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Desmoplastic and Desmoplastic Neurotropic
Experience with 280 Patients
n their article on desmoplastic and desmoplastic neurotropic melanoma Quinn et al.1 have extended our knowledge of this unusual
subtype of melanoma. However, the authors do not address the
question of whether there is any difference in the biologic behavior of
desmoplastic melanoma that arises within a “conventional” melanoma, one with an atypical intraepidermal melanocytic component,
and “de novo” desmoplastic melanoma, one in which there is little or
no atypical intraepidermal melanocytic “precursor.” This classification first was proposed by Jain and Allen in 1989 but has received little
attention since.2
We reviewed the subsequent literature including the large series
of desmoplastic melanomas reported by Skelton et al. and Smithers et
al.3,4 None of these series differentiated their cases according to this
classification. We believe that distinguishing between these two
groups of desmoplastic melanoma is important. It is clear that the “de
novo” desmoplastic melanoma is more difficult to diagnose, both
clinically and histologically, than desmoplastic melanoma arising in a
conventional melanoma. Therefore it is likely that the “de novo”
lesions comprise the majority of desmoplastic melanomas that are
treated inadequately. The delay in treatment may lead to a higher
recurrence rate and thereby convey a worse prognosis for patients
with this subtype of neoplasm.
We would speculate that de novo desmoplastic melanoma, if
diagnosed correctly and excised adequately, may have a significantly
better prognosis than conventional melanoma of comparable thickness and we would hope that Quinn et al. would be able to draw on
their large series of cases to address this issue.
Quinn MJ, Crotty KA, Thompson JF, Coates AS, O’Brien CJ, McCarthy WH.
Desmoplastic and desmoplastic neurotropic melanoma: experience with 280
patients. Cancer 1998;83(6):1128 –35.
Jain S, Allen PW. Desmoplastic malignant melanoma and its variants. A study
of 45 cases. Am J Surg Pathol 1989;13(5):358 –73.
Skelton HG, Smith KJ, Laskin WB, McCarthy WF, Gagnier JM, Graham JH, et al.
Desmoplastic malignant melanoma. J Am Acad Dermatol 1995;32(5 Pt 1):717–
Smithers BM, McLeod GR, Little JH. Desmoplastic, neural transforming and
neurotropic melanoma: a review of 45 cases. Aust NZ J Surg 1990;60(12):967–
Igor Shendrik, M.D.
Department of Pathology
Columbia Presbyterian Medical Center
New York, New York
© 1999 American Cancer Society
CANCER June 1, 1999 / Volume 85 / Number 11
David N. Silvers, M.D.
Department of Dermatology and Pathology
Columbia Presbyterian Medical Center
New York, New York
desmoplastic component. The high proportion of de
novo cases that they observed may reflect the fact that
their series was selective because it was based on
patients with soft tissue tumors who were referred for
histopathologic consultation.
Author Reply
rs Shendrik and Silvers ask whether there is any
difference between the biologic behavior of desmoplastic melanomas arising within conventional
melanomas and those that are wholly desmoplastic.
The wholly desmoplastic melanomas are categorized
further into those with an atypical intraepidermal
component and those that have arisen de novo with
little or no intraepidermal melanocytic “precursor.”
We agree that this is an interesting and important
question. Unfortunately, we currently are unable to
provide an answer because we have analyzed all our
desmoplastic melanomas as one group. A subsequent
study will attempt to answer this question. However,
assessing the presence or absence of an intraepidermal component can be difficult because the epidermis
may be missing in some biopsies (especially those that
were not suspected to be melanocytic lesions) and, if
the epidermal component is slight, it may be missing
from the sections that are examined.
Although it is possible that de novo lesions may
comprise the majority of desmoplastic melanomas
that are treated inadequately, we have seen several
cases in which desmoplastic melanoma at the base of
a conventional melanoma was missed at the time of
the initial diagnosis. This appears to have led, in some
patients, to inadequate initial treatment and subsequent recurrence and metastasis. We believe that desmoplastic melanoma arising within a conventional
melanoma is an underdiagnosed lesion.
Drs. Shendrik and Silvers refer to the classification
of desmoplastic melanoma proposed in 1989 by Jain
and Allen.1 This classified desmoplastic melanomas
into three categories: 1) desmoplastic melanoma with
an atypical intraepidermal component, so-called
“classic” desmoplastic melanoma; 2) desmoplastic
melanoma without an atypical intraepidermal melanocytic component de novo desmoplastic melanoma;
and 3) predominantly nerve-centered superficial malignant tumors with or without an atypical intraepidermal melanocytic component. Twenty-one of the 40
cases reported by Jain and Allen fell into the second
category of de novo desmoplastic melanoma. However, they noted that some of their cases had the
pattern of a conventional melanoma as well as the
Jain S, Allen PW. Desmoplastic malignant melanoma and its
variants. Am J Surg Pathol 1989;13:358 –73.
Michael J. Quinn, M.B., B.S.
Sydney Melanoma Unit
Royal Prince Alfred Hospital
Camperdown, NSW
Department of Surgery
University of Sydney
Sydney, NSW
Kerry A. Crotty, M.B., B.S.
Department of Pathology
University of Sydney
Sydney, NSW
John F. Thompson, M.D., B.S.
Sydney Melanoma Unit
Royal Prince Alfred Hospital
Camperdown, NSW
Department of Surgery
University of Sydney
Sydney, NSW
Outcome and Complications of
Epidural Analgesia in Patients with
Chronic Cancer Pain
read with interest the article by Sillevis Smith et al.1
about their experience with the outcomes and complications of epidural analgesia in cancer patients with
chronic pain. Current indications for spinal therapy include effective pain relief, but this is achieved only at the
cost of unacceptable side effects with systemic opioids,
and treatment with strong opioid drugs was unsuccessful in a series of trials despite escalating doses.2 This is
correctly pointed out at the end of the article. However,
the authors report to have achieved adequate pain relief
for about 75% of patients, regardless of the pain mechanism, with adequate pain relief defined as a .50%
decrease in oral or parenteral opioids compared with
pre-epidural catheter levels. Should patients who experience adequate pain relief with oral or systemic opioids
switch to an epidural route and then have their outcomes considered, regardless of the previous pain situation? This seems to be a difficult question. In fact, no
data on previous pain therapy with systemic opioids and
clear indications for the initiation of epidural treatment
have been reported. Of concern, neither epidural opioid
doses nor subsequent dose escalation, if any, have been
reported. It is well known that the success rate with
epidural morphine is inversely related to the preceding
opioid dose. Similarly, the degree and intensity of adverse effects cannot be reliably determined if the previous clinical conditions and drugs used are unknown.
Insufficient pain relief was the reason for removal of five
catheters. Which alternative strategies, if any, were used?
Use of an intrathecal route has been found to be
effective in regaining pain relief in most patients who
do not benefit from epidural analgesia.3 Other advantages of an intrathecal route include lower daily doses
and volumes and a lower rate of malfunction, whereas
similar infection rates have been reported with intrathecal or epidural administration.4,5 As patients with
advanced cancer have little time to participate in trials
of multiple spinal approaches, an intrathecal route
should be preferred.
Long term treatment administered with externalized, tunneled intrathecal catheters has been reported
to be safe and may reduce the frequency of infection
or dislodgement.6 It is not surprising that .50% of
catheters had to be removed and that all dislocated
catheters were nontunneled. I was impressed by the
high rate of epidural infections reported, especially
considering that four patients underwent decompressive laminectomy. With this serious outcome, I should
be somewhat worried by such a high risk (4.5%, 4 of 91
patients). In a study of 350 patients into whom long
term epidural catheters were inserted, none of the
patients required surgery for spinal cord decompression.7 Could the choice of not tunneling the catheter
have affected this outcome?
The authors report that the main organism cultured was Staphylococcus aureus and that the source
of contamination was most likely cutaneous. To prevent this, we have been administering vancomycin by
intrathecal route, with optimal results.8 More than 30
consecutive patients with advanced cancer who had a
mean survival of less than 30 days and were at high
risk of infection underwent subcutaneous tunneling
and received vancomycin 100 mg weekly through an
intrathecal catheter. No signs of infection have been
reported, although catheters were not cultured for
possible subclinical infection.
We suggest that the intrathecal route, a subcuta-
neously tunneled and externalized catheter, and the
preventive use of vancomycin may reduce the high
rate of complications when spinal therapy is given to
cancer patients after adequate conventional treatment
with systemic opioids has failed.
Sillevis Smitt P, Tsafka A, Teng-van de Zande F, van der Holt
R, Elswijk-de Vries I, Elfrink E, et al. Outcome and complications of epidural analgesia in patients with chronic cancer
pain. Cancer 1998;83:2015–22.
Krames ES. Intrathecal infusional therapies for intractable
pain: patient management guidelines. J Pain Symptom
Manage 1997;13:118 –21.
Nitescu P, Appelgren L, Linder LE, Sjoberg M, Hultman E,
Curelaru I. Epidural versus intrathecal morphine-bupivacaine: assessment of consecutive treatments in advanced
cancer pain. J Pain Symptom Manage 1990;5:18 –26.
Crul BJ, Delhaas EM. Technical complications during longterm subarachnoid or epidural administration of morphine
in terminally ill cancer patients: a review of 140 cases. Reg
Anesth 1991;16:209 –13.
Mercadante S. Problems of long-term spinal opioid treatment in advanced cancer patients. Pain. 1999;79:1–13.
Nitescu, Daham P, Appelgren L, Curelaru I. Continuous
infusion of opioid and bupivacaine by externalized intrathecal catheters in long-term treatment of “refractory” nonmalignant pain. Clin J Pain 1998;14:17–28.
Du Pen SL, Peterson DG, Williams A, Bogosian AC. Infection
during chronic epidural catheterization: diagnosis and
treatment. Anesthesiology 1990;73:905–9.
Mercadante A, Serretta R, Sapio M, Villari P, Calderone L.
When all else fails: stepwise multiple solutions for a complex
cancer pain syndrome. Support Care Cancer. 1999;7:47–50.
Sebastiano Mercadante
Palermo & Pain Therapy Section
Department of Anesthesia and Intensive Care
Buccheri La Ferla Fatebenefratelli Hospital
Palermo, Italy
Author Reply
ercadante correctly points out that we achieved
adequate pain relief for about 75% of patients.
We defined adequate pain relief as a .50% decrease
in oral or systemic opioid dose compared with the
pre-epidural catheter levels. In addition, both the
patient and physician had to describe the pain relief
as “adequate” or “acceptable.”1 All patients were
given morphine orally (mean dose, 220 mg/day) or
either intravenously (i.v.) or subcutaneously (s.c.)
(mean dose, 250 mg/day), and some also received
methadone or fentanyl. All patients were then
switched to epidural administration because of in-
CANCER June 1, 1999 / Volume 85 / Number 11
sufficient pain relief in the presence of side effects.
As Mercadante correctly states, there is a tendency
to try more systemic opioid rotations prior to changing to the spinal route, resulting in a decrease in the
number of spinal catheters at many institutions,
including ours.
All five patients for whom the epidural catheter
was not effective were changed to i.v. or s.c. morphine,
with consequent side effects. Four patients died
within 5 days of catheter removal. The fifth patient
had a Pancoast tumor with invasion of the brachial
plexus and metastasis to the scapula. Despite escalating doses of s.c. morphine, steroids, and nonsteroidal
anti-inflammatory drugs, his pain score remained 6 – 8
on an 11-point scale. A chordotomy was considered,
which the patient refused.
Intrathecal administration requires lower doses
and volumes of opioids than epidural administration,
an advantage to patients requiring high doses. In addition, Mercadante claims that the intrathecal route of
opioid administration is more efficacious and that the
intrathecal route should therefore be preferred for all
patients. However, studies that directly compare both
methods are lacking, and many groups have demonstrated that the epidural route is very effective in the
long term treatment of cancer pain.1–3 As demonstrated, the early complication rate associated with
intrathecal catheters is higher (e.g., leaking of cerebrospinal fluid), which may offset the advantages of lower
doses and volumes needed with intrathecal administration.4
Infections are probably better prevented by subcutaneous tunneling, and we agree with Mercadante
that most catheters should be tunneled. However, we
do not agree with the intermittent prophylactic administration of intrathecal antibiotics because its efficacy is uncertain and it may also select for vancomycin-resistant organisms.
Sillevis Smitt PAE, Tsafka A, Teng-van de Zande F, van der
Holt MJ, Elswijk-de Vries I, Elfrink E, et al. Outcome and
complications of epidural analgesia in patients with chronic
cancer pain. Cancer 1998;83:2015–22.
de Jong PC, Kansen PJ. A comparison of epidural catheters
with or without subcutaneous injection ports for treatment
of cancer pain. Anesth Analg 1994;78:94 –100.
Ballantyne JC, Carr DB, Berkey CS, Chalmers TC, Mosteller
F. Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to
cancer. Reg Anesth 1996;21:542–56.
Crul BJP, Delhaas EM. Technical complications during longterm subarachnoid or epidural administration of morphine
in terminally ill cancer patietns: a review of 140 cases. Reg
Anesth 1991;16:209 –13.
Peter Sillevis Smitt, M.D.
Anna Tsafka, M.D.
Charles Vecht, M.D.
Department of Neuro-oncology
Daniel den Hoed Cancer Center
University Hospital Rotterdam
Rotterdam, The Netherlands
Prenatal Exposure to Metronidazole
and Risk of Childhood Cancer
A Retrospective Cohort Study of Children
Younger than 5 Years
e read with interest the report by Thapa et al.1 We
agree with their final conclusions but think that
some of their arguments deserve a more detailed analysis.
All neoplasms are ultimately the result of the variable interplay of two classes of determinants, genetic
(hereditary) and environmental (exogenous).2 In view
of the relatively high level of consumption of drugs by
pregnant women and the rarity of childhood cancer, a
possible carcinogenic effect is very difficult to establish. When evaluating the association between prenatal exposure to metronidazole and pediatric tumors, it
is important to collect case reports systematically3 and
conduct retrospective case– control studies4 and cohort studies. Prospective cohort studies, although difficult to undertake due to the need for big samples,
long follow-up periods (decades), and control of both
carcinogenics and protective factors (such as the content of selenium, retinol and retinoids, a-tocopherol,
acid ascorbic, etc. in maternal diet) are needed to
establish definitive association.5,6
Thapa et al. limited their study to children
younger than 5 years to minimize loss of follow-up
due to out-of-state migration of patients.1 However,
the validity of the results may have been affected by
two factors: 1) the possible effect on the later development of other pediatric neoplasms (Hodgkin disease, Ewing sarcoma family of tumors, osteosarcoma,
etc.) would be unnoticed;7 and 2) this study’s design
would prevent the detection of any causal relation
between the maternal consumption of diethylstilbestrol during pregnancy and subsequent development of
vaginal adenocarcinoma in female offspring.8 Diethylstilbestrol is the only well-established transplacental
carcinogen, with a minimal and maximal latency period of 12 and 42 years, respectively, until tumor development.9
As in studies of other potentially carcinogenic
agents, the limitations involved in conducting studies
to detect small increases in conditions that occur with
low baseline frequency in the population indicate that
the question of childhood cancer risk after prenatal
exposure to metronidazole is likely to remain unresolved.10
10. Paul ME. Physical agents in the workplace. Semin Perinatol
Octavio Berbel-Tornero, M.D.
Juan A. López-Andreu, Ph.D.
Josep Ferris-Tortajada, Ph.D.
Pediatric Oncology Unit
Department of Pediatrics
Hospital Infantil La Fe
Valencià, Spain
Thapa PB, Whitlock JA, Brockman Worrell KG, Gideon P,
Mitchel EF Jr., Roberson P, et al. Prenatal exposure to metronidazole and risk of childhood cancer: a retrospective
cohort study of children younger than 5 years. Cancer 1998;
83:1461– 8.
Saracci R. Neoplasms. In: Detels R, Holland WW, McEwen J,
Omen GS, editors. Oxford textbook of public health. 3rd
edition. New York: Oxford University Press, 1997:1043– 63.
Satgé D, Sasco AJ, Little J. Antenatal therapeutic drug exposure and fetal/neonatal tumours: review of 89 cases. Pediatr
Perinatol Epidemiol 1998;12:84 –117.
Crombie IK. The limitations of case– control studies in the
detection of environmental carcinogens. J Epidemiol Comm
Health 1981;35:281–7.
Feinleib M, Breslow NE, Detels R. Cohort studies. In: Detels
R, Holland WW, McEwen J, Omen GS, editors. Oxford textbook of public health. 3rd edition. New York: Oxford University Press, 1997:557–70.
Alexandrov V, Aiello C, Rossi L. Modifying factors in prenatal
carcinogenesis [review]. In Vivo 1990;4:327–36.
Kosary CL, Ries LAG, Miller BA, Hankey BF, Harras A, Edwards BK, editors. SEER cancer statistics review, 1973–1992:
tables and graphs. NIH Publication No. 96-2789. Bethesda,
MD: National Cancer Institute, 1995.
Melnick S, Cole P, Anderson D, Herbst A. Rates and risks of
diethylstilbestrol-related clear-cell adenocarcinoma of the
vagina and cervix: an update. N Engl J Med 1987;316:514 – 6.
Giusti RM, Iwamoto K, Hatch EE. Diethylstilbestrol revisited: a review of the long-term health effects. Ann Intern
Med 1995;122:778 – 88.
Author Reply
e appreciate the thoughtful comments of Dr. Berbel-Tornero et al. regarding our recently published study. As noted in our “Materials and Methods”
and “Discussion” sections and in their letter, our study
did not include children 5 years of age or older. Thus,
our article could not provide any data about the effects of in utero exposure to metronidazole on cancer
occurrence in children of this age. Given the high
prevalence of metronidazole use during pregnancy,
we concur that further study of this question, albeit
difficult, is of importance to public health.
I would also like to take this opportunity to correct
a typographic error in our article. On page 1467, the
last sentence of the penultimate paragraph should
read “out-of-state migration would be no more than
6%” rather than “ . . ..60%.”
Wayne A. Ray, Ph.D.
Division of Pharmacoepidemiology
Vanderbilt University School of Medicine
Nashville, Tennessee
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