I think that it has been frequently cited because it is one of my
pivotal papers in the last 10 years: it validates the technique of
sentinel node mapping as performed by multidisciplinary teams at
internationally known melanoma centers. However, this study is neither
the first nor the most important of my studies on sentinel node
biopsy.
The landmark trial of intraoperative lymphatic mapping to identify
and biopsy the sentinel lymph node was conducted by our group in the
late 1980s and first published in 1990 (Morton DL, et al.,
"Technical details of intraoperative lymphatic mapping for early
stage melanoma," Arch. Surg. 127:392-9, 1992). That paper
described the concept and application of lymphatic mapping to identify
the first tumor-draining lymph node (the sentinel node) in patients
with clinically localized primary cutaneous melanoma.
Sentinel node biopsy is important because it accurately assesses
the regional lymph nodes without significant operative morbidity. The
tumor status of these nodes is the most important determinant of
clinical outcome for all cancers that spread through the lymphatics,
i.e., 90% of human cancers.
Before the advent of sentinel node biopsy, the common practice was
radical node resection, a procedure not without significant morbidity.
Moreover, because only 20% of patients with clinically localized
primary melanoma have nodal metastases, routine use of radical node
resection exposes 80% of patients to operative risks without potential
benefit.
Although many investigators have attempted selective biopsy for
regional nodes, most of their techniques have been based on nodal
anatomy. This approach is not particularly accurate because lymphatic
pathways vary in each patient.
By contrast, the sentinel node concept is based on lymphatic flow,
not lymphatic anatomy. It identifies the first tumor-draining lymph
node, which is the node most likely to contain any cancer cells that
have spread from the primary tumor. If this node is tumor-free, then
all other nodes in the lymphatic drainage basin are very unlikely to
contain tumor.
Our studies of lymphatic mapping began over 30 years ago. In 1977,
we published a study describing the intradermal injection of colloidal
gold at the site of a primary melanoma. The colloid was tracked as it
flowed from the primary tumor to the regional lymphatic drainage
basin.
By identifying the lymphatic drainage basin, we were able to avoid
inadequate or incorrect lymphadenectomy in patients with primary
tumors on the head/neck, trunk, or other sites with ambiguous or
multiple drainage patterns (Holmes EC, et al., "A rational
approach to the surgical management of melanoma," Ann. Surg.
186:481-490, 1977; Robinson DS, et al., "Regional
lymphatic drainage in primary malignant melanoma of the trunk
determined by colloidal gold scanning," Surg. Forum
28:147-8, 1977; Morton DL, Goodnight JE Jr., "Clinical trials of
immunotherapy. Present status," Cancer 42:2224-33, 1978;
Fee HJ, et al., "The determination of lymph shed by
colloidal gold scanning patients with malignant melanoma: A
preliminary study," Surgery 84:626-32, 1978).
In the mid-80s we began to focus on identifying tumor-draining
nodes within a drainage basin. In animal studies, we used intradermal
injection of a vital blue dye to demonstrate compartmentalization of
lymphatic drainage: each area of skin drained to a different lymph
node. Our preclinical and clinical studies of dye-directed lymphatic
mapping after lymphoscintigraphic identification of the drainage basin
led to the development of sentinel node biopsy as described in our
seminal 1992 paper in Archives of Surgery (see above).
Although this paper described sentinel node biopsy for melanoma,
the technique applies to all solid cancers that metastasize via the
lymphatics. Thus by 1994 we reported successful application of
sentinel node biopsy in patients with primary breast cancer (Giuliano
AE, et al., "Lymphatic mapping and sentinel
lymphadenectomy for breast cancer," Ann. Surg.
220:391-401, 1994). We subsequently applied sentinel node biopsy to
colon cancer, head and neck cancer, and lung cancer.
Sentinel node biopsy is a multidisciplinary technique; although it
requires surgical expertise to identify the first tumor-draining lymph
node, it also relies on accurate histopathologic assessment of this
node to identify any tumor cells. In the early 1980s, we reported
results of laboratory work to develop an immunohistochemical assay for
tumor cells in the lymph nodes (Gaynor R, Irie R, Morton DL, Herschman
HR, "S100 protein is present in cultured human malignant
melanomas," Nature 286:400-1, 1980; Gaynor R, et al.,
"S100 protein: A marker for human malignant melanomas?" Lancet
1:869-72, 1981).
By the late 1980s, we reported the clinical application of our
immunohistochemical assay (Cochran AJ, Wen DR, Morton DL, "Occult
tumor cells in the lymph nodes of patients with pathological Stage I
malignant melanoma," Am. J. Surg. Path. 12[8]:612-8,
1988). This study demonstrated the detection of very small numbers of
tumor cells in the lymph nodes of patients who had no clinical
evidence of nodal metastases.
After developing surgical techniques to map the drainage basin and
identify tumor-draining nodes within that basin, we went one step
further and developed a surgical technique to identify intranodal
sites of metastasis and a molecular technique to increase the
sensitivity of tumor detection. The result was a seminal study on the
use of carbon dye and RT-PCR (Morton DL, et al.,
"Lymphatic mapping and sentinel lymphadenectomy for early-stage
melanoma: therapeutic utility and implications of nodal microanatomy
and molecular staging for improving the accuracy of detection of nodal
micrometastases," Ann. Surg. 238:538-50, 2003).
Your
most-cited papers from 1995 to about 2000 seem to cover lymphatic
mapping and sentinel lymphadenectomy, markers for melanoma, and
melanoma vaccines. Do you consider these the three most important
areas in melanoma research? Why or why not?
My work on active specific (vaccine) immunotherapy in melanoma
actually began decades ago, when I became intrigued by several case
reports of spontaneous regression of cancer. While at the National
Cancer Institute, I treated a patient whose melanoma regressed
without intervention. I began to investigate the immune response in
cancer, using melanoma as a model because this cancer is
exceptionally immunogenic.
In 1968 I reported the first evidence of antibodies against human
melanoma (Morton DL, et al., "Demonstration of
antibodies against human malignant melanoma by immunofluorescence,"
Surgery 64:233-40, 1968). I subsequently initiated
preclinical studies to induce to induce immunity against cancers.
The first clinical demonstration of immunotherapy for melanoma
was my report on intratumoral injection of BCG (Bacille
Calmette-Guérin) to induce complete regression of cutaneous lesions
(Morton DL, et al., "Immunological factors which
influence response to immunotherapy in malignant melanoma," Surgery
68:158-64, 1970). This was the first evidence that immunotherapy
could induce regression of a metastatic human cancer.
The follow-up trial published several years later remains a
pivotal study on active nonspecific immunotherapy in melanoma
(Morton DL, et al., "BCG immunotherapy of malignant
melanoma: Summary of a seven-year experience," Ann. Surg.
180:635-43, 1974).
In 1975, I reported the first use of intralesional BCG to cause
regression of melanoma metastatic to the bladder (deKernion JB, et
al., "Successful transurethral intralesional BCG therapy of
a bladder melanoma," Cancer 36:1622-67, 1975). Although
that application was for melanoma, this study eventually led to the
FDA’s approval of BCG to treat superficial bladder cancer. Thirty
years after the study, BCG remains the only FDA-approved treatment
for bladder cancer.
Although BCG is an excellent nonspecific local immunostimulant,
intralesional injection is limited to the very few cancers that are
in the skin or bladder and therefore accessible. However, our early
animal models showed that BCG acted as an immune adjuvant when
administered with a crude vaccine made of irradiated tumor cells.
We therefore began a series of clinical trials in which patients
were immunized with a therapeutic vaccine comprising melanoma cells
and various immune adjuvants. Although we could only immunize about
one-third of patients, those whom we did immunize had a much more
favorable clinical course than those who could not be immunized. The
problem was that the vaccine did not stimulate a very strong immune
response.
In 1984, we developed a new vaccine (Canvaxin) made of three
carefully selected human melanoma cell lines that expressed strongly
immunogenic tumor-associated antigens. This vaccine was highly
successful in phase II trials for patients with regional or distant
metastatic melanoma (Morton DL, et al.,
"Prolongation of survival in metastatic melanoma after active
specific immunotherapy with a new polyvalent melanoma
vaccine,". Ann. Surg. 216[4]:463-82, 1992; Morton DL, et
al., "Prolonged survival of patients receiving active
immunotherapy with Canvaxin therapeutic polyvalent vaccine after
complete resection of melanoma metastatic to regional lymph
nodes," Ann. Surg. 236:438-449, 2002).
Although Canvaxin has not shown a significant overall survival
benefit in phase III trials, data suggest that it may be clinically
effective in certain subgroups of patients. We are now attempting to
define these groups in an immunologic response model.
What
do your colleagues tell you about the value of your work?
Because I am my harshest critic, I am always encouraged by
feedback from my colleagues, friends, and patients. Most recently, I
was thrilled to receive the National Cancer Fighters Award at the
American College of Surgeons Clinical Congress in San Francisco, and
an award for my lifelong contributions to melanoma research at the
International Melanoma Congress in Vancouver. I also take great
pride in my tenures as president of two international and one
national surgical society.
What
are you working on now?
We’re waiting for the final results of the first Multicenter
Selective Lymphadenectomy Trial (MSLT-I). Our initial report on the
morbidity and accuracy of sentinel node biopsy in this phase III
trial was just published (Morton DL, et al., "Multicenter
Selective Lymphadenectomy Trial Group: Sentinel node biopsy for
early-stage melanoma: accuracy and morbidity in MSLT-I, an
international multicenter trial," Ann. Surg. 242:302-11,
2005).
You
are on the editorial boards of many journals. Do you think that you
have influenced the direction of any of these journals?
Perhaps because I have successfully published so many
peer-reviewed papers, I am also a very objective reviewer. My most
important contribution to a journal’s goals and direction was made
as founding associate editor of the Annals of Surgical Oncology,
now one of the top-ranked surgical journals.
I
note that you are a practicing physician. Do you still see patients on
a regular basis or are you brought in for difficult cases or for
patients whose cases would be good for research purposes?
I am most emphatically a practicing surgical oncologist. I cannot
imagine continuing in surgical oncology without my clinical
practice. Yes, I do tend to receive many referrals for
"difficult" cases from all over the world. Many of these
patients have melanoma and are enrolled in one of the clinical
research studies that I direct.
What
in your career are you most proud of?
Probably one of the things I’m most proud of is my citation by
the journal Science, June 15, 2001, as one of the top
clinical investigators with respect to competitive funding awards
from the National Institutes of Health. That’s probably the
greatest recognition, because it means my scientific peers and
colleagues have entrusted our tax money for cancer research with me.
And I think it’s wisely used.
I am also proud of my pivotal role in bringing the TA90 immune
complex assay into clinical practice. This immune assay for early
diagnosis of new or recurring cancer is available through Quest
Laboratories (Kelley MC, et al., "Tumor-associated
antigen TA90 immune complex assay predicts recurrence and survival
after surgical treatment of stage I-III melanoma," J. Clin.
Oncol. Classic Papers Current Comments 7:477-84, 2002,
originally published in J. Clin. Oncol. 19:1176-82, 2001).
As one of the first surgeons to specialize in surgical oncology,
I take great pride in my enduring contribution to the training of
many top surgical oncologists now in practice today. During the last
30 years, I have mentored more than 90 fellows. Two thirds of them
have an academic teaching position. Of those who graduated from our
training program before 1992, 56% are departmental chairs or chiefs
of surgical oncology; of those who graduated since 1992, about 40%
are in leadership roles in surgical oncology. Although I cannot take
credit for their innate ability, I am very proud to have guided
their path to a successful surgical career.
My parents always told me: If you’re going to do something, do
it well.
Donald L. Morton, M.D.
John Wayne Cancer Institute
Santa Monica, CA, USA
n
the fall of 2005, Special Topics correspondent Myrna Watanabe
talked with Dr. Donald L. Morton about his highly cited work
in melanoma research. According to our analysis of melanoma
research over the past decade, Dr. Morton’s work ranks at
#4, with 106 papers cited a total of 3,001 times. His citation
record in 
includes 156 papers cited a total of 4,684 times to date, most
of which are in the field of Clinical Medicine.
