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The Management of Regional Lymph Nodes in Cancer
D.B. Pharis; J.A. Zitelli
Br J Dermatol 149(5):919-925, 2003. ©© 2003 Blackwell Publishing
Posted 12/12/2003
Summary and Introduction
Summary
Early clinical observation in cancer patients suggested that tumours spread in a
methodical, stepwise fashion from the primary site to the regional lymphatics, and
only then to distant locations. Based on these observations, the regional
lymphatics were believed to be mechanical barriers preventing the widespread
dissemination of tumour. Despite evidence now available disputing its validity,
this barrier theory has guided the surgical management of the regional lymphatics
for more than a century, influencing the use of such surgical modalities as
therapeutic lymph node dissection, elective lymph node dissection and most
recently sentinel lymph node biopsy. No published randomized controlled trial
exists that demonstrates improved overall survival for patients with cancer of any
type undergoing surgery of the regional lymphatics. We believe the presence of
tumour in the regional lymphatics indicates the presence of systemic disease, and
therapeutic interventions should be directed accordingly.
Introduction
Management of the regional lymph nodes (RLNs) in potentially metastatic cancer
is fraught with controversies and misunderstandings. Early surgical oncologists
observed many times that the RLNs were enlarged in advanced cancers before
distant disease appeared, leading to the theory that the RLNs served as mechanical
barriers temporarily preventing systemic dissemination of tumour. Based on this
theory, surgeons removed these enlarged lymph nodes along with the primary
tumour, an approach known as therapeutic lymph node dissection (TLND), in an
attempt at surgical cure of locally advanced disease. Unacceptable cure rates,
believed to be a result of unresected microscopic disease, led to the removal of
clinically normal RLNs, a procedure known as elective lymph node dissection
(ELND), in an effort to remove these nonpalpable tumour deposits. By the early
twentieth century, routine dissections of the regional lymphatics in an effort to
remove all microscopic disease had become the dogma of surgical oncology based
exclusively on observation and theory rather than sound scientific evidence. This
barrier theory of lymph node biology continues to influence the management of
the RLNs in cancer surgery today.
In light of current knowledge, does it make sense to perform surgical dissection of
RLNs in patients with cancer? Through well-designed laboratory studies we know
that the lymph nodes serve specific and important functions that aid in essential
immunological responses. We also know that an intact immune system is critical
for host tumour defence mechanisms. Laboratory and clinical studies have cast
doubt on the theory that lymph nodes serve as mechanical barriers to widespread
tumour dissemination. Furthermore, abundant randomized controlled clinical
trials have critically evaluated the role of lymph node dissections in cancer
management and have failed to demonstrate a significant survival advantage. This
paper will review this evidence and will make recommendations regarding the
management of the RLNs in cancer patients, with an emphasis on patients with
melanoma.
Historical Perspective
The theoretical value of TLND, or removal of clinically palpable lymph nodes,
was proposed by the earliest surgical oncologists. In the late eighteenth century,
Heister first advocated axillary dissection for the treatment of breast cancer after
observing the clinical course of patients with advanced disease.[1] Clinical
observation in these patients suggested that the tumour spread in an orderly
fashion from the primary site to the RLNs, and finally to distant locations. Based
on these observations, the prevailing theory that developed and was perpetuated
until late in the twentieth century was that the lymph nodes served as physical
barriers to tumour dissemination. This was tested by Halsted's experiments in
radical mastectomies for breast cancer that entailed en bloc removal of the breast,
the pectoralis muscles and the entire axillary contents.[2] Although Halsted initially
reported improved survival for patients undergoing his radical surgery in 1894, he
later retracted this conclusion after re-analysing the data in 1907.[3]
Halsted's contemporaries argued that the reason the radical mastectomy failed to
improve survival was that trapped, nonpalpable (microscopic) disease was left
behind in other nondissected lymph node basins. However, attempts to improve
on the results of the Halsted mastectomy by dissecting all regional nodal basins
(including the supraclavicular and internal mammary nodes) were met only with
increased operative mortality.[4,5] If more aggressive surgery failed to improve
survival in patients with advanced disease, perhaps earlier, prophylactic lymph
node surgery in patients with more localized disease would. The emphasis of
cancer treatment subsequently shifted to early diagnosis in order to facilitate
surgery in advance of the development of palpable lymphadenopathy. The
theoretical goal of surgical oncology remained removal of trapped tumour cells
within the lymphatics, but at a time when tumour burden was small and the
chance of systemic dissemination was thought to be insignificant. Thus dawned
the age of the ELND.
The theoretical benefit of ELND seemed unassailable when considered in the
context of the belief that the RLNs served as physical barriers to tumour
dissemination. During a time when little else could be offered to cancer patients,
this seemingly rational theory and the chance of a surgical cure for this dreaded
disease captured the attention of surgeons around the world. Numerous
retrospective and single institutional studies were published that supported the
widespread use of ELND in nearly all forms of cancer with the potential for nodal
metastasis including cancer of the breast, uterus, cervix, vulva, prostate, head and
neck, penis and, of course, melanoma.[6-14] Advocates of ELND used the results of
these uncontrolled studies to validate the theory that the RLNs were in fact
barriers to systemic tumour dissemination. Consequently, the role of ELND in
cancer surgery remained unchallenged in surgical oncology until late in the
twentieth century.
A turning point in this story began in 1960 when Bernard Fisher, then the director
of the National Surgical Adjuvant Breast and Bowel Program, began an ambitious
study that was to be the first randomized controlled trial (RCT) investigating the
value of the ELND in breast cancer patients.[15] To the surprise of most, Fisher's
study of 1700 patients failed to reveal any statistically significant survival
advantage for patients undergoing ELND. Although the lymph node dissection
group experienced fewer recurrences in the treated lymph node basin, this
improvement in local control did not translate to a benefit in overall survival. In
fact, when these patients did have recurrences, these were more likely to be distant
disease. Since Fisher's landmark study, five RCTs evaluating ELND in breast
cancer patients have failed to reveal a statistically significant survival advantage
for patients treated with ELND.[16] The lack of evidence supporting the value of
ELND for breast cancer patients in these five trials raised significant questions
regarding the dogmatic but unproven traditional approach to surgical management
in patients with cancer.
Based on the results of Fisher's work in breast cancer, other researchers began
critical evaluation of the value of ELND in other cancers. There have been four
RCTs evaluating ELND in 1718 patients with cutaneous melanoma.[17-20]
Melanoma patients randomized to ELND experienced fewer recurrences in the
dissected lymph node basin, but none of the studies showed a statistically
significant survival advantage. The largest of these trials, the Intergroup
Melanoma Surgical Trial,[17] included 740 patients with melanomas 1-4 mm thick.
As with the other three trials, there was no survival advantage for those patients
undergoing ELND compared with those patients treated with TLND at disease
recurrence. Even though retrospective subgroup analysis found trends in favour of
ELND in patients less than 60 years old with nonulcerated, intermediate thickness
melanomas (1-2 mm thick), this type of post hoc analysis attempts to discern
therapeutic benefits in subsets of patients for which the study was not initially
designed, and is fraught with considerable bias. For this reason, many experts
remain hesitant to advocate ELND for their patients based on this type of
statistical analysis.
Published RCTs evaluating ELND in the management of other cancers are few.
Two small RCTs of only 35 and 75 patients failed to reveal any statistically
significant survival advantage for patients with squamous cell carcinoma of the
oral cavity undergoing ELND.[21,22] Although statistically meaningful conclusions
cannot be made from such a small patient population, as in breast cancer and
melanoma patients those patients randomized to ELND experienced fewer
regional recurrences in the dissected lymph node basin. The improvement in local
control offered by ELND in patients with head and neck cancer may provide a
tangible benefit in this functionally important area. Control of disease influence
on tracheal, oesophageal and cervical neurovascular function would certainly
maintain a high priority in disease management. This may explain why neck
dissections remain an important tool in the treatment of patients with head and
neck cancer despite a lack of evidence of improved overall survival for those
undergoing such interventions.
As sound scientific evidence accumulated to show that ELND offered no survival
advantage for cancer patients, surgeons in the late twentieth century began to look
for other ways to assess the status of the regional lymphatics for staging purposes.
In 1992, Morton et al. reported the technique of sentinel lymph node (SLN)
biopsy (SLNB) in patients with early stage melanoma.[23] As initially described,
isosulfan blue dye was injected around the primary melanoma and soon
afterwards the RLN basin was dissected to locate the initial or sentinel draining
lymph node. Because of the prevailing belief in the barrier theory of the regional
lymphatics, it was theorized that the histological status of the sentinel node would
accurately predict whether or not the tumour had metastasized from the primary
site. In patients with melanoma, the status of the SLN using standard histology
became the single most accurate prognostic indicator of metastatic disease.[24]
Now performed with the use of radiolabelled sulphur colloid, SLNB has become a
widely used staging tool in cancers of all types with the potential for spread to the
regional lymphatics.[25-31] In these cancers, the status of the SLN often guides
further therapeutic interventions including completion lymphadenectomy and
adjuvant chemotherapy or radiation therapy. However, like TLND and ELND
before it, the theoretical value of SLNB is based on the barrier theory of the RLNs
and remains an experimental procedure with no proven therapeutic benefit.
The Role of the Regional Lymph Nodes
So why are surgeons continuing to submit cancer patients to surgery of the RLNs
without any sound scientific evidence of significant survival benefit? Perhaps
some continue to dissect RLN basins in cancer patients based more on surgical
tradition rather than scientific evidence. Many surgeons probably remain
convinced that the RLNs are mechanical barriers preventing tumour dissemination
and that design flaws in the RCTs testing ELND prevent the detection of a small
but real benefit for patients undergoing elective node dissection. Likewise, some
melanoma experts argue that all studies evaluating ELND in melanoma patients
prior to the advent of SLNB are confounded by the fact that in a small but
significant percentage of patients the wrong lymph node basin would have been
dissected. These arguments may have some validity, but with each large-scale
RCT published that fails to demonstrate a survival advantage for ELND,
regardless of cancer type, it becomes more difficult to dismiss all these studies as
scientifically flawed.
We believe that the reason ELND does not benefit patients with cancer is because
the RLNs are not mechanical filters or dams preventing the spread of tumour to
the systemic circulation but are instead indicators of the presence of systemic
metastasis. Therefore, removal of lymph nodes, even in early disease, will only
remove the metastases that are in the RLNs, not those that simultaneously
metastasize elsewhere. Early research by Fisher that led to the initiation of his
landmark breast cancer trial cast significant doubt on the belief that lymph nodes
were passive filters for metastasizing cancer cells or that nodes were exposed to
tumour before the systemic circulation. His studies in rodents demonstrated that
tumour emboli, even when large, could pass through the draining lymphatics and
at times bypassed the lymph node altogether.[32-35] Other studies demonstrated
malignant cells in the venous runoff from various types of solid tumours thought
at that time to spread only via lymphatics.[36,37] This lymph node permeability is
due in part to abundant intranodal and lymphaticovenous shunts that can be
demonstrated by functional studies as well as by electron microscopy.[32,35,38-42]
If lymph nodes are not mechanical filters for tumour emboli, then what influences
the location where a tumour metastasis develops? Recent research illustrates that
various tumour types clearly have organ specificity for their metastases.[43-47] This
organ specificity appears to be dictated by surface proteins called adhesion
molecules on both the tumour cells and the tissue where the metastasis comes to
rest. After the tumour cell breaks away from the primary lesion, it circulates
through the lymphatic and arteriovenous system, bouncing and even rolling across
the endothelium within various organs and tissues. As it does so, adhesion
molecules on the tumour cell regularly come in contact with adhesion molecules
on the endothelium of the organ or tissue in question. These adhesion molecules
must be complementary in order for metastases to develop.[48,49] If complementary
adhesion molecules exist, the tumour cell binds to the endothelium and may
become a clinical metastasis if it is successful at avoiding tumour defence
mechanisms. Consequently, if complementary adhesion molecules do not exist in
the RLNs, tumour emboli circulating in the lymphatic system will bypass the
RLNs while metastasizing to distant locations.[44,45,50-53] This means that the
presence of tumour within RLNs, as in a positive SLNB, indicates only that the
primary tumour has gained the ability to spread and that complementary adhesion
molecules exist on both the tumour surface and the lymph node stroma. Removal
of the RLNs at this point does nothing to counteract the systemic nature of the
disease unless the RLNs are the only anatomical location that contains the
necessary complementary adhesion molecules. Whether the tumour has
disseminated to other distant locations depends on the presence of the
corresponding adhesion molecule in the tissue in question rather than any intrinsic
property of the RLNs.
If lymph nodes are not passive filters for tumour emboli, then what role do they
play in metastatic disease? We know that the lymph nodes, and other lymphoid
organs, serve to orchestrate important immunological responses to foreign
antigens.[54] This immunological process is important for host defence
mechanisms in the early stages of primary tumour growth when appropriate
antigen recognition and immunological response may prevent the widespread
dissemination of tumour cells.[55-57] Surgical alteration of regional lymphatic
structure and function at this early stage of tumour growth may provide the
tumour with a growth advantage. Surgical alteration of RLN function may also
affect future therapeutic interventions, as research in both animals and humans has
demonstrated that removal of the tumour-draining RLNs prior to antitumour
vaccination significantly diminishes antitumour activity.[58,59] With recent efforts
to develop immunological therapies for many forms of cancer, the value of
maintaining an intact RLN basin in this process will need critical evaluation.
What then are the consequences of tumour metastases developing in the RLNs?
When the volume of metastasis is small, the immunological effect generated
against the primary tumour can be sufficient to control potentially lethal cells in a
dormant state for a long period of time[60,61] and occasionally may result in cell
death without further growth or dissemination.[38] Removal of these clinically
irrelevant cells would be unnecessary and might even be harmful from an
immunological standpoint. Yet, as the tumour grows, eventual
immunosuppression is likely to develop through a variety of tumour-induced
mechanisms.[62] Eventually, the normal lymph node architecture is destroyed
rendering the lymph node immunologically ineffective and a possible source for
further tumour dissemination. At this point, once the tumour has become
biologically active and has obliterated the normal structure and function of the
node, removal would serve to decrease tumour burden and potentially decrease
further tumour-based immunosuppression.[38,63-65]
Unfortunately, current technology does not permit us to determine what
constitutes relevant nodal disease. In one breast cancer trial, 20% of the
observation group eventually developed clinically palpable lymph node
metastases as the site of first recurrence.[15] This is much less than the 38% of
patients found to have microscopic tumour by standard histology after ELND,
suggesting that an immunological response against the tumour cells may have
prevented further growth of microscopic disease in 18% of patients. The use of
more sensitive techniques such as serial sectioning and immunohistochemistry
further increases the number of patients with 'positive' axillary metastases who
never go on to develop clinically positive axillary disease: this was as high as 60%
in one study.[66] When nodes are examined even more closely for submicroscopic
disease via polymerase chain reaction (PCR) analysis, the results are even more
surprising. In melanoma, 60% of patients with primary tumours < 0.75 mm thick
had SLNs that were positive by PCR analysis.[67] This is a remarkably high
number of patients labelled as having positive nodes by PCR in a subset of
melanoma patients who historically have a very favourable prognosis and never
go on to develop clinical lymph node disease. Clearly, the presence of
microscopic and submicroscopic disease does not correlate with clinical course
and overestimates the number of patients who will develop clinically positive
nodal disease. Future research may allow for a determination of which patients
among those with microscopic or submicroscopic disease contain actively
proliferating nodal disease. Identification of these patients would create a
classification of patients who could potentially benefit from lymph node
dissection.
Conclusions
One can conclude from this discussion that the RLNs are biologically important
organs that play a vital role in tumour defence mechanisms. The presence of
metastases in the RLNs is an indication that the tumour has gained the ability to
spread and that the stroma of the lymph node contains the necessary surface
proteins to facilitate tumour attachment. The RLNs should no longer be
considered mechanical filters or barriers preventing the systemic dissemination of
metastatic tumour. In fact, tumour dissemination and ultimately tumour metastasis
is a much more active process than once believed, and results from a dynamic
interaction between the tumour cell and the surface of the endothelium of the
organ where the metastasis eventually develops. Traditional surgical management
of the RLNs for most of the twentieth century was based on the theory that the
lymph nodes served to limit the systemic spread of tumour metastasis. We now
know this theory to be false and we have demonstrated that no scientific evidence
exists to support the routine elective removal of clinically uninvolved lymph
nodes in any cancer in an attempt to prolong survival.
Based on the arguments presented in this article, specific recommendations
regarding the management of the regional lymphatics in cancer can be made.
When no effective adjuvant therapy exists for metastatic disease, close clinical
follow-up and TLND at disease recurrence is an acceptable approach in patient
management. TLND in this case allows for improved local control and may on
occasion even salvage a small number of patients. ELND in this patient
population may also improve local control and assist with staging procedures but
this potential benefit should be weighed against the risks of the procedure, and in
patients who desire more prognostic information SLNB may be a more
appropriate intervention. When proven effective adjuvant therapy exists for
patients with cancer, SLNB can be used as a staging tool to determine those
patients eligible for adjuvant treatment. Staging information obtained from lymph
node dissection, whether used for prognostic purposes or for decisions about
adjuvant therapy, should be interpreted with caution and an understanding that the
presence or absence of metastatic disease in the RLNs is unrelated to the presence
of metastatic disease in other organs.
For patients with melanoma, the above guidelines also apply. The routine use of
ELND offers patients no survival advantage vs. observation and TLND upon
nodal recurrence, and should be abandoned. However, TLND is a useful tool in
the clinical management of patients with recurrent nodal disease and will serve to
improve local control.[68-74] The use of SLNB is a valuable prognostic tool, but
attempts to justify this procedure as standard of care in patients with melanoma
are premature. As no proven effective adjuvant therapy exists for patients with
metastatic melanoma, the additional prognostic information gained by SLNB
should be weighed against the small but real risks of the procedure. As SLNB
remains an experimental procedure, we believe that the use of the procedure in
patients with melanoma should only be performed within the confines of a
controlled experimental protocol. Furthermore, the use of ultrasensitive diagnostic
techniques such as serial sectioning, immunohistochemistry and PCR, made
technically more practical with SLNB, may serve to upstage patients with nodal
disease that will never become biologically meaningful. These techniques should
be considered experimental until evidence exists that validates their use in routine
patient management.
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The Management of Regional Lymph Nodes in Cancer
D.B. Pharis; J.A. Zitelli
Br J Dermatol 149(5):919-925, 2003
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----------------------------------------------------
Page updated January 12, 2006
D.B. Pharis; J.A. Zitelli
Br J Dermatol 149(5):919-925, 2003. ©© 2003 Blackwell Publishing
Posted 12/12/2003
Summary and Introduction
Summary
Early clinical observation in cancer patients suggested that tumours spread in a
methodical, stepwise fashion from the primary site to the regional lymphatics, and
only then to distant locations. Based on these observations, the regional
lymphatics were believed to be mechanical barriers preventing the widespread
dissemination of tumour. Despite evidence now available disputing its validity,
this barrier theory has guided the surgical management of the regional lymphatics
for more than a century, influencing the use of such surgical modalities as
therapeutic lymph node dissection, elective lymph node dissection and most
recently sentinel lymph node biopsy. No published randomized controlled trial
exists that demonstrates improved overall survival for patients with cancer of any
type undergoing surgery of the regional lymphatics. We believe the presence of
tumour in the regional lymphatics indicates the presence of systemic disease, and
therapeutic interventions should be directed accordingly.
Introduction
Management of the regional lymph nodes (RLNs) in potentially metastatic cancer
is fraught with controversies and misunderstandings. Early surgical oncologists
observed many times that the RLNs were enlarged in advanced cancers before
distant disease appeared, leading to the theory that the RLNs served as mechanical
barriers temporarily preventing systemic dissemination of tumour. Based on this
theory, surgeons removed these enlarged lymph nodes along with the primary
tumour, an approach known as therapeutic lymph node dissection (TLND), in an
attempt at surgical cure of locally advanced disease. Unacceptable cure rates,
believed to be a result of unresected microscopic disease, led to the removal of
clinically normal RLNs, a procedure known as elective lymph node dissection
(ELND), in an effort to remove these nonpalpable tumour deposits. By the early
twentieth century, routine dissections of the regional lymphatics in an effort to
remove all microscopic disease had become the dogma of surgical oncology based
exclusively on observation and theory rather than sound scientific evidence. This
barrier theory of lymph node biology continues to influence the management of
the RLNs in cancer surgery today.
In light of current knowledge, does it make sense to perform surgical dissection of
RLNs in patients with cancer? Through well-designed laboratory studies we know
that the lymph nodes serve specific and important functions that aid in essential
immunological responses. We also know that an intact immune system is critical
for host tumour defence mechanisms. Laboratory and clinical studies have cast
doubt on the theory that lymph nodes serve as mechanical barriers to widespread
tumour dissemination. Furthermore, abundant randomized controlled clinical
trials have critically evaluated the role of lymph node dissections in cancer
management and have failed to demonstrate a significant survival advantage. This
paper will review this evidence and will make recommendations regarding the
management of the RLNs in cancer patients, with an emphasis on patients with
melanoma.
Historical Perspective
The theoretical value of TLND, or removal of clinically palpable lymph nodes,
was proposed by the earliest surgical oncologists. In the late eighteenth century,
Heister first advocated axillary dissection for the treatment of breast cancer after
observing the clinical course of patients with advanced disease.[1] Clinical
observation in these patients suggested that the tumour spread in an orderly
fashion from the primary site to the RLNs, and finally to distant locations. Based
on these observations, the prevailing theory that developed and was perpetuated
until late in the twentieth century was that the lymph nodes served as physical
barriers to tumour dissemination. This was tested by Halsted's experiments in
radical mastectomies for breast cancer that entailed en bloc removal of the breast,
the pectoralis muscles and the entire axillary contents.[2] Although Halsted initially
reported improved survival for patients undergoing his radical surgery in 1894, he
later retracted this conclusion after re-analysing the data in 1907.[3]
Halsted's contemporaries argued that the reason the radical mastectomy failed to
improve survival was that trapped, nonpalpable (microscopic) disease was left
behind in other nondissected lymph node basins. However, attempts to improve
on the results of the Halsted mastectomy by dissecting all regional nodal basins
(including the supraclavicular and internal mammary nodes) were met only with
increased operative mortality.[4,5] If more aggressive surgery failed to improve
survival in patients with advanced disease, perhaps earlier, prophylactic lymph
node surgery in patients with more localized disease would. The emphasis of
cancer treatment subsequently shifted to early diagnosis in order to facilitate
surgery in advance of the development of palpable lymphadenopathy. The
theoretical goal of surgical oncology remained removal of trapped tumour cells
within the lymphatics, but at a time when tumour burden was small and the
chance of systemic dissemination was thought to be insignificant. Thus dawned
the age of the ELND.
The theoretical benefit of ELND seemed unassailable when considered in the
context of the belief that the RLNs served as physical barriers to tumour
dissemination. During a time when little else could be offered to cancer patients,
this seemingly rational theory and the chance of a surgical cure for this dreaded
disease captured the attention of surgeons around the world. Numerous
retrospective and single institutional studies were published that supported the
widespread use of ELND in nearly all forms of cancer with the potential for nodal
metastasis including cancer of the breast, uterus, cervix, vulva, prostate, head and
neck, penis and, of course, melanoma.[6-14] Advocates of ELND used the results of
these uncontrolled studies to validate the theory that the RLNs were in fact
barriers to systemic tumour dissemination. Consequently, the role of ELND in
cancer surgery remained unchallenged in surgical oncology until late in the
twentieth century.
A turning point in this story began in 1960 when Bernard Fisher, then the director
of the National Surgical Adjuvant Breast and Bowel Program, began an ambitious
study that was to be the first randomized controlled trial (RCT) investigating the
value of the ELND in breast cancer patients.[15] To the surprise of most, Fisher's
study of 1700 patients failed to reveal any statistically significant survival
advantage for patients undergoing ELND. Although the lymph node dissection
group experienced fewer recurrences in the treated lymph node basin, this
improvement in local control did not translate to a benefit in overall survival. In
fact, when these patients did have recurrences, these were more likely to be distant
disease. Since Fisher's landmark study, five RCTs evaluating ELND in breast
cancer patients have failed to reveal a statistically significant survival advantage
for patients treated with ELND.[16] The lack of evidence supporting the value of
ELND for breast cancer patients in these five trials raised significant questions
regarding the dogmatic but unproven traditional approach to surgical management
in patients with cancer.
Based on the results of Fisher's work in breast cancer, other researchers began
critical evaluation of the value of ELND in other cancers. There have been four
RCTs evaluating ELND in 1718 patients with cutaneous melanoma.[17-20]
Melanoma patients randomized to ELND experienced fewer recurrences in the
dissected lymph node basin, but none of the studies showed a statistically
significant survival advantage. The largest of these trials, the Intergroup
Melanoma Surgical Trial,[17] included 740 patients with melanomas 1-4 mm thick.
As with the other three trials, there was no survival advantage for those patients
undergoing ELND compared with those patients treated with TLND at disease
recurrence. Even though retrospective subgroup analysis found trends in favour of
ELND in patients less than 60 years old with nonulcerated, intermediate thickness
melanomas (1-2 mm thick), this type of post hoc analysis attempts to discern
therapeutic benefits in subsets of patients for which the study was not initially
designed, and is fraught with considerable bias. For this reason, many experts
remain hesitant to advocate ELND for their patients based on this type of
statistical analysis.
Published RCTs evaluating ELND in the management of other cancers are few.
Two small RCTs of only 35 and 75 patients failed to reveal any statistically
significant survival advantage for patients with squamous cell carcinoma of the
oral cavity undergoing ELND.[21,22] Although statistically meaningful conclusions
cannot be made from such a small patient population, as in breast cancer and
melanoma patients those patients randomized to ELND experienced fewer
regional recurrences in the dissected lymph node basin. The improvement in local
control offered by ELND in patients with head and neck cancer may provide a
tangible benefit in this functionally important area. Control of disease influence
on tracheal, oesophageal and cervical neurovascular function would certainly
maintain a high priority in disease management. This may explain why neck
dissections remain an important tool in the treatment of patients with head and
neck cancer despite a lack of evidence of improved overall survival for those
undergoing such interventions.
As sound scientific evidence accumulated to show that ELND offered no survival
advantage for cancer patients, surgeons in the late twentieth century began to look
for other ways to assess the status of the regional lymphatics for staging purposes.
In 1992, Morton et al. reported the technique of sentinel lymph node (SLN)
biopsy (SLNB) in patients with early stage melanoma.[23] As initially described,
isosulfan blue dye was injected around the primary melanoma and soon
afterwards the RLN basin was dissected to locate the initial or sentinel draining
lymph node. Because of the prevailing belief in the barrier theory of the regional
lymphatics, it was theorized that the histological status of the sentinel node would
accurately predict whether or not the tumour had metastasized from the primary
site. In patients with melanoma, the status of the SLN using standard histology
became the single most accurate prognostic indicator of metastatic disease.[24]
Now performed with the use of radiolabelled sulphur colloid, SLNB has become a
widely used staging tool in cancers of all types with the potential for spread to the
regional lymphatics.[25-31] In these cancers, the status of the SLN often guides
further therapeutic interventions including completion lymphadenectomy and
adjuvant chemotherapy or radiation therapy. However, like TLND and ELND
before it, the theoretical value of SLNB is based on the barrier theory of the RLNs
and remains an experimental procedure with no proven therapeutic benefit.
The Role of the Regional Lymph Nodes
So why are surgeons continuing to submit cancer patients to surgery of the RLNs
without any sound scientific evidence of significant survival benefit? Perhaps
some continue to dissect RLN basins in cancer patients based more on surgical
tradition rather than scientific evidence. Many surgeons probably remain
convinced that the RLNs are mechanical barriers preventing tumour dissemination
and that design flaws in the RCTs testing ELND prevent the detection of a small
but real benefit for patients undergoing elective node dissection. Likewise, some
melanoma experts argue that all studies evaluating ELND in melanoma patients
prior to the advent of SLNB are confounded by the fact that in a small but
significant percentage of patients the wrong lymph node basin would have been
dissected. These arguments may have some validity, but with each large-scale
RCT published that fails to demonstrate a survival advantage for ELND,
regardless of cancer type, it becomes more difficult to dismiss all these studies as
scientifically flawed.
We believe that the reason ELND does not benefit patients with cancer is because
the RLNs are not mechanical filters or dams preventing the spread of tumour to
the systemic circulation but are instead indicators of the presence of systemic
metastasis. Therefore, removal of lymph nodes, even in early disease, will only
remove the metastases that are in the RLNs, not those that simultaneously
metastasize elsewhere. Early research by Fisher that led to the initiation of his
landmark breast cancer trial cast significant doubt on the belief that lymph nodes
were passive filters for metastasizing cancer cells or that nodes were exposed to
tumour before the systemic circulation. His studies in rodents demonstrated that
tumour emboli, even when large, could pass through the draining lymphatics and
at times bypassed the lymph node altogether.[32-35] Other studies demonstrated
malignant cells in the venous runoff from various types of solid tumours thought
at that time to spread only via lymphatics.[36,37] This lymph node permeability is
due in part to abundant intranodal and lymphaticovenous shunts that can be
demonstrated by functional studies as well as by electron microscopy.[32,35,38-42]
If lymph nodes are not mechanical filters for tumour emboli, then what influences
the location where a tumour metastasis develops? Recent research illustrates that
various tumour types clearly have organ specificity for their metastases.[43-47] This
organ specificity appears to be dictated by surface proteins called adhesion
molecules on both the tumour cells and the tissue where the metastasis comes to
rest. After the tumour cell breaks away from the primary lesion, it circulates
through the lymphatic and arteriovenous system, bouncing and even rolling across
the endothelium within various organs and tissues. As it does so, adhesion
molecules on the tumour cell regularly come in contact with adhesion molecules
on the endothelium of the organ or tissue in question. These adhesion molecules
must be complementary in order for metastases to develop.[48,49] If complementary
adhesion molecules exist, the tumour cell binds to the endothelium and may
become a clinical metastasis if it is successful at avoiding tumour defence
mechanisms. Consequently, if complementary adhesion molecules do not exist in
the RLNs, tumour emboli circulating in the lymphatic system will bypass the
RLNs while metastasizing to distant locations.[44,45,50-53] This means that the
presence of tumour within RLNs, as in a positive SLNB, indicates only that the
primary tumour has gained the ability to spread and that complementary adhesion
molecules exist on both the tumour surface and the lymph node stroma. Removal
of the RLNs at this point does nothing to counteract the systemic nature of the
disease unless the RLNs are the only anatomical location that contains the
necessary complementary adhesion molecules. Whether the tumour has
disseminated to other distant locations depends on the presence of the
corresponding adhesion molecule in the tissue in question rather than any intrinsic
property of the RLNs.
If lymph nodes are not passive filters for tumour emboli, then what role do they
play in metastatic disease? We know that the lymph nodes, and other lymphoid
organs, serve to orchestrate important immunological responses to foreign
antigens.[54] This immunological process is important for host defence
mechanisms in the early stages of primary tumour growth when appropriate
antigen recognition and immunological response may prevent the widespread
dissemination of tumour cells.[55-57] Surgical alteration of regional lymphatic
structure and function at this early stage of tumour growth may provide the
tumour with a growth advantage. Surgical alteration of RLN function may also
affect future therapeutic interventions, as research in both animals and humans has
demonstrated that removal of the tumour-draining RLNs prior to antitumour
vaccination significantly diminishes antitumour activity.[58,59] With recent efforts
to develop immunological therapies for many forms of cancer, the value of
maintaining an intact RLN basin in this process will need critical evaluation.
What then are the consequences of tumour metastases developing in the RLNs?
When the volume of metastasis is small, the immunological effect generated
against the primary tumour can be sufficient to control potentially lethal cells in a
dormant state for a long period of time[60,61] and occasionally may result in cell
death without further growth or dissemination.[38] Removal of these clinically
irrelevant cells would be unnecessary and might even be harmful from an
immunological standpoint. Yet, as the tumour grows, eventual
immunosuppression is likely to develop through a variety of tumour-induced
mechanisms.[62] Eventually, the normal lymph node architecture is destroyed
rendering the lymph node immunologically ineffective and a possible source for
further tumour dissemination. At this point, once the tumour has become
biologically active and has obliterated the normal structure and function of the
node, removal would serve to decrease tumour burden and potentially decrease
further tumour-based immunosuppression.[38,63-65]
Unfortunately, current technology does not permit us to determine what
constitutes relevant nodal disease. In one breast cancer trial, 20% of the
observation group eventually developed clinically palpable lymph node
metastases as the site of first recurrence.[15] This is much less than the 38% of
patients found to have microscopic tumour by standard histology after ELND,
suggesting that an immunological response against the tumour cells may have
prevented further growth of microscopic disease in 18% of patients. The use of
more sensitive techniques such as serial sectioning and immunohistochemistry
further increases the number of patients with 'positive' axillary metastases who
never go on to develop clinically positive axillary disease: this was as high as 60%
in one study.[66] When nodes are examined even more closely for submicroscopic
disease via polymerase chain reaction (PCR) analysis, the results are even more
surprising. In melanoma, 60% of patients with primary tumours < 0.75 mm thick
had SLNs that were positive by PCR analysis.[67] This is a remarkably high
number of patients labelled as having positive nodes by PCR in a subset of
melanoma patients who historically have a very favourable prognosis and never
go on to develop clinical lymph node disease. Clearly, the presence of
microscopic and submicroscopic disease does not correlate with clinical course
and overestimates the number of patients who will develop clinically positive
nodal disease. Future research may allow for a determination of which patients
among those with microscopic or submicroscopic disease contain actively
proliferating nodal disease. Identification of these patients would create a
classification of patients who could potentially benefit from lymph node
dissection.
Conclusions
One can conclude from this discussion that the RLNs are biologically important
organs that play a vital role in tumour defence mechanisms. The presence of
metastases in the RLNs is an indication that the tumour has gained the ability to
spread and that the stroma of the lymph node contains the necessary surface
proteins to facilitate tumour attachment. The RLNs should no longer be
considered mechanical filters or barriers preventing the systemic dissemination of
metastatic tumour. In fact, tumour dissemination and ultimately tumour metastasis
is a much more active process than once believed, and results from a dynamic
interaction between the tumour cell and the surface of the endothelium of the
organ where the metastasis eventually develops. Traditional surgical management
of the RLNs for most of the twentieth century was based on the theory that the
lymph nodes served to limit the systemic spread of tumour metastasis. We now
know this theory to be false and we have demonstrated that no scientific evidence
exists to support the routine elective removal of clinically uninvolved lymph
nodes in any cancer in an attempt to prolong survival.
Based on the arguments presented in this article, specific recommendations
regarding the management of the regional lymphatics in cancer can be made.
When no effective adjuvant therapy exists for metastatic disease, close clinical
follow-up and TLND at disease recurrence is an acceptable approach in patient
management. TLND in this case allows for improved local control and may on
occasion even salvage a small number of patients. ELND in this patient
population may also improve local control and assist with staging procedures but
this potential benefit should be weighed against the risks of the procedure, and in
patients who desire more prognostic information SLNB may be a more
appropriate intervention. When proven effective adjuvant therapy exists for
patients with cancer, SLNB can be used as a staging tool to determine those
patients eligible for adjuvant treatment. Staging information obtained from lymph
node dissection, whether used for prognostic purposes or for decisions about
adjuvant therapy, should be interpreted with caution and an understanding that the
presence or absence of metastatic disease in the RLNs is unrelated to the presence
of metastatic disease in other organs.
For patients with melanoma, the above guidelines also apply. The routine use of
ELND offers patients no survival advantage vs. observation and TLND upon
nodal recurrence, and should be abandoned. However, TLND is a useful tool in
the clinical management of patients with recurrent nodal disease and will serve to
improve local control.[68-74] The use of SLNB is a valuable prognostic tool, but
attempts to justify this procedure as standard of care in patients with melanoma
are premature. As no proven effective adjuvant therapy exists for patients with
metastatic melanoma, the additional prognostic information gained by SLNB
should be weighed against the small but real risks of the procedure. As SLNB
remains an experimental procedure, we believe that the use of the procedure in
patients with melanoma should only be performed within the confines of a
controlled experimental protocol. Furthermore, the use of ultrasensitive diagnostic
techniques such as serial sectioning, immunohistochemistry and PCR, made
technically more practical with SLNB, may serve to upstage patients with nodal
disease that will never become biologically meaningful. These techniques should
be considered experimental until evidence exists that validates their use in routine
patient management.
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