its reaction with iodine and sulphuric acid in the brain, and the term “granuloma.”11Turk J.L. Rudolf Virchow—father of cellular pathology.J R Soc Med. 1993; 86: 688-689PubMed Google Scholar, 20Klippe H.J. Kirsten D. Andree C. [Rudolf Virchow (1821-1902) and the origin of the term “Granuloma”].Pneumologie. 2016; 70: S122-S127Crossref PubMed Scopus (3) Google Scholar, 21George D.R. Whitehouse P.J. D'Alton S. Ballenger J. Through the amyloid gateway.Lancet. 2012; 380: 1986-1987Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Indisputably, the first description of an enlarged supraclavicular lymph node involved in metastatic malignancies dates back to Virchow. In 1848, he outlined in his article “Zur Diagnose der Krebse im Unterleibe“ (Fig. 2):…namentlich bei Krebsen des Magens, des Pankreas, der Eierstöcke, etc., wie sich der Prozess allmählich von den Lymphdrüsen des Unterleibs auf die im hinteren Mediastinum neben dem Ductus thoracicus gelegenen Drüsen fortsetzt und endlich bis auf die Jugulardrüsen fortkriecht, welche rings um die Einmündungsstelle des Ductus thoracicus (in der linken Supraclavicular-Grube…1Virchow R.L.K. Zur diagnose der krebse im unterleibe.Med Reform. 1848; 45: 248Google Scholar This part has been translated by Morgenstern in 1979:…Thus, particularly in cancer of the stomach, the pancreas, the ovaries, etc. the process gradually spreads from the glands of the lower abdomen to the glands in the posterior mediastinum along the ductus thoracicus and finally involves the jugular glands around the junction of the ductus thoracicus (in the left supraclavicular fossa)….22Morgenstern L. The Virchow-Troisier node: a historical note.Am J Surg. 1979; 138: 703Abstract Full Text PDF PubMed Scopus (37) Google Scholar In 1889, Charles-Emile Troisier (1844-1919) also reported on the findings in 27 cases of gastric carcinoma and noted a palpable, hard, left supraclavicular node being present.23Troisier C.E. L'adenopathie sus-claviculaire dans les cancers de l'abdomen.Arch Gén de Méd. 1889; 1 (297-309): 129-138Google Scholar It has been thought that the cancerous enlargement of the left supraclavicular node at the junction of the thoracic duct and the left subclavian vein, and the tendency of gastric carcinoma to metastasize toward this region are related to tumor emboli migration through the thoracic duct. The thoracic duct is a continuation of the cisterna chyli at the L1 level, which then enters the thoracic cavity through the aortic hiatus and continues in the posterior mediastinum between the aorta and azygos vein.24Siosaki M.D. Souza A.T. Images in clinical medicine. Virchow's node.N Engl J Med. 2013; 368: e7Crossref PubMed Scopus (9) Google Scholar The duct drains lymphatic fluid into the angle of the left subclavian and internal jugular veins. The end node of the thoracic duct is the so-called Virchow node and is located near or at this jugulo-subclavian venous junction.25Mizutani M. Nawata S. Hirai I. Murakami G. Kimura W. Anatomy and histology of Virchow's node.Anat Sci Int. 2005; 80: 193-198Crossref PubMed Google Scholar The involvement of the Virchow node by metastasis can be seen in several types of cancer. Viacava and Pack investigated 4365 patients suffering from abdominal and thoracic tumors and found an enlarged Virchow node in 2.8% of the patients.2Viacava E.P. Pack G.T. Significance of supraclavicular signal node in patients with abdominal and thoracic cancer—a study of one hunded and twenty-two cases.Arch Surg. 1944; 48: 109-199Crossref Google Scholar The highest frequency was observed in patients suffering from cancers of the lung, pancreas, esophagus, kidney, ovary, testicle, stomach, prostate, corpus uteri, cervix uteri, and rectum.2Viacava E.P. Pack G.T. Significance of supraclavicular signal node in patients with abdominal and thoracic cancer—a study of one hunded and twenty-two cases.Arch Surg. 1944; 48: 109-199Crossref Google Scholar Despite its first description more than 150 years ago, the underlying anatomy of the thoracic duct end node has just been investigated more recently. More specifically, in 2005, Mizutani et al found that the thoracic duct is divided into 3-10 several collateral ducts and these ducts surround the Virchow node.25Mizutani M. Nawata S. Hirai I. Murakami G. Kimura W. Anatomy and histology of Virchow's node.Anat Sci Int. 2005; 80: 193-198Crossref PubMed Google Scholar The first description of the pathologic enlargement of the left supraclavicular node in gastric cancer was provided by Virchow in 1848. A number of other malignancies are now known to spread to this anatomic site. Whereas prostate cancer has not classically been thought to have a propensity for metastasizing to the Virchow node, advances in molecular imaging have revealed the contrary. The prevalent involvement of the Virchow node in prostate cancer has likely been underestimated in the past due to our inability to effectively characterize non–pathologically enlarged lymph nodes in this patient population. More than one and a half centuries after its first description, this in vivo detection of supraclavicular lymphadenopathy using prostate molecular imaging emphasizes the importance of the insightful and visionary work of Dr. Virchow. Further studies on the nature of the prostate cancer cells that are disseminated to the Virchow node may shed light on the mechanism of prostate cancer metastases, the transition from the oligometastatic to the polymetastatic state, and the tumor microenvironment needed to maintain prostate cancer cells within this unique lymph node. However, if one might consider a molecular imaging approach to obtain specimen from the Virchow node (eg, by performing PET-guided biopsies), the costs for those types of studies have to be taken into account and the risk should be balanced against the clinical need.