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Original Article |
Professor of Surgery, Brown Medical School Interim Director, Comprehensive Breast Center, Rhode Island Hospital 593 Eddy Street, APC 4 Providence, RI 02903, United States
Correspondence: Address correspondence and reprint requests to: Blake Cady, MD; E-mail: bcady{at}usasurg.org
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONTHE EVOLUTION AND PHYSIOLOGY...SUMMARYREFERENCES |
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Appreciating lymphatic system embryology, anatomy, and physiology is necessary for understanding lymph node metastases. The primary lymphatic system function was to return interstitial fluid to the circulation. Later evolutionary insertion of lymphocyte collections in lymph nodes interrupting lymph flow completed a system of analyzing external antigens to enable adaptive immunologic responses. Human cancers seldom elicit major immunological responses; they are not generally "foreign" enough. Therefore, lymphatic metastases have little meaning in evolutionary terms.
Organ specificity of both lymphatic and distant metastases occurs as metastatic cells lie dormant, but grow selectively only in liver, lung, bone, or lymph nodes. These organ specific metastatic cells have little ability to produce different organ site clinical metastases.
Thus, laboratory findings and clinical correlations emphasize that surgical lymph node removal should be de-emphasized or omitted. More physiological approaches to the highly manipulable multi-step processes of clinical metastases arising from host microenvironments will eventually prevail.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTHE EVOLUTION AND PHYSIOLOGY...SUMMARYREFERENCES |
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Regional lymph node metastases have always been of concern to surgeons since they are usually removed as part of the primary cancer resection, and the presence or absence of lymph node metastases frequently foretell in statistical probability the future risk or current presence of distant vital organ metastases. Thus, surgeons have focused their clinical energies on removing and analyzing lymph nodes and their research interest in understanding the relationship of lymph node metastases to distant organ metastases and survival. In contemporary surgical reports of cancers from a variety of organs, surgeons frequently continue to assume that lymphatics have the primary role as the principal pathway for the cancer to spread to other distant sites, a biological view espoused 100 years ago by Halsted in breast cancer,8 Moynihan in colorectal cancer,9 and Snow in melanoma,10 However, critical appraisal of the massive amount of clinical and laboratory research indicates metastatic cells probably spread simultaneously via lymphatics and/or hematogenously. Lymph node metastases that are manifestations of the lymphatic route are by themselves non-lethal, as regional lymph nodes do not contribute an essential life sustaining function. Uncommon exceptions occur in the lymphatics (not lymph nodes) where lethal lymphangitic pulmonary carcinoma may cause death; such extensive lymphatic vessel spread also may occur locally in inflammatory breast cancer, "en-curassé " chest wall recurrent breast cancer, primary linitis plastica gastric cancer, or extensive lymphatic vessel involvement in melanoma. By secondary narrowing of an adjacent hollow lumen, lymph node metastases themselves occasionally contribute to death such as with biliary, esophageal, bronchial, or ureteral obstruction. This assumption of non-lethal behavior confirms and elaborates laboratory conclusions regarding the lymphatic metastatic process and provides the rationale for adapting a far more restrictive role for the surgical approach to lymph node resection.11 Recent research also elaborates the metastatic cascade to more distant vital organs2–6 as well as lymph nodes1 and suggests similar metastatic mechanisms and phenomenon seen in regional lymph nodes (usually excised) and in vital organs (not initially removed), and thus suggests a commonality to metastatic development.
Ultimately, of course, lymph flows into the vascular system through the thoracic duct or lymphovascular shunts in more peripheral regions; thus, the eventual path of circulating cancer cells to distant organs is via the general circulation to illustrate the eventual common pathway. Although this discussion will focus on breast and other cancers as clinical models of lymphatic and distant organ metastases generally, conclusions can be applied to all lymphatic and other distant metastases based on extensive animal and clinical research.
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THE EVOLUTION AND PHYSIOLOGY OF THE LYMPHATIC SYSTEM |
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Lymph nodes are also porous organs that allow passage of cells and antigens to prevent obstruction.7,13,15 They are not millipore filters, which would rapidly fill, obstruct lymph flow, and cause edema in tissues or limbs. When radio labeled tumor cells are injected into the afferent nodal lymphatic vessel, they rapidly appear in the efferent lymphatic vessel and in the thoracic duct.15 Thoracic duct cannulation with selective removal of lymphocytes and return of lymph produces immuno-incompetence, and in the past permitted successful human organ transplantation. Currently, this elimination of lymphocyte immunological function in organ transplantation is replicated by use of anti-lymphocyte globulin, Thymoglobulin® (Sangstat), Campath® (ILEX Pharmaceuticals), or a host of lymphocyte depleting or inactivating drugs, or interruption of the dendritic cell antigen delivery system.16,17 It may well be that some cancers utilize "immune escape" mechanisms by cytokine interaction to avoid lymphatic trapping and antibody production.
Thus, while the original evolutionary purpose of the lymphatic system was to return interstitial fluids and nutrients to the circulation, the insertion of lymph node lymphocytes into the lymph flow completed a system of analyzing antigens (viral, bacterial, parasitic, chemical) from the hostile external environment, enabling a multilayered immunologic defensive response. Lymph nodes do not have, as a basic evolutionary function, the capturing, and immunologic response to cancer cells, which in general are not originally "foreign" in the sense of representing an external non-host substance, with some exceptions where immunological responses can be elicited i.e.: melanoma, renal cell carcinoma. Altered cancer cell antigens produced by viral infection or BCG inoculation, for instance, are manipulations or alterations of usual "self" cancer cell antigens that, in turn, may elicit immunological responses. Indeed, as described later, deliberate immunosuppression may allow apparently dormant cancer cells to proliferate rapidly, and cause death after transplantation; when such immunosuppression is withdrawn, complete metastatic cancer regression may occur, preventing death. These examples indicate potential immunologic responses to cancer cells, as yet incompletely understood. In addition, since cancer is largely a phenomenon of an aging organism, we can be assured that lymph node metastases have little basic meaning in Darwinian evolutionary, or developmental embryological terms.
Lymphatic Anatomy and Sentinel Node Biopsy
Anatomic studies of sentinel lymph nodes, particularly in breast cancer and melanoma, have indicated that there is a rational and coherent flow of lymph from the organ or limb tumor site into the regional lymphatic basin with one or two, or occasionally more, sentinel nodes initially encountered.18 This lymph flow to lymph nodes is thus not a random event, but a highly structured, anatomically defined, lymphatic vessel and lymph node pattern. The first lymph node was called the "sentinel node" by Cabanas,19 studying penile cancer, who defined the concept of the sentinel node being the doorway to the regional node basin. This assumption has now been firmly established in breast cancer, melanoma, and other cutaneous sites such as vulvar and Merkel cell cancers but is less well defined in thyroid, head and neck, gastric, colorectal, cervical, and endometrial cancers. Multiple lymph node metastases from cancers may occur as cells traverse the sentinel nodes to appear and perhaps grow in sequential echelons of nodes. In some situations, a lymph node metastases in a sentinel node grows to block lymphatic flow, thus directing lymph and cells to other, possibly not ordinarily sequential, nodes also.
The false negative rate (finding node metastases in the regional nodal dissection carried out after an initial negative sentinel node) is remarkably low in breast cancer, usually less than 5%, as quality guide lines suggest, and in more recent studies probably not more than 1% to 2%.20 This confirms the assumption of rational and sequential flow to regional nodes through lymph vessels from superficial cancers. When positive sentinel nodes do occur in breast cancer patients, there is a clear relationship between the size and prognostic features of the primary cancer and the size and number of nodal metastases probably representing the dose of metastatic cells. Thus, when patients with T1a (>1 mm to 5 mm) and T1b (>5 mm to 10 mm) breast cancers have a sentinel node metastasis, the vast majority (>70%) are found to have only one or two node metastases and these are frequently micrometastases (<2 mm) or even smaller (<0.2 mm), and in the latter case defined as N0(IHC+).21 Subsequent axillary dissection, particularly when the nodes have micrometastases, seldom reveal other nodal metastases. Contrariwise, when T2 cancers are found to have a sentinel lymph node metastasis, even a micrometastasis, the chance of finding other nodal metastases in the regional node basin at later axillary dissection may exceed 50%, and these are usually macrometastases (>2 mm). An extensive literature review, however, indicates no survival advantage for removing lymph node metastases from any organ site cancer.7,13,22 Admittedly, criticisms have been made of these conclusions because of wide confidence intervals on the basis of less than adequate numbers of cases in individual trials; nevertheless, the overall generalization looking over the many trials of lymphatic resections in cancers of the esophageus, lung, stomach, colon and rectum, breast, head and neck, and melanoma is clear.7,11,13,21 Lymph node metastases, while providing a staging or prognostic role, probably have no governing or controlling role in developing later distant vital organ metastases, which in turn are what control survival.
Organ Specific Metastatic Patterns
Organ specific clinical metastases are derived from cells that escape the primary cancer and previously lodged but then later grew in the liver, lung, lymph node, or other organs. The metastatic cascade of cells escaping from the primary cancer by entering either the vascular or lymphatic system (intravasation), circulating, lodging in a distant organ vascular system or lymph node lymphatic vessel (HEV), leaving this vascular space by adhering to or traversing the endothelial lining (extravasation), and either dying, becoming viable but dormant cells growing to 1 to 2 mm3 to survive by diffusion, or undergoing progressive growth by acquisition of new blood vessels (angiogenesis), is an extremely complicated and inefficient process.23 This multi-step metastatic process has been well outlined and is based on extensive laboratory and animal experiments. There is no reason to assume that these basic concepts elaborated for blood vessels in distant organs are different than lymphatics in the lymph nodes. Interesting research in recent years demonstrated that human breast cancer lymph node metastatic cells when injected systemically in animal models specifically lodged in lymph node stromal sites.1 This preferential selectivity of lymph node metastatic cells to lymph node stroma could be blocked, experimentally, by specific cytokines,24 thus exemplifying the highly focused metastatic pattern and the important function of the host environment.25 Research indicates that insulin-like growth factor 1 (IGF-1),26 vascular endothelial growth factor C (VEGF-C),27 and other features such as specific gene over expressions can be lymph node metastases controlling substances.28 Other research demonstrates that liver and lung metastatic cells sequentially developed in animal models can be exquisitely cell and organ specific in later metastatic distribution.23,29,30,31 Thus, cells from liver metastases derived from sequential generations of experimental liver metastases, when injected intravenously, caused only liver metastases. Similarly, recent genetic profiling of lung,5 bone,6 and even adrenal gland6 metastases from human breast cancer metastatic cell lines injected in animal models had selective propensity to lodge in those same organs with a similar genetic profile indicating highly complex selective metastatic site behavior. Such a lung specific metastatic pattern could be selectively inhibited by the transcription factor Twist. "Suppression of Twist expression in highly metastatic mammary carcinoma cells specifically inhibits their ability to metastasize from the mammary gland to the lung. Ectopic expression of Twist results in loss of E-cadherin-mediated cell-cell adhesion, activation of mesenchymal markers, and induction of cell motility, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition (EMT)."3 These organ site specificity phenomena have been linked to a "zip-code" concept where biochemical, electrical, physical, genetic, or protein features of the cancer cell surface must interdigitate or interrelate with matched susceptible features of the organ vascular, capillary, or lymphatic endothelium (HEV) or lymph node stroma.32 A recent review33 highlights this dendritic cell, lymphocyte, and lymph node specificity in inflammation, undoubtedly with correlates in oncology: "The signatures are imprinted on lymphocytes in draining lymph nodes, in which antigen-presenting cells direct lymphocytes to return to the organs in which they first encountered antigen. Each major organ system probably has a unique "area code" that consists of lymphocyte surface molecules and counter receptors on endothelial beds. Indeed, initial indicators of distinct leukocyte-homing determinants for the lungs, joints, and the brain have been found, but much work remains to be done, including the identification of chemokine receptors on the cells that home to these various organs".33
Similar metastatic specificity also exists clinically in humans; for instance, resection of selected hepatic34 or pulmonary metastases from patients with colorectal carcinoma, or pulmonary metastases from patients with sarcomas,35 can result in substantial long-term disease free survival rates (25–30%), despite the presumed flooding of the host systemic circulation with huge numbers of circulating tumor cells over long periods of time. Another classical clinical example of such selective metastases is the high rate of liver metastases following liver transplantation for hepatocellular cancers (HCC).36 These HCC cells, presumably circulating in the recipient after excision of the diseased liver, may lodge exclusively in the new normal donated liver to produce liver metastatic HCC, and are a major cause of failure of liver transplantation for HCC. Widespread peritoneal metastases with ascites rich with metastatic cells from ovarian cancer does not produce pulmonary metastases following peritoneovenous shunting to relieve the ascites, despite the direct shunting of malignant peritoneal metastatic cells into the central venous confluence, and thereby the pulmonary arteries and lungs.37 Clearly, the exact mechanism of such organ specific "homing", or controlling features of metastatic cells is at this time being elaborated,1,2,32 but extensive research into the metastatic cascade and micro environmental control of extravasated metastatic cancer cell growth or dormancy bears on such a complicated interrelationship.
As a human clinical model of such a highly selective organ specific lymph node metastatic pattern, papillary thyroid carcinoma in young "low risk" patients is very pertinent. These young patients have a pattern of frequent regional nodal metastases (up to 75%) when routine nodal resections are performed but uncommon (<3%) distant metastases, (entirely confined to lung), and a 99% disease free survival at 20 years.38 Two thirds of recurrences after initial surgery are lymph node metastases, which even when delayed in clinical appearance have no adverse effect on survival. This selective nodal metastatic pattern is mimicked in carcinoid and islet cell tumors of the foregut and midgut organs such as stomach, duodenum, pancreas, and intestine.39 Nodal metastases are required to even define carcinoma in many pancreatic islet cell tumors, since histological criteria alone do not clearly differentiate malignant from benign. Lymph node metastases are common, but are not controlling influences on survival, since that is determined entirely by distant vital organ metastases, particularly the liver in carcinoid tumors or islet cell cancers, or lung in low risk thyroid cancers. This pattern of specific "lymph node only" metastases without the poor prognosis arising from vital organ metastases (liver, lung, brain) mimics the animal research studies mentioned1,16,24,26–31 that elaborate organ-specific metastatic patterns.
Despite the very frequent differentiated thyroid cancer lymph node metastases detected histologically, few low risk group patients actually develop palpable clinical regional nodal metastases. However, 25% of young patients with clinical papillary thyroid cancer present because of palpable cervical metastases that may arise from even very small (1 to 3 mm) occult primary thyroid cancers.38 This presentation because of the clinical lymph node metastases from miniscule primary cancers also occurs with small intestine carcinoid tumors, where the marked desmoplastic reaction to and the bulk of the lymph node metastases is the usual cause of the clinical bowel obstruction, even when the primary carcinoid tumor is very small (< 1cm) and itself asymptomatic. Jejunal carcinoid primary tumors 5 mm or less in diameter have a node metastatic rate of 70%, and when between 5 and 10 mm in diameter have lymph node metastases in 94%. Duodenal carcinoid tumors from 8 mm to 1.5 cm in diameter have a high lymph node metastatic rate yet rarely die of disease, even when bulky, or multiple, or recurrent in lymph nodes.40 These midgut and fore-gut carcinoid cancer patients uncommonly die of distant liver metastases despite common nodal metastases. The organ specificity of nodal metastases is here again uniquely displayed clinically. These dramatic examples of the lymph node organ specificity of metastatic cancer cells provides insight into the general metastatic pattern, for it illustrates why many non-vital organ metastatic sites (lymph nodes especially, but also bone, subcutaneous, or cutaneous) may seem more "benign" in behavior, in terms of reduced survival duration, while in reality they are vividly demonstrating a key aspect of the metastatic process – highly specific metastatic cell to organ site behavior for separate clones of cancer cells that escape the primary tumor and complete the metastatic cascade.23 Since lymph nodes are not vital organs, unlike liver, lung, or brain, their localized involvement, or even destruction, by metastatic involvement causes, by itself, no loss of overall vital function or death. If all lymph node lymphocytes in the body are eliminated, however, immuno-incompetence and death from infection may occur, but this clearly does not apply to regional lymph node metastases.
A corollary of lymphatic or other organ specificity may be the presumed sequential node to node (or liver to liver, or lung to lung) spread when multiple lymph node (or liver or lung) metastases appear. Whether these sequential regional nodal metastases arise from further shedding of specific primary cancer cells, or, alternatively, from the first node specific focus to the next and subsequent sequential regional nodes, is unclear and open to debate. However, the success, by long term disease free survival, of liver or lung (or node) resection of a few such distant organ metastases (oligometastases) without later other liver or lung (or nodal) metastases indicates that such a cascade of organ specific cells is not universal, and may even be uncommon.
This selective metastatic process relies on highly sophisticated and complex interactions between the metastatic cell surface and the capillary endothelium in various recipient organs32,41 or the stroma or HEV of the lymph node.42 A reasonable hypothesis to explain why many patients with lymph node metastases survive long-term free of vital organ metastases is that metastatic cells having the ability to lodge and grow in lymph nodes may have no capacity to lodge in, extravasate, and grow progressively in other organs, although retaining the ability to sequentially involve lymph nodes. Contrary-wise, many patients with cancers in a variety of organs with negative lymph nodes still die of systemic vital organ metastases, indicating the disassociation of direct cause and effect between lymph node metastases and distant vital organ metastases that govern survival. Sarcomas have frequent pulmonary metastases, but few lymph node metastases. The vast majority (>90%) of long-term survivors in lung, gastric, colorectal, or breast cancers who had lymph node metastases at their original surgery had only one, two, or occasionally three positive lymph nodes.43 Patients who have more than five lymph node metastases at the time of the original surgical procedure in a variety of human cancers (larynx, oral cavity, stomach, esophagus, lung, colorectal, breast, and melanoma), who survive long-term disease free are the exception (<5%, usually only 1% or 2%).43 Between 80% and 93% of ten-year disease free survivors in these various primary cancer sites had either negative nodes or only one nodal macrometastasis detected by a single histological section through the multiple lymph nodes in the regional nodal basin. Another 4% to 6% had only 2 and another 0% to 4% had three nodal metastases.43 Interestingly, almost all of the cures from resection of liver or lung metastases in colorectal cancers or sarcomas have only one or two, or occasionally three, separate metastatic nodules, perhaps indicating a more universal relationship between survival after resection and the number of clinical metastatic sites.34,44 When more than a few lymph node metastases occur in breast, gastric, colorectal, lung, or other cancers or melanoma, this is likely associated with a high rate of other clones of metastatic cells escaping the primary cancer with liver, lung, brain, or other vital organ selectivity and specificity, and/or a systemic effect that alters the distant organ micro-environment (trauma, immunosuppression, fever, etc), that enable such selective cells to complete the metastatic cascade and become clinical metastases.
Micrometastases, and Metastatic Tumor Cell Clusters and Tumor Cells
In recent years, with the advent of sentinel node biopsy, especially in breast cancer and melanoma where extensive experience has accumulated, many sections of each sentinel lymph node (median 2) utilizing Hematoxylin and Eosin staining but also immunohistochemical (IHC) staining, and even reverse transcriptase polymerase chain reaction (RTPCR) has frequently been performed. These exquisitely sophisticated techniques of lymph node analysis may detect a few metastatic cells, or even single metastatic cells, frequently in the subcapsular sinus of the lymph node. The relationship of these few metastatic cells, tumor cell clusters, or lymph node micrometastases detected only by IHC or RTPCR, to survival prognosis is at the present time uncertain.45,46 A recent report documents circulating tumor cells in a high proportion (>33%) of patients surviving "disease-free" for many years ("7 to 22 years after mastectomy") and on more than one occasion, indicating viable continuing, but clinically dormant, sites of ongoing metastatic disease with cancer cell shedding even in patients apparently free of clinical disease.47 Such tumor dormancy undoubtedly occurs as single cells, tumor cell clusters, or the one to two millimeter foci of cancer cells surviving by diffusion only of nutrients and waste products. Only when angiogenesis occurs with its efficiency in oxygenation and metabolic by product elimination does progressive growth occur to escape from dormancy.
The biological meaning of such scattered clusters or single metastatic cells or even small micrometastases is currently widely studied in clinical cancer research but is put into perspective by the results of bone marrow aspiration to detect disseminated cancer cells. The long term outcome of patients with IHC stained bone marrow aspirates that reveal metastatic cancer cells in breast cancer patients as reported by Diehl48 and Braun49 and recently summarized by Braun et al.50 bear on the relationship between cells in sites distant from the primary cancer and survival. Patients that had neither lymph node nor bone marrow metastatic cells had an excellent disease free prognosis (over 95% at four years), while patients with both bone marrow and lymph node metastatic cells had an extremely poor prognosis (50% with clinical distant vital organ metastases at four years). Most interesting in their original reports, however, is the fact that patients with either bone marrow or lymph node metastatic cells have an exactly similar survival curve of about 85% disease free at four years, suggesting that metastatic cells detected by highly sophisticated histological techniques wherever they lodge (lymph node, bone marrow) are indicators, in a statistical sense, of the metastatic cell load, risk of later clinical metastases, and death from disease, but are not necessarily predictors of particular selective distant metastatic sites. For instance, 25% of T1a and 35% of T1b breast cancers have metastatic bone marrow cells, yet have 20 year disease free survival rates of over 95% and 90%, respectively. 10%–15% of esophageal cancers have iliac crest marrow metastatic cells by IHC staining of aspirations; however, ribs, removed to enable esophageal resection, when flushed with fluid, revealed that the rib marrow contained metastatic cells in 80–90% of those patients.51,52 Rib flushing is a much more extensive marrow sampling than a needle aspiration and indicates that such bone marrow metastatic cells may be much more common than ever suspected.
The implications of bone marrow or regional lymph node micrometastatic cells in early cancers are expanded by appreciation of the transplantation literature, which demonstrates the not-uncommon phenomena of donor organ dormant metastatic cells from previous "cured" donor cancers becoming clinical metastases in immunosuppressed recipients.53 Thoracic organ donors (heart and/or lung) who previously have had cured cancer from a variety of primary sites, may transmit that cancer to almost 50% of recipients.54 Of necessity, these transplanted cancers arose from viable but dormant cancer cells, tumor cell clusters, or micrometastases, harbored in the transplanted donor organ. These organ donors have had cancers of a variety of organ sites including the cervix, prostate, lung, liver, kidney, or angiosarcoma, choriocarcinoma, and even glioblastoma of the brain, a malignancy assumed to never escape the cranium. Renal transplantation from a patient 16 years after cured early melanoma resulted in melanoma transplantation to both recipients in a recent report.55 Thus, cells from primary cancers may not only be shed to regional lymph nodes, or bone marrow, but to distant organs, such as lung, heart, or liver, and lie dormant for decades before the microenvironment is altered (immunosuppression, trauma) and progressive rapid growth occurs.47 These disseminated cancer cells in various organs of the donor after cancers "cured" for many years bring into question what constitutes a metastases56 and emphasizes the host factors that enable scattered but dormant metastatic cells to grow, since such cells are far more frequent than ever imagined.47,57,58
This phenomenon of discovering a few metastatic cells is accentuated in regional sentinel node biopsy because this tissue is easily available, routinely removed, and extensively analyzed utilizing multiple thin sections and contemporary detailed histologic immunohistochemical or molecular techniques. If distant organs were inspected as carefully as regional lymph nodes in cancer patients, micrometastatic cells would undoubtedly be discovered in the same frequency in the liver, lung, heart, or other organs, as displayed by transplanted cancers from donor organs.
Metastatic Inefficiency and Biological Models of Cancer Development and Spread
Viable metastatic cells lodging without growth in organs transplanted from "cured" cancer patients belies assumptions of metastatic efficiency; the process of the evolution of cells shed from primary cancers via either the lymphatics or blood vessels to clinical metastases is obviously very inefficient.23,25 This inefficient process of progression from circulating cancer cells, to adherence on distant organ endothelium, to vessel wall penetration, to dormant but viable cells, to initial growth to only two millimeters limited by nutrition through diffusion, to further subsequent progressive growth after acquisition of a blood supply with oxygenation and nutrition via angiogenesis to become a clinical metastases has been elaborated and appreciated by researchers utilizing animal models.59 The development of clinical metastases may be heavily impacted by the "dose" of cancer cells shed from primary cancers which likely is directly related to the volume and perhaps duration of the primary cancer, as well as specific poor prognostic features. This progressive behavior of cancers is postulated in the "spectrum" clinical biological model proposed by Hellman,60 which could only be elaborated through the study of the earliest and smallest cancers discovered by screening. The "Spectrum" biological model of cancer development evident in breast cancer (USA and Europe) and gastric cancer (Japan)61 detected by screening elaborated the progression from small cancers of lower grade and high curability, to later, larger cancers of higher grade and significant fatality, and postulates an increase in virulence, metastatic cell load, and metastagenicity over time, with increasing size and increasing dedifferentiation. A similar pattern has been elaborated in cervix cancer screening and is currently being demonstrated in colorectal cancer as more widespread screening is being achieved.
The entire clinical pattern of frequent cell dissemination and infrequent clinical vital organ metastases that causes death is entirely concordant with the large body of basic research in the in-vitro laboratory and in-vivo animal studies. This multi-step metastatic processes has been summarized by Chambers,59 Fidler,23,25 Stetler-Stevenson,62 and others, and reflects decades of research activity by many authors and laboratories. Fidler has emphasized the current relationship of understanding all aspects of the metastatic process to Paget’s description in 1889 of both the "seed and soil", the cancer cell, and the microenvironment of the metastatic cell lodging site.23 This voluminous contemporary research bears extensive review and comprehension for it so predicts and explains clinical scenarios, which frequently seem illogical, contradictory, or unreasonable to the clinician. While animal and laboratory studies have elaborated each of the many steps in the metastatic process from intravasation to lodgment to extravasation, to dormancy, to angiogenesis, recent research has been particularly noteworthy in emphasizing features of the host metastatic cell microenvironment. These studies indicate a symbiotic relationship between the extravasated metastatic cells and their surrounding tissue, such that host defense factors can be modified by the metastatic cells, and the metastatic cells can respond and be modified by host features. This cancer cell-host microenvironment "cross-talk" occurs with hormonal, genetic, protein, extra cellular fluid, and physical environment effects.23 Metastatic cells may have paracrine effects that overwhelm local control factors to promote growth, and host tissue cells may decrease the metastatic potential of cancer cells by similar mechanisms. Highly metastatic cells from a primary cancer such as colon or skin, when grown in a subcutaneous site, may lose metastatic potential. Metastatic cell lines grown together with skin epithelium may lose metastatic ability. Different animal cancer cell lines may produce different growth and organ metastatic patterns when injected via the same route. Specific cytokines or growth factors may cause different growth patterns, and blocking of these factors may completely prevent metastatic potential, while not preventing local progressive growth. All these scenarios portray an extraordinarily complex system of cell dissemination, host function, and metastatic growth.23,25 Cancer cell progression may be highly inefficient in some aspects, and overall, but very efficient in specific steps or in other aspects of dissemination and growth. Appreciating this complex array, however, provides insights that suggest the development of a variety of mechanisms that lead to clinical metastases, but a commonality regarding the site of metastatic growth, whether that be lymph node, liver, lung, or other sites.
Clinical Aspects of Lymph Node Metastases
Substantial data exist that indicate no survival difference in cancer patients subjected to radical regional node dissection compared to those with lesser dissections or even without dissection, in melanoma, and in head and neck, gastric, colorectal cancers, and particularly breast cancers.7 These clinical studies all confirm the indicator function, or statistical relationship, but question the outcome governing role of lymph node metastases.7 Thus, the purpose of a sentinel node biopsy or regional node dissection is not to improve survival, since that has not been clearly demonstrated, but to collect diagnostic and prognostic information for aid in systemic therapy selection to improve prognosis. Since patients do not die of regional nodal disease, but from systemic metastases in vital organs, prognosis can only be improved by preventing distant micrometastases from occurring or from developing into the clinical vital organ metastases that cause death. When clinically node negative breast cancer patients do not have axillary dissection with breast conservation and radiation therapy, the clinical risk of axillary recurrence may be 2% or less.63–66 Thus, we not only do not jeopardize patient’s lives by not dissecting the axilla in breast cancer, but we do not jeopardize them regionally because of a very low clinical regional recurrence rate. Even with sentinel lymph node biopsy that reveals metastases, failure to perform a subsequent axillary dissection is not accompanied by frequent regional nodal recurrences (±2%) but the patient’s survival is also not jeopardized.61–67
In breast cancer patients at extremely low risk of axillary nodal metastases, such as mammographically discovered, low grade T1a or T1b cancers or cancers with special low risk features without lymph vessel invasion or poor nuclear grade, even sentinel node evaluation can be avoided.22,67 Sentinel node biopsy may be useful in patients with a modest incidence of lymph node metastases (5% or more) and where the primary tumor features alone would not allow decisions about systemic therapy. Finally, traditional regional nodal dissection may be appropriate in primary breast or thyroid cancers or melanoma with clinical metastases to remove a palpable lesion that might undergo progressive growth and create local palliative problems. In a clinically positive axilla, when confirmed by fine needle aspiration cytology, one might argue that axillary dissection has therapeutic benefit in breast cancer since it removes a palpable lesion and results in extremely low rates of axillary recurrence. Similar implications regarding lymph node metastases also occur in lung, esophagus, gastric, pancreatic, colorectal, and other cancers, but in these other situations, adjacent regional lymph nodes are removed as part of the primary surgery. Only in breast and cutaneous cancers can the option of removing or not removing regional lymph nodes be applied.
Contemporary Disease Presentation
In recent years, there has been a dramatic decrease in the size, grade, lymph node metastases rate and, as a result, the stage of breast cancer under the impact of extensive mammographic screening.68 Melanoma patients, gastric cancer patients in Japan, and colorectal cancers are also seen at much earlier presentations as a result of screening. The current median maximum diameter of all breast cancer in the State of Rhode Island is only 1.5 cm and the lymph node metastatic rate is only 26%.68 In invasive breast cancer discovered only mammographically, the median maximum diameter is about 1 cm and the positive node rate less than 20% and few are of high grade.69–71 80% of breast cancer sentinel node biopsy programs in the United States utilize routine IHC staining of multiple sections of the sentinel nodes without, at present, understanding the meaning of such special technique discovered micrometastases. As an example, the results of one report are biologically implausible, since a single IHC discovered micrometastasis in a single lymph node in a retrospective subset analysis 10 years later of about 10% of patients out of almost 1,000 in a randomized trial, decreased the survival rate by as much as 50%.72 Such a dramatic survival decrement associated with a few metastatic cells is greater than that seen when patients have one to three lymph node macrometastases in traditional nodal analysis. This particular study, while originally a randomized controlled trial, was subject to this retrospective selective subset analysis by pathological redefinition of axillary lymph nodes, and thus cannot be taken at face value.
The current most appropriate clinical biologic model (spectrum model)60 supplants the previous "Fisherian" model, which assumed that all breast cancers were systemic from onset, which in turn had displaced the "Halstedian" lymphatic system dominant model8 that controlled thinking until the 1970’s and is still widely accepted. In the time of Halsted8 and Moynihan,9 it was assumed that lymph nodes were filters and only when the filter was filled with cancer cells did further cells "spill over" into the distant lymphatic vessels, which led directly to distant organs.8 In the contemporary "spectrum" model,60 the size and evolving features of the genetically unstable primary cancer undergoes continued alteration, and results in greater virulence, increased likelihood of metastatic spread, a greater dose of metastatic cancer cells, and increasing risks of death. The vast majority (>75%) of current breast cancers, and in all likelihood other cancers, correspond to this model in which the ability to metastasize increases as size and resultant biological potential increases. Very small cancers with few exceptions have little ability to develop clinical metastases,73–75 or even recur locally76 despite the documented dissemination of cells. How the "Fisherian" biological model of "systemic from origin" will eventually relate to the new information regarding the frequency of disseminated cells rather than clinical metastases as elaborated in this paper is yet to be understood.
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Thus, the future may allow us to abandon some aspects of our surgical or systemic attack on clinical cancer metastases, such as lymph node removal or use of toxic chemotherapy, but open the door to more physiological and hopefully less traumatic approaches to the highly manipulable multi-step genetic and physiological process of metastatic development.
The future biological models of clinical cancer behavior will have to incorporate aspects of understanding the intricate metastatic cascade, and particularly the host microenvironmental factors that permit or prevent progressive growth of dormant cells or cell clusters to clinical metastases.
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ACKNOWLEDGMENTS |
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Received for publication May 17, 2006. Accepted for publication August 31, 2006.
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