A Selective Approach to the Resection of Cystic Lesions of the Pancreas

Article (PDF Available)inAnnals of Surgery 244(4):572-82 · November 2006with22 Reads
DOI: 10.1097/01.sla.0000237652.84466.54 · Source: PubMed
To define a group of patients with pancreatic cysts who do not require resection. The increased use of cross-sectional imaging has resulted in an increased identification of small, asymptomatic pancreatic cysts. Data have not been available to determine which lesions should be resected. All patients evaluated at our institution between January 1995 and January 2005 for the ICD-9 diagnosis of pancreatic cyst were reviewed. Analysis was performed to identify associations between patient and cyst characteristics, and selection of operative or nonoperative management. Pancreatic cysts were evaluated in 539 patients. Initial management was operative in 170 patients (32%), and nonoperative (radiographic follow-up) in 369 patients (68%). Factors associated with initial operative management included presence of a solid component (45% vs. 6%, P < 0.001), larger size of the lesion (mean 4.8 cm vs. 2.4 cm, P = 0.001), and presence of symptoms (44% vs. 16%, P = 0.001). Malignancy was present in 18% (32 of 170) of patients initially resected. Mucinous tumors (n = 18) were the most common malignant histologic subtype. None of the invasive cancers arising from mucinous cysts was <3 cm. Median radiographic follow-up in patients initially managed nonoperatively was 24 months (range, 1-172 months). In 29 patients (8%), changes developed within the cyst that resulted in resection; malignancy was present in 11 of 39 (38%), representing 3% (11 of 369) of all patients being followed radiographically. Selected patients with cystic lesions <3 cm in diameter and without a solid component may be followed radiographically with a malignancy risk (3% this study) that approximates the risk of mortality from resection. Malignancy within mucinous tumors is associated with size, and small mucinous tumors are very unlikely to be malignant.
A Selective Approach
to Resection of Cystic
Lesions of the
Pancreas: Results From
539 Consecutive
To the Editor:
would like to congratulate Dr. Allen
and colleagues for this very fine paper
on what is probably the largest series to
date addressing cystic lesions of the
pancreas (CLP).
The authors concluded
that adopting a selective approach was
appropriate in the management of CLP
based on the results of their study, and
this could be done by using preoperative
characteristics such as cyst size, pres-
ence of solid components, presence of
symptoms, and age of patients. They
came to this conclusion as their data
demonstrated that these characteristics
were significantly different in patients
who underwent immediate surgery com-
pared with those who were initially man-
aged conservatively and that the propor-
tion of malignant cysts in those managed
conservatively was only 3% compared
with those who underwent immediate sur-
gery (18%). However, I do not agree en-
tirely with their conclusion.
In my opinion, the conclusion that
the proportion of malignant cysts in pa-
tients managed conservatively was only
3% may be an underestimate. The au-
thors came up with this calculation by
dividing the entire cohort of 369 patients
who were selected for observation with
the number of patients (n 11) who had
a malignant cyst. By doing this, they
were working on the assumption that the
majority of patients without a definite
pathologic diagnosis (n 340) did not
have a malignant CLP. In fact, of the 29
patients selected for observation whom
eventually underwent resection, 11 (38%)
were found to have a malignant cyst.
Hence, I would challenge the assump-
tion that all the patients without a patho-
logic diagnosis did not have a malignant
cyst. I would argue that it is possible that
a significant proportion of the patients
observed may harbor a malignant cyst,
which has yet to manifest as the median
follow-up of these patients was only 24
months. This hypothesis is further sup-
ported by the fact that the authors re-
ported that 3 of the 11 patients only had
the malignancy identified after more that
48 months from initial detection. It is
also interesting to note that, despite this
study spanning a period of 10 years, the
median follow-up was only 24 months.
Was this because many patients were
lost to follow-up or that the surgeons
tended to adopt a more conservative
approach only recently?
Curiously although it is widely
known that pancreatic pseudocysts are
the most common CLP,
the proportion
of pseudocysts in this series is poten-
tially relatively low as only 38 patients
(7%) had a history of pancreatitis. Could
this be due to the referral pattern at
MSKCC, which is a tertiary level cancer
institution, or were some of these pa-
tients for some reason or another not
included in the study? How many of the
CLP managed conservatively were clin-
ically diagnosed as pseudocysts based
on a history or biochemical or radiologic
evidence of pancreatitis? In my opinion,
these patients should be excluded and
only patients with “suspected cystic
neoplasms” or “indeterminate CLP” be
included in the analysis as it gives a
“false impression” that many CLP can
be managed safely with follow-up. Fur-
thermore, was a clinical picture sugges-
tive of pancreatitis a criterion used in
favor of conservative management? It
would be important to know how many
of the patients with pancreatitis eventu-
ally were found to have pseudocysts or
other pancreatic neoplasms.
I think it would also be useful if
the authors can provide us with some
data from the 199 patients with a patho-
logic diagnosis on the predictive effect
of each of the above-mentioned charac-
teristics on the premalignant and/or ma-
lignant potential of CLP. The utility of
the selection criteria would be further
supported if these characteristics did in-
deed predict a premalignant or malig-
nant CLP with a high positive predictive
value. We and several others have also
previously demonstrated that the pres-
ence of symptoms and cyst size are
useful predictors of malignancy.
ditionally, did the authors use other cri-
teria, such as serum tumor markers and
presence of a dilated pancreatic duct,
which have been shown to be useful in
predicting malignancy in CLP?
Finally, I would like to add that
the finding in this study where none of
the 40 small (3 cm) mucinous neo-
plasms was found to have an invasive
carcinoma is important as it confirms the
strong association of cyst size with ma-
lignancy for mucinous neoplasms. This
finding is also reflective of the results
from our recent review of 344 mucinous
cystic neoplasms where we found that
none of the malignant mucinous cystic
neoplasms was less than 3 cm.
Brian K. P. Goh, MBBS, MRCS,
Department of Surgery
Singapore General Hospital
1. Allen PJ, D’Angelica MD, Gonen M, et al. A
selective approach to the resection of cystic le-
sions of the pancreas: results from 539 consecu-
tive patients. Ann Surg. 2006;244: 572–582.
2. Brugge WR, Lauwers GY, Sahani D, et al.
Cystic neoplasms of the pancreas. N Engl
J Med. 2004;351:1218 –1226.
3. Goh BK, Tan YM, Cheow PC, et al. Cystic
lesions of the pancreas: an appraisal of an
aggressive resection policy adopted at a single
institution during 14 years. Am J Surg. 2006;
192:148 –154.
4. Fernandez-del Castillo C, Targarona J, Thayer
SP, et al. Incidental pancreatic cysts: clinicopath-
ologic characteristics and comparison with symp-
tomatic patients. Arch Surg. 2003;138:427–434.
5. Fernandez-del Castillo C, Alsfasser G, Targa-
rona J, et al. Serum CA 19-9 in the manage-
ment of cystic lesions of the pancreas. Pan-
creas. 2006;32:220.
6. Goh BK, Tan YM, Chung YF, et al. A review
of mucinous cystic neoplasms of the pancreas
defined by ovarian-type stroma: clinicopatho-
logical features of 344 patients. World J Surg.
2006;30:2236 –2245.
e appreciate Dr. Goh’s thoughtful
comments regarding our recent
paper on the management of pancreatic
cysts, and we would like to respond to
several points discussed in his letter. We
agree that 3% may be an underestimate
with respect to the percentage of pa-
tients followed radiographically who are
later identified with a malignant cyst.
The median follow-up in our study was
24 months, and the percentage of pa-
Annals of Surgery Volume 245, Number 5, May 2007 825
tients with malignancy can only increase
as follow-up continues. We would like
to highlight, however, that the 11 pa-
tients with malignancy who were ini-
tially followed radiographically (11 of
349, 3%) consisted of 8 patients with
adenocarcinoma and 3 patients with
neuroendocrine tumors. We would an-
ticipate that any cystic lesion truly asso-
ciated with pancreatic adenocarcinoma
would demonstrate some progression
within 24 months. We would also high-
light that no patient with a malignant
mucinous tumor underwent delayed re-
section. With longer follow-up, addi-
tional lesions may develop changes that
prompt resection; however, many of
these may also be resected prior to the
development of malignancy.
There were very few patients
(n 38, 7%) in this study with a history
of pancreatitis, and this certainly reflects
the referral bias of our institution. We
did not exclude these patients because
they comprised a significant minority of the
overall group, and the level of certainty as to
whether the lesion represented a pseudocyst
or cystic neoplasm was variable. In addition,
several of these patients presented with an
episode of pancreatitis, were resected, and
were discovered to have a malignant pro-
cess. Certainly, our approach toward patients
with presumed pseudocyst is different from
the approach toward patients with cystic
neoplasms. However, since such a small
percentage of patients in this study group
had pancreatitis, we did not find this to be
associated with management.
We do not have enough data to
comment on the value of serum markers.
Patients with dilation of the main pan-
creatic duct are typically considered to
have main-duct intraductal papillary
mucinous neoplasm (IPMN), which has
a high rate of invasive malignancy, or
pancreatic adenocarcinoma not in asso-
ciation with IPMN. Both of these groups
of patients are not typically labeled as
“cystic lesions of the pancreas” and are
treated with resection. The primary
characteristics listed in the decision tree
analysis included the presence of a solid
component and cyst size. Resection was
performed in 80 of the 105 patients with
solid component, and malignancy was
identified in 22 of these patients (28%).
The radiographic diameter of the lesions
without a solid component was 2.5 cm
in 309 patients; and in 272 of these
patients, radiographic follow-up was
performed. Within this group of 272
patients, subsequent malignancy has
been identified in 8 patients (3%).
We agree with Dr. Goh’s recom-
mendations for the management of small
(3 cm) mucinous lesions. Similar to Dr
Goh’s group, we have not encountered
invasive malignancy in any mucinous cyst
3 cm, and this is similar to other re-
ported series.
Our goal in initiating this
project was to help identify a group of pa-
tients with cystic lesions who have a risk of
malignancy that is less than the risk of mor-
tality from pancreatectomy, and this group
of patients appears to fit into this category. It
must be emphasized, however, that these
lesions do have malignant potential and
must be followed radiographically. We are
encouraged by the fact that no patient with a
malignant mucinous tumor underwent de-
layed resection, and we think that, with care-
ful follow-up, we may be able to selectively
resect those mucinous lesions progressing
toward malignancy.
Peter J. Allen, MD
Murray F. Brennan, MD
Memorial Sloan-Kettering Cancer Center
New York, NY
1. Sahani DV, Saokar A, Hahn PF, et al. Pancreatic
cysts 3 cm or smaller: how aggressive should
treatment be? Radiology. 2006;238:912–919.
2. Zamboni G, Scarpa A, Bogina G, et al.
Mucinous cystic tumors of the pancreas: clini-
copathological features, prognosis, and rela-
tionship to other mucinous cystic tumors.
Am J Surg Pathol. 1999;23:410 422.
A Selective Approach
to the Resection of
Cystic Lesions of the
Pancreas: Results From
539 Consecutive
To the Editor:
e read with interest the recent ar-
ticle by Allen et al on pancreatic
cysts, which discusses the role of non-
operative management for the majority
of these lesions. We fully agree with
them that a selective approach is needed
when evaluating a patient with a pancre-
atic cyst, particularly if it is an incidental
finding, to avoid operations on benign
neoplasms that may be associated with
early and late complications.
However, we have some reserva-
tions about this study:
1. The term “cystic lesions of the pan-
creas” is too heterogeneous, and any
decision regarding treatment needs to
go several steps further by selective
use of dedicated pancreatic imaging
(computed tomography and/or mag-
netic resonance imaging resonance
with cholangiopancreatography) and
endoscopic ultrasound. Even assum-
ing that a distinction between inflam-
matory and neoplastic cyst has been
made (hopefully on the basis of a
clinical correlate), merely dichoto-
mizing neoplastic cysts into serous
and mucinous may result in danger-
ous oversimplification, since not all
mucinous cysts are equal.
It is
important that both the radiologist
and the clinician who is responsi-
ble for the patient make the effort
to differentiate between a mucinous
cystic neoplasm, a branch-duct intra-
ductal papillary mucinous neoplasm
(IPMN), or a main-duct IPMN. Dr.
Allen and coworkers wrongly as-
sume that main-duct IPMNs are un-
likely to present as a cystic lesion in
the pancreas. Several papers have
highlighted that the radiologic pre-
sentation of main-duct IPMN can be
that of an isolated cyst
8 –10
; and with
a frequency of malignancy in main-
duct IPMN of 70% and a rate of
invasive carcinoma of 40%,
this is
not a lesion that should be observed.
Likewise, if the lesion is suspected to
be a mucinous cystic neoplasm (be-
cause there is no connection to the
ductal system of the pancreas, the
patient is female, and the cyst is in
the distal pancreas), the current rec-
ommendation is to proceed with re-
section and not to observe.
radiologist and the clinician also
need to keep in mind that there are
other neoplastic cysts that are nonse-
rous and nonmucinous. These include
solid pseudopapillary neoplasm and
cystic neuroendocrine tumors, both of
which should be resected. Finally,
other factors, such as a family history
Letters to the Editor Annals of Surgery Volume 245, Number 5, May 2007
© 2007 Lippincott Williams & Wilkins826
of pancreatic cancer or an elevated se-
rum CA 19.9, should be considered in
the decision-making.
2. An adenocarcinoma was found in
8 patients initially followed radio-
graphically and, unfortunately, 5 of
them had unresectable or metastatic
disease when surgical intervention
was finally taken. In 3 of them, the
time between initial diagnosis and
identification of a malignancy was
more than 4 years. In these patients,
the definitive histologic diagnosis is
not known since their neoplasms
were not resected (a biopsy showing
adenocarcinoma cannot distinguish
between ductal adenocarcinoma and
adenocarcinoma arising in IPMN).
The authors make the statement that
“no patient with a malignant muci-
nous tumor underwent a delayed re-
section.” We challenge that assertion
and propose that some or all of those
5 patients could have had a malignant
mucinous neoplasm at the onset be-
cause it is extremely unlikely that
ductal adenocarcinoma of the pancreas
would progress so slowly (range,
57– 84 months). In these cases, it is
more likely that an adenocarcinoma
arose in the background of an IPMN.
3. Among mucinous neoplasms, a
nonoperative management should
be proposed only for branch-duct
IPMNs, as suggested by the Interna-
tional Association of Pancreatology
These guidelines state
that asymptomatic patients affected
by branch-duct IPMN with a diame-
ter less than 3 cm, with a nondilated
(5 mm) main pancreatic duct and
without any malignancy-related pa-
rameters (presence of nodules and/or
thick wall) can be considered for
careful nonoperative follow-up with
computed tomography or magnetic
resonance imaging resonance with
cholangiopancreatography every 6
months, at least initially.
4. The 3% malignancy risk in cysts 3
cm and without solid component may
not be accurate because the denomi-
nator of 369 that the authors used
included patients who had solid com-
ponent, symptoms, or lesions 2.5
cm, but still were managed nonop-
eratively. It would be very useful to
the reader to know what happened
to the 25% of patients with solid
components and the 37% who had
symptoms but were not resected.
Furthermore, the 3% may be falsely
reassuring because the median fol-
low-up was only 24 months, which
is very short for malignant neo-
plasms with a less aggressive biol-
ogy, such as IPMNs and neuroen-
docrine neoplasms.
We would like also to highlight
that knowledge of the natural history of
these neoplasms is incomplete; there-
fore, data from large series with longer
follow-up are needed to confirm the
proper application and safety of a sur-
veillance approach. For this reason,
follow-up should preferably be per-
formed in referral centers by surgeons,
radiologists, and gastroenterologists
with expertise and interest in pancre-
atic diseases.
Stefano Crippa, MD
Carlos Fernández-del Castillo, MD
Department of Surgery
Massachusetts General Hospital
Boston, MA
1. Salvia R, Fernandez-del Castillo C, Bassi C,
et al. Main-duct intraductal papillary muci-
nous neoplasms of the pancreas: clinical
predictors of malignancy and long-term sur-
vival following resection. Ann Surg. 2004;
239:678 685.
2. Tseng JF, Warshaw AL, Sahani DV, et al.
Serous cystadenoma of the pancreas: tumor
growth rates and recommendations for treat-
ment. Ann Surg. 2005;242:413–419.
3. Sohn TA, Yeo CJ, Cameron JL, et al.
Intraductal papillary mucinous neoplasms of
the pancreas: an updated experience. Ann
Surg. 2004;239:788 –797.
4. Zamboni G, Scarpa A, Bogina G, et al.
Mucinous cystic tumors of the pancreas:
clinicopathological features, prognosis, and
relationship to other mucinous cystic tu-
mors. Am J Surg Pathol. 1999;23:410 422.
5. Sarr MG, Carpenter HA, Prabhakar LP, et
al. Clinical and pathologic correlation of 84
mucinous cystic neoplasms of the pancreas:
can one reliably differentiate benign from
malignant (or premalignant) neoplasms?
Ann Surg. 2000;231:205–212.
6. Kobari M, Egawa S, Shibuya K, et al.
Intraductal papillary mucinous tumors of
the pancreas comprise 2 clinical subtypes:
differences in clinical characteristics and
surgical management. Arch Surg. 1999;134:
7. Terris B, Ponsot P, Paye F, et al. Intraductal
papillary mucinous tumors of the pancreas
confined to secondary ducts show less aggres-
sive pathologic features as compared with
those involving the main pancreatic duct.
Am J Surg Pathol. 2000;24:1372–1377.
8. Lim JH, Lee G, Oh YL. Radiologic spec-
trum of intraductal papillary mucinous tu-
mor of the pancreas. Radiographics. 2001;
9. Megibow AJ, Lavelle MT, Rofsky NM.
Cystic tumors of the pancreas: the radiologist.
Surg Clin North Am. 2001;81:489 495.
10. Fernandez-del Castillo C, Targarona J, Thayer
SP, et al. Incidental pancreatic cysts: clinico-
pathological characteristics and comparison
with symptomatic patients. Arch Surg. 2003;
138:427– 433.
11. Tanaka M, Chari S, Adsay V, et al.
International Association of Pancreatology:
international consensus guidelines for man-
agement of intraductal papillary mucinous
neoplasms and mucinous cystic neoplasms of
the pancreas. Pancreatology. 2006;6:17–32.
e appreciate the interest that Dr.
Crippa and Dr. Fernandez-del
Castillo had in our article, and we
appreciate the opportunity to respond
to their comments and criticisms. We
would like to begin with where we
agree. We agree that not all cystic le-
sions of the pancreas should be resected.
We agree that selected patients with
branch-duct IPMN 3 cm in diameter
and without concerning radiographic
features can be monitored safely. We
agree that the natural history of these
lesions (serous cystadenoma, mucinous
cystic neoplasm, IPMN) is unknown and
that only through careful assessment
and surveillance by dedicated sur-
geons, gastroenterologists, and radiol-
ogists will the optimal treatment ap-
proach be realized.
These statements alone are a dra-
matic departure from what was typically
published just a decade ago, when most
reports recommended resection for all
patients with cystic lesions of the
Recent improvements in
cross-sectional imaging, the resultant
increase in identification of small
asymptomatic cysts (often between 4
mm and 2 cm in diameter), and the
improving ability to determine histo-
logic subtype without resection make
the former approach impractical and
potentially harmful to the patient. Af-
ter a thorough diagnostic evaluation,
treatment recommendations should be
made that are based on the balance
between the risk of malignancy within
the given lesion and the risk of pan-
createctomy to the individual patient.
Annals of Surgery Volume 245, Number 5, May 2007 Letters to the Editor
© 2007 Lippincott Williams & Wilkins 827
For patients with presumed mucinous
tumors, this balance must also include
the possible risk of developing malig-
nancy in the future.
We agree with some of Dr. Crippa’s
concern regarding the terminology used
to describe these lesions; and with im-
provements in diagnosis we hope to ap-
proach these lesions with histopatho-
logic terminology (serous, mucinous,
malignant IPMNs) rather than radio-
logic terminology (cystic lesion). We
do approach main-duct IPMNs differ-
ently than branch-duct IPMNs, and Dr
Crippa’s statement that we “assume
that main-duct IPMNs are unlikely to
present as a cystic lesion of the pan-
creas” is a misunderstanding of state-
ments within the discussion of the paper
and should be clarified. This is a denom-
inator issue and one that was touched
upon in the discussion by Dr Lillemoe.
Patients were included in this study (as
noted in METHODS) if they were coded
for the ICD-9 diagnosis of pancreatic
cyst (577.2), had a cystic lesion of the
pancreas on imaging, and were evalu-
ated by a surgeon or gastroenterologist.
We thought that these criteria best de-
fined the group of patients with the ra-
diographic finding of a “cystic lesion of
the pancreas.” Most patients with main-
duct IPMNs will have malignancy, and
these patients were typically coded with
the ICD-9 code 157.9 (pancreatic ade-
nocarcinoma). This would be similar in
a patient with an obvious pancreatic ad-
enocarcinoma that had cystic degenera-
tion: they would not typically be coded
as a pancreatic cyst but rather as an
adenocarcinoma. Patients with a cystic
tumor that was biopsy-proven as an ad-
enocarcinoma were also not included.
Including these patients would have
changed the overall denominator but
would not have changed the number of
patients initially followed radiographi-
cally. Yes, main-duct IPMNs are “cys-
tic” but these lesions have a high-rate of
malignancy and should be approached
in that fashion.
Where do we disagree? We dis-
agree with Dr. Crippa’s conclusion in
point 2. The 8 patients with adenocar-
cinoma who were initially followed
radiographically could have had a ma-
lignant mucinous tumor that slowly
progressed, but most likely did not. In
only 3 of the 8 patients was the period
between the identification of the cyst
and the diagnosis of carcinoma 48
months, and in these patients it is un-
clear whether there was an association
between the cyst and the subsequent
malignancy. In addition, pathology re-
ports from the 3 resected patients (in-
cluding the patient presented in Fig. 5)
demonstrated retention cysts in the
same location as the cysts that were
identified radiographically. No IPMN
was noted in the specimen. We think
that these cysts most likely repre-
sented retention cysts that developed
adjacent to a radiographically occult
carcinoma. We emphasize the need to
thoroughly assess both the cyst and
the surrounding parenchyma during the
evaluation of these lesions. With the in-
crease in awareness of this phenome-
non, we hope to decrease even further
the possibility of overlooking small
We disagree that all mucinous
cystic neoplasms (MCNs) should be re-
sected. Current diagnostic limitations
make it very difficult to differentiate
between a small branch-duct IPMN and
a small MCN in the tail of the pancreas.
Because of this, Dr Crippa’s recommen-
dation to resect all MCNs cannot prac-
tically be followed. Our data, as well as
data from other series, have yet to iden-
tify malignancy within small (3 cm)
The time period during which
MCNs progress to malignancy is un-
known; therefore, our approach to the
small presumed MCN is similar to that
of the small branch-duct IPMN.
We appreciate the ongoing dia-
logue regarding the management of
these lesions. Future efforts must be
directed at improvements in nonresec-
tional diagnosis and improvements in
the understanding of progression to
malignancy in mucinous lesions. Until
these improvements are realized, treat-
ment recommendations must balance
the risk of pancreatectomy with the
risk of malignancy (or future malig-
nancy) within the specific lesion.
Peter J. Allen, MD
Murray F. Brennan, MD
Memorial Sloan-Kettering Cancer Center
New York, NY
1. Fernandez-Del CC, Warshaw AL. Cystic tu-
mors of the pancreas. Surg Clin North Am.
2. Horvath KD, Chabot JA. An aggressive resec-
tional approach to cystic neoplasms of the pan-
creas. Am J Surg. 1999;178:269 –274.
3. Siech M, Tripp K, Schmidt-Rohlfing B, et al.
Cystic tumours of the pancreas: diagnostic ac-
curacy, pathologic observations and surgical
consequences. Langenbecks Arch Surg. 1998;
383:56 61.
4. Tanaka M, Chari S, Adsay V, et al. International
consensus guidelines for management of intra-
ductal papillary mucinous neoplasms and muci-
nous cystic neoplasms of the pancreas. Pancre-
atology. 2006;6:17–32.
5. Goh BK, Tan YM, Chung YF, et al. A review
of mucinous cystic neoplasms of the pancreas
defined by ovarian-type stroma: clinicopatho-
logic features of 344 patients. World J Surg. In
6. Zamboni G, Scarpa A, Bogina G, et al.
Mucinous cystic tumors of the pancreas: clin-
icopathological features, prognosis, and rela-
tionship to other mucinous cystic tumors.
Am J Surg Pathol. 1999;23:410 422.
Authors’ Response to a
Letter to the Editor Re:
Sentinel Node Biopsy
for Early-Stage
e thank Dr. Twomey for his recent
letter endorsing the design of the
first Multicenter Selective Lymphade-
nectomy Trial (MSLT-I).
Although he
challenges our statement that sentinel
node biopsy is now a standard of care
for patients with primary melanoma, his
concerns relate primarily to outcome
measures of clinical efficacy. As stated
in our paper,
these measures were not
considered in that report on the accuracy
and morbidity of the procedure. How-
ever, outcome measures based on the
third interim analysis of MSLT-I have
since been reported in the New England
Journal of Medicine.
We caution Dr. Twomey not to
conflate elective lymph node dissection
and sentinel node biopsy, a common
error. Elective lymph node dissection
blindly excises clinically normal re-
gional nodes as a prophylactic measure;
sentinel node biopsy selectively re-
moves only the most likely nodal tar-
Letters to the Editor Annals of Surgery Volume 245, Number 5, May 2007
© 2007 Lippincott Williams & Wilkins828
get(s) of metastasis. Elective dissection
thus carries considerable potential mor-
bidity; sentinel node biopsy does not.
Only if careful histopathologic examina-
tion of the sentinel node specimen re-
veals tumor will the patient undergo
complete lymphadenectomy. Remember
that only about 20% of patients with
intermediate-thickness melanoma will
have nodal metastases; in clinical trials,
the benefit of elective lymph node dissec-
tion in this minority was inevitably diluted
by its lack of benefit in the remaining
80% without nodal metastases.
Interim comparison of the 2 treat-
ment arms of MSLT-I shows that nodal
management based on sentinel node sta-
tus confers a survival benefit: disease-
free survival (an endpoint used as a basis
for regulatory approval of new cancer
) was significantly higher in pa
tients assigned to wide excision plus sen-
tinel node biopsy than in those assigned to
wide excision plus watch-and-wait nodal
observation (P 0.009).
among patients with nodal metastases,
the 5-year survival rate was higher for
those who underwent immediate lymph-
adenectomy than for those in whom
lymphadenectomy was delayed (72.3%
vs. 52.4%, hazard ratio for death 0.51,
P 0.004). MSLT-I data also show the
prognostic importance of the sentinel
node’s tumor status: 5-year survival rate
was 90.2% for patients with tumor-neg-
ative sentinel nodes compared with 72.3%
for patients with tumor-positive sentinel
nodes (P 0.001).
Dr. Twomey notes a higher inci-
dence of nodal metastases in the sentinel
node biopsy group than in the observa-
tion group at the time of interim analy-
sis, and he criticizes the “excess rate of
node dissection” in the biopsy group.
However, it is not accurate to compare
the incidence of early (subclinical) me-
tastases and delayed (clinically palpa-
ble) metastases because the latter will
steadily increase with time. In fact, our
recent data indicate that by 10 years the
mean projected incidence of nodal me-
tastases in patients with intermediate-
thickness melanomas will be 20.5%
2.6% (standard error) in the observa-
tion group and 20.8% 1.7% in the
biopsy group.
Data from interim analysis of
MSLT-I provide evidence that occult
micrometastases in the sentinel node
usually progress to aggressive regional
or distant disease. Were this not the
case, we would not have seen an overall
improvement in disease-free survival
among patients assigned to sentinel
node biopsy, nor would there have been
a significant difference in the rate of
nodal relapse between patients with tu-
mor-negative sentinel nodes and those
assigned to nodal observation (4% vs.
15.6%, P 0.001).
For all patients
with nodal metastases identified either
by sentinel node biopsy or during obser-
vation, the mean number of tumor-in-
volved nodes was only 1.4 in the biopsy
group, as compared with 3.3 in the ob-
servation group, indicating disease pro-
gression in the regional nodal basin dur-
ing nodal observation. The impact of the
sentinel node’s tumor status on disease-
free and melanoma-specific survival
also indicates the aggressive potential of
micrometastases in this node (P 0.001
for both comparisons).
We firmly believe that sentinel
node biopsy is the standard of care for
staging primary melanomas of interme-
diate thickness and for treatment plan-
ning. Although the standard of care des-
ignation is applied to many clinical
procedures that do not directly lead to
survival benefit,
our findings indicate
that immediate complete lymphade-
nectomy after identification of a tu-
mor-positive sentinel node improves
survival. In patients with primary mel-
anomas that are intermediate in thick-
ness, sentinel node biopsy is preferred
to nodal observation.
Donald L. Morton, MD*
Alistair J. Cochran, MD
John F. Thompson, MD
*John Wayne Cancer Institute
at Saint John’s Health Center
Santa Monica, CA
University of California at Los Angeles
Los Angeles, CA
Royal Prince Alfred Hospital
Camperdown, NSW, Australia
1. Twomey P. Sentinel node biopsy for early-
stage melanoma: accuracy and morbidity in
MSLT-1, an international multicenter trial. Ann
Surg. 2007;245:156 –157.
2. Morton DL, Cochran AJ, Thompson JF, et al.
Sentinel node biopsy for early-stage melanoma:
accuracy and morbidity in MSLT-I, an interna-
tional multicenter trial. Ann Surg. 2005;242:
3. Morton DL, Thompson JF, Cochran AJ, et al.
Sentinel-node biopsy or nodal observation in mel-
anoma. N Engl J Med. 2006;355:1307–1317.
4. Morton DL, Cochran AJ, Thompson JF.
Sentinel-node biopsy in melanoma letter.
N Engl J Med. 2007;356:419 420.
5. Johnson JR, Williams G, Pazdur R. End points
and United States Food and Drug Administra-
tion approval of oncology drugs. J Clin Oncol.
2003;21:1404 –1411.
6. Balch CM, Cascinelli N. Sentinel-node biopsy
in melanoma letter. N Engl J Med. 2007;356:
420 421.
Annals of Surgery Volume 245, Number 5, May 2007 Letters to the Editor
© 2007 Lippincott Williams & Wilkins 829
    • "Similarly to the mucinous cystic neoplasms and the pancreatic intraepithelial neoplasia (PanIN), IPMNs are currently considered precursors and precancerotic lesions of the pancreas [13]. The transformation from a benign into a malignant histologic type may take several years (approximately 5 years) and this event is not observed in all cases [14]. Cystic pancreatic neoplasms include a large spectrum of lesions with different radiological appearance [1, 3, 15– 18]. "
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