Positive lymph nodes do not metastasize
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Our understanding of the role of lymph nodes (LN) in the metastasization process (MET) is marginal. Positive LNs (pLN) are the most important prognostic factor and lymph node dissection (LND) is still standard practice in primary treatment. However, up to now, there is almost no evidence that elective LND has a survival benefit. Based on many clinical and experimental findings, we propose that tumor foci in regional LN are incapable of metastasization and can therefore not infiltrate further LN and organs. Available data demonstrate a very early infiltration of MET capable tumor cells from the primary tumor into regional LN, and thereafter an increased probability of subsequent LN infiltrations. Disparate growth rates of the first versus subsequent infiltrating tumors as well as the asymptotic growth and prognosis of large tumor foci in LN explain many clinical observations for solid tumors. The consequence of the hypothesis “pLN do not metastasize” would impact clinical treatment and research and contribute to understanding the mounting evidence against LND.
KeywordsBreast cancer Colorectal cancer Positive lymph node Tumor cell dissemination Tumor growth
Positive lymph node(s)
Lymph node dissection
Sentinel lymph node
Tumor cell (dissemination)
Volume doubling (time)
Isolated TC in LN <0.2 mm
Micrometastasis in LN (0.2–2 mm)
Pathological classification of regional lymph node
1 Randomized trials do not show a survival benefit of LND
Elective regional lymph node dissection (LND) has been a standard in tumor surgery for more than a century. Increasingly, however, many randomized trials are challenging this paradigm [1, 2, 3, 4, 5, 6, 7, 8, 9]. Not even a single randomized trial indicates a benefit of LND for survival for any solid tumor [10, 11, 12, 13, 14]. That is, the highest level of clinical evidence demonstrates no survival benefit. If this is true, then the lack of survival benefit from LND must also be logically deducible from the plethora of published data. The prognosis and growth rate of positive LN (pLN), the estimated time of first and subsequent LN infiltrations, and their very different probabilities will be discussed. The interpretation of and logical deduction from these data supports the basic LN hypothesis: “pLN do not metastasize”.
2 PT-size-dependent LN status predicts mortality
Breast cancer: lymph node status, primary M1, and 10-year tumor-related mortality is dependent on pT category (MCR data n = 40,698—1988–2008)
Tumor Ø mm
10-year tumor-related mortality %
mean pLN n
Percentile pLN (n)
3 Primary and secondary infiltration of the lymphatic network
4 Growth time of involved lymph nodes versus PT
From these observations it may be deduced that LN are infiltrated sequentially. LN infiltration begins with isolated TC or with tiny TC clusters which, after successful colonization , grow up to 0.2 mm (pNITC), to a microscopic focus that reaches 2 mm (pNmicro), and further to a macroscopic focus with over 2 mm diameter (pN+). To reach these sizes with mean diameters of 0.1, 1, or 8 mm, approximately 10, 20, or 29 volume doublings (VD), respectively, are needed. Each focus has, in each case, a cellular mass of approximately 1,000, 1 million, or 0.5 milliard TCs, respectively. Figure 3b depicts the LN foci distribution in a pT1c cohort. A ranking according to number of LN and the size of microscopically involved SLN reflects the differing prognosis of the particular subgroup, with poorest being those with 10 and more pLN.
Meticulous histopathologic preparations of SLN provide crucial information regarding the distribution of ITC and microfoci in SLN [20, 21]. Approximately 10–20% of all patients show microscopic foci within SLN (pNmicro) [22, 23, 24, 25, 26, 27, 28]. Data about pNITC in SLN are more heterogeneous because such findings are necessarily dependent on the number and width interval of sections that are cut [29, 30]. In Fig. 2, the two dashed lines indicate about 10% pNmicro and a hypothetical 10% pNITC that contribute to the occurrence of pLN.
These clinical data indirectly allow estimations for the growth time. For patients with a PT of 10 mm diameter, about 24.1% are pN+ cases and an additional 10% are pNmicro positive (Fig. 2). If the PT grows further, new foci have to be continuously initiated in previously tumor free LN, and existing small foci will grow into macroscopic pN+. If the PT achieves 15, 20, or 30 mm, then the fraction of pN+ increases along the regression line, from 24.1% to 30.2%, 36.3%, and 48.5%, respectively. Therefore, even the dashed lines in Fig. 2 are parallel to the pN+ regression line because any positive SLN must have been initiated about 29 VD earlier and no change of VD time of LN foci or with tumor size has been observed. A varying frequency of prevalent submacroscopical foci would be an indication.
A logical consequence of continuous TCD is that pNmicro foci of 0.2–2 mm grow in parallel to a PT until they become macroscopic foci (pN+). About 10% of the pNmicro fraction of a 10 mm PT will grow to macroscopic pN+ by the time the PT reaches a diameter of about 18 mm (middle blue arrows in Fig. 2). A 2 mm focus will reach a macroscopic size of 8 mm after six VD, while a 0.2 mm focus needs 16 VD to achieve this size. A mean of 1 mm corresponds to 20 VD. If such a pNmicro focus reaches a mean diameter of 8 mm after another nine VD, then the PT would continue to grow from 10 to 18 mm. With the assumed 10% pNmicro fraction, one VD in the LN would occur in about 45 days, while the PT requires 407 days for this growth . If the fraction of pNmicro would account for 20% of the diagnoses, then the corresponding size of the PT would be 26 mm after a 73-day VDT. That is, the higher the fraction, or prevalence, of pNmicro, the slower the growth of that tumor in the LN.
5 Early infiltration of LN before removal of the PT
If between 45 to 73 (mean 59) days are assumed for a VD in LN, and 29 VD are required before a pN+ status comes up, then the initiation of TC dissemination into the first LN must occur 3.6 to 5.8 (mean 4.7) years before the diagnosis of a 10 mm PT. This is consistent with 8.4 to 13.5 (mean 10.9) VD of the PT with a VDT of 157 days , and with an initiation of the first LN when the PT has a size of only 3 × 106 to 1 × 105 (mean 5 × 105) TC. Receptor negative BC and their MET show a 2-fold increased growth rate which is likely true for pLN as well . If 59-day VDT is required for foci in pLN and about 13% of BC are receptor negative (with a 2-fold increased growth rate), then the VDT would be about 32 or 63 days for receptor negative or positive foci, respectively. Even if very early infiltration of LN is possible and TCD, once initiated, is a continuous process, then further LN infiltrations will occur up to the removal of the PT.
6 LN foci distribution
Figure 4b depicts several ordinary cases for different PT diameters. Just before the detection of the PT, the first (case 1) or further LN must be infiltrated from an ITC represented by red dots near the regression line. In addition, it is logical that the SLN is infiltrated at about the same time in most ordinary cases and further infiltrations into other LN continue to run in parallel, up to the removal of the PT. Furthermore, it can be estimated that in about 8–12 months the next LN will be infiltrated. With a VDT of 59 days about 4.7 years are needed for the tumor in an LN to grow up to a focus of 8 mm. That is, in three to four LN, smaller foci are already growing beneath macroscopical size (Fig. 4a–b).
7 pLN do not initiate regional MET
The anatomy of the lymphatic system and corresponding experiments show that LNs are not filters for TC [33, 34, 35]. Due to the function of LNs, it is clear that neither vasculatory nor lymphatic vessels can be considered as isolated, independent routes for TCD [36, 37]. The distinction of a hematogenous or lymphatic TCD seems to be quite artificial . Furthermore, it is important to note that TC can traverse interstitial space of an extravascular position, invade the lymphatics again, invade nearby LN of the MET organ, or follow the course of other TC that have previously been disseminated via the lymphatics that drain the PT . The rationale for LND, the filter function of LN and a delayed TC dissemination by a pLN, implies a temporary blockade of TCD from pLN, which excludes the possibility of a continuous flow through. The prognostic significance of circulating TC and their association with LN status also support the ubiquitous presence of TC from the PT as the cause of all secondary foci [39, 40].
The characteristics of a spatial, directed lymphatic network suggest the existence of at least one proximal LN, the SLN, as a needle eye, which drains the area surrounding a tumor. Of course, two and more LN can drain larger tumor infiltrated areas or different effluent vessels may exist near, for example, a BC tumor in medial quadrants [13, 34]. Bypass and flow through of TC to the next echelon of the network are possible because of this secure and optimized immune and drainage function. Also, the increase of MET frequency with increasing PT size but without LN infiltration supports the concept that TC can flow through the LN network without leaving a trace. An exclusively hematogenous TCD for the pN0 subgroup with MET is implausible.
From the linear and temporally sequential increase of the number of pLN, it can likely be concluded that a pLN does not infiltrate other negative LN. Although the SLN holds a special anatomic position, it is functionally equivalent to all other LN. Therefore, the SLN would not be the only bridgehead but rather each pLN could also be a source of TCD. Such a simultaneous increase of pLN with a growing PT would be exponential but is not observed. The effectivity of the LN infiltration is very remarkable if competent TCs reach the first LN because a positive SLN has a sensitivity of about 95%. This is also relevant for the infiltration of further, non-involved LN. Because flow through is possible, and infiltration of LN is stopped by R0 resection according to the randomized trials, infiltration must be caused by TC of the PT and not by TC in pLN. An alternative, a remote control of the homing of TC by the PT, is not a plausible explanation for the ending of further LN infiltration with a R0 resection.
The existence of many involved LN with differently sized tumor foci is another consequence of the temporally sequential infiltration of the LN network. This aspect of tumor growth is confirmed by results of a randomized SLN trial for melanoma . Patients were assigned to immediate SLN biopsy or a delayed treatment only if nodal relapse occurred. In the first group, 1.4 pLN were removed; in the second, 3.3. The proposed LN hypothesis would suggest that at diagnosis, about three LN were already microscopically involved. Obviously, these already involved autonomous foci grow in LN, up to macroscopic size, without telecontrol by the PT. Also, in routine care, successive pLN can be detected along an infiltrated LN chain during the course of disease. Therefore, “LN recurrences” do not refute the LN hypothesis rather the term recurrence is appropriate and should be reconsidered because it is a delayed appearance.
Uncountable trials confirm for several different tumors that the number of detectable pLN increases with surgical radicalness . But an expected benefit for survival has until now never been confirmed. Furthermore, the LND trials have demonstrated that neither a more conservative LND nor a complete waiving increases regional recurrences or mortality rates, despite unremoved pLN. Therefore, pLN are dead ends of TCD and do not further infiltrate other negative LN .
A cascade-like infiltration is also implausible due to the sequential initiation of LN foci. This would require that a disseminating pLN would acquire MET capability already as a tiny focus (Fig. 4a). Even the PT seems to need about 1 million TC before disseminating the first potent TC, which occurs perhaps only after a successful angiogenesis of the PT focus . Moreover, genetic data are available, especially the sequences of genomes from different pLN which show that the genetic evolution of the PT can be detected in different pLN [44, 45, 46]. This insight into tumor development confirms the temporally delayed initiation by different TC of the PT or the inability that even in pLN successful TC do not infiltrate other LN in a cascade-like fashion. Such evidence reflects the regional aspect of the LN hypothesis.
8 pLN do not initiate distant MET
The second part of the LN hypothesis addresses whether distant MET can be initiated by pLN. Again, many observations and logical deductions confirm the LN hypothesis. The noted randomized trials have provided the highest level of evidence that pLN do not metastasize. This argument is strong and timely. Furthermore, the LN hypothesis is generalizable for all solid tumors.
Figure 2 shows two linear and parallel regression lines for the 10-year BC specific mortality. The parallelism of the 10-year BC specific mortality with pN+ confirms the association only with the pN+ status and the beginning of an at least regionally successful TCD of the PT. The number of pLN is, for this reason, not only a marker for TC spread but an excellent chronometer for the TCD of the PT because the risk of distant MET increases with the duration of TCD. This is also supported by the resulting curves of the mortality differences of pN+ to pN0 from Fig. 1, which have an identical form, with a descent that increases with the number of pLN up to a constant survival rate relative to pN0 (curves not shown). A further continuous dissemination of TC from all pLN, which together can have a tumor mass greater than the PT, contradicts the clinical observation of a linear increase of mortality with PT size.
The ratio of pN+ and deceased patients according to the regression lines depicted in Fig. 2 is also remarkable. It amounts to 3.2 for 7.5 mm and to 1.3 for 47.5 mm BC tumor diameter. The decreasing ratio indicates a constantly delayed initiation of distant foci compared to regional LN foci. It is unknown whether different characteristics are necessary for regional and distant infiltration, or whether the easier, nearly passive access of TC to the LN is a sufficient explanation for the delay. The conformity of the survival curves in Fig. 1 is important. If each additional pLN during the growth of PT were to be a new source for MET, then a nonlinear increase of mortality in Fig. 2 or concave instead of convex survival curves in Fig. 1 would be necessary. However, the contrary is true; the more pLN, the more primary advanced BC will be observed. Therefore, MET within the subgroup of pN0 and pN+ have the same cause, the TC of the disseminating PT.
The remaining survival time for the subgroup with multiple pLN (e.g., ≥10) is comparable or even shorter than for primary M1, probably because the high number of pLN correlates with a longer TCD, followed by longer MET growth and with more and larger tumor foci in distant organs. The marginally decreasing median survival after primary MET with increasing pLN is in part a lead time effect due to the longer growth of the MET. The comparable shapes of survival curves after MET, with or without pLN, is a further argument for the lack of impact of pLN on survival. If the number of pLN were an additional cause of MET, it would result in an increased opening of the survival curves in Fig. 1.
The predictive power of the number and size of pLN foci is a further aspect of LN status that must be considered (Fig. 3b and Table 1). Patients without any detectable TC in SLN would represent a true pN0 status. The smaller the pN focus, the smaller the mortality risk. However, Fig. 3b suggests that even pNmicro and pNITC are risk factors, even if only the sentinel LN (SLN) is involved [8, 26, 47, 48, 49, 50, 51]. Therefore, a macroscopic pN0 cohort in Fig. 1 could be separated into the three prognostic subclasses, true pN0, pNITC, and pNmicro. Indeed, it has been shown that even only pNITC in a SLN is a risk factor, and patients benefit from adjuvant treatment [52, 53]. In these studies, the curves for disease-free survival for the pNITC subgroups with and without treatment or for the pN0 versus pNITC subgroups open like scissors after 2 years. Additionally, disease-free survival is shorter if SLN already harbors pNmicro. The obvious explanation is the longer TCD of the PT . An initiation of distant MET by pNITC is hardly possible in such a short MET free interval because the growth time required for distant MET is quite longer, in BC about 7 years . Again, this supports a delayed but parallel TCD by the PT into all possible locations . Therefore, also pNITC and pNmicro support the chronometer function of involved LN and are not the cause of distant MET.
LND and irradiation of the regional LN network have the same goal, which is to optimize regional control and improve survival. Up to now, convincing data are missing for a survival benefit of irradiation. For BC, LND and irradiation yield comparable long-term results [57, 58, 59]. This is remarkable if level III and supraclavicular lymph nodes receive radiotherapy, in contrast to the locally limited surgical procedure, and therefore an advantage for irradiation should be expected. But both treatments are effectively equal concerning regional and distant control and therefore support the LN hypothesis.
Of special interest is also the location of BC, which influences TCD infiltration, and corresponding survival rates. The most frequent lateral BC are predominantly drained by axillary LN. In contrast, medial BC of comparable size have less axillary and more parasternal pLN. Normally, parasternal LN are not treated and as such, one would expect that unremoved pLN would influence survival, but this is not the case [60, 61, 62].
A self-contained argument in the sense of the philosophy of science is the obvious inability of the other secondary foci, true local recurrences and distant MET, to metastasize [55, 63]. Because pLN likewise cannot infiltrate the regional neighborhood, it is important to question why a pLN should be able to initiate a focus in a distant organ. There is evidence that the requisites on TC to achieve successful MET in one organ are not reversible in a new environment, and this suggests the uncomplex principle: only a PT can initiate MET.
The increasing knowledge about seed and soil conditions, and the LN-independent predictability of MET location and mortality by gene expression profiles of the PT, are further sound arguments for the LN hypothesis [64, 65, 66, 67]. The genetic characterization delivers increasingly important prognostic and predictive information which overwhelm the informative capacity of LN status [64, 68, 69, 70, 71, 72].
It is well known that multifocal MET in one organ are not monoclonal. They are caused by different TC . It is implausible to suggest that TC could make a detour across LNs, initiate a focus, and disseminate MET competent TC. Despite a logical conflict in the case of only one pLN and two non-monoclonal distant MET today, more and more hypotheses can be verified. The previously mentioned data generated by sequencing genomes from different areas of a PT and from different pLN, as well as from distant organs within one patient, already confirm the causal relationship. The data can even show the geographic origin, and the time of infiltration due to the genomic instability of the PT and its evolutionary development [45, 74, 75, 76, 77, 78]. The development of a phylogenetic tree for all foci would clarify the hypotheses about the PT as the only source of infiltrating TC.
9 Clinical considerations and the LN hypothesis
In the context of the LN hypothesis, multiple clinical aspects such as adjuvant and neoadjuvant radio- and chemotherapies, the impact on hospital outcome, or research strategies could be discussed. We will address only two aspects, namely LND and the existence of a SLN. The reluctance to accept the LN hypothesis is in part due to the age of the applied LND paradigm and in part to the association between the number of removed LN and survival. The latter is predominantly a stage migration effect [79, 80]. This effect is dependent on the anatomy of the LN network and is very small if a valid sentinel LN exists as in BC and in contrast to colon cancer. The staging function of LND is independent of the LN hypothesis and benefits from the chronometer function of the size and number of pLN. Also, the tiny risk of LN recurrences in the subgroup with positive SLN cannot generally be a justification to continue LND.
Even if some questions are answered by a true LN hypothesis, multiple others remain or arise. If tumor progression is a Poisson process with millions of TC disseminated from the PT resulting in only few initiated foci, then the existence of a valid SLN and the sequential infiltration of LN are remarkable [81, 82]. The infiltration of a LN must be very efficient. All sizes of foci are detectable in SLN and skipped pLN are few. Therefore, the number of competent TC within the stream of disseminated TC must be very few.
The LN hypothesis has long been known: already 30 years ago, L. Weiss summarized the hypothesis very strikingly: “The removal of LN will no more effectively control MET than removal of the speedometer from a car will reduce its speed (cited from )”. Nowadays additional arguments based on molecular research strengthen the LN hypothesis. The multiple statements about LN infiltration are based on observational data along with some basic assumptions, and are generalizable for all solid cancers. It is important, on the one hand, that the assumptions are falsifiable and can, in part, be rendered more precisely. On the other hand, many other observations around the LN hypothesis can be explained. Therefore, it is necessary to reconsider current treatment strategies in light of the evidence that pLN do not metastasize. Data from clinical cancer registries about the course of diseases for many different solid tumors allow for comparisons that can contribute to advancing knowledge.
We thank the many doctors and clinicians who cooperate within the complex network of the Munich Cancer Registry (MCR), despite the back-breaking medical bureaucracy required for daily health care. Especially, we thank our co-workers in the MCR who handle hundreds of thousands of findings and treatment reports and compile them into valid courses of disease. We are also indebted to I Bauerfeind, HP Bruch, J Haier, R Holland, M Hölzel, CA Klein, U Löhrs, D Meyer, K Pantel, G Riethmüller, H-J Sauer, U Schumacher, J. Werner, and F Winkler for insightful information and discussions, especially concerning contrary positions, because dissent rather than consensus is a prime motivation for innovations.
Conflicts of interest
We declare that we have no conflicts of interest.
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