Are there factors that predict the result of selective sentinel lymph

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ORIGINALES
Are there factors that predict the result of selective
sentinel lymph-node biopsy in melanoma?
Antonio Piñero Madrona, Jorge Martínez-Escribanoa, Enrique Martínez-Barbab, Belén Ferri Ñiguezb,
Manuel Canteras Jordanac, Francisco Nicolás-Ruizd, José Manuel Rodríguez González,
José Frías Iniestaa and Pascual Parrilla Paricio
Department of General Surgery. Virgen de la Arrixaca University Hospital. Murcia. Spain. aDepartment of Dermatology. Virgen de
la Arrixaca University Hospital. Murcia. Spain. bDepartment of Pathology. Virgen de la Arrixaca University Hospital. Murcia.
Spain. cDepartment of Statistics. School of Medicine. Murcia University. Spain. dDeparment of Nuclear Medicine. Virgen de la
Arrixaca University Hospital. Murcia. Spain.
Background. Sentinel lymph node biopsy is an appropriate method to assess lymphatic involvement
in cutaneous melanoma. We collated clinical and
histo-pathological parameters of primary tumours
to assess their predictive value of sentinel lymph
node involvement.
Patients and methods. Factors such as age, gender,
histology subtype, site, Breslow index, lesion size,
and the presence of ulceration, signs of regression,
lympho-vascular invasion and/or inflammatory infiltration of the primary lesion were collated from
142 patients diagnosed with cutaneous melanoma.
During the scheduled surgery, a selective sentinel
lymph node biopsy was taken. The procedure was
successful in terms of localisation with scintigraphy, detection and surgical removal. Univariate
and multivariate statistical analyses were applied to
the variables in relation to the sentinel lymph node
biopsy results.
Results. There were significant differences with respect to size (p=0.046), the presence of ulceration in
the primary lesion (p=0.0146), the Breslow index
(p=0.0001) and lympho-vascular invasion in the primary lesion (p=0.00005). Logistic regression showed
an independent predictive value for sentinel lymph
node involvement.
Conclusions. The data indicate that, apart from
Breslow index, the presence of lymphatic invasion
in the primary tumour, the size of the melanoma,
and the presence of ulceration are independent factors predictive of a positive result of selective senti-
Correspondence: Dr. A. Piñero.
Servicio de Cirugía General y del Aparato Digestivo I.
Hospital Universitario Virgen de la Arrixaca. 3ª planta.
30120 El Palmar. Murcia. España.
E-mail: apm.cg@ono.com
Received 27 November 2003; Revised 25 February 2004; Accepted 1
March 2004.
35
nel lymph node biopsy in cutaneous melanoma.
Although prospective studies are still awaited, these
variables need to be taken into account when such
biopsies are proposed, even with less thick tumours.
Key words: melanoma, sentinel lymph node.
Piñero Madrona A, Martínez-Escribano J, Martínez-Barba E,
Ferri Ñíguez B, Canteras Jordana M, Nicolás-Ruiz F, Rodríguez González JM, Frías Iniesta J, Parrilla Paricio P. Are there factors that predict the result of selective sentinel lymph-node biopsy in melanoma? Rev Oncol 2004;6(5):283-8
¿Hay factores que predigan el resultado de
la biopsia selectiva del ganglio centinela
en el melanoma?
Introducción. La biopsia selectiva del ganglio centinela en el melanoma cutáneo es un método válido
para conocer si existe afectación fática. Pretendemos estudiar la existencia de parámetros clínicos e
histopatológicos relacionados con el tumor primario que pudieran ser predictivos de la afectación del
ganglio centinela.
Material y métodos. Se estudiaron 142 pacientes intervenidos por melanoma cutáneo a los que se les
realizó la biopsia del ganglio centinela habiéndose
localizado al menos un ganglio tanto en la gammagrafía como en la cirugía. Se valoraron la edad, sexo, tipo histológico, localización, índice de Breslow,
tamaño de la lesión y presencia o no de ulceración,
regresión, invasión linfovascular y/o infiltrado inflamatorio en la lesión primaria. Se realizó un análisis univariante y multivariante para estudiar la relación de estos factores con el resultado del ganglio
centinela.
Resultados. Se encontraron diferencias significativas para el tamaño (p=0,046), la ulceración en
el tumor primario (p=0,0146) y, sobre todo, para el
índice de Breslow (p=0,0001) y la invasión linfovascular (p=0,00005). La regresión logística mostró
un valor predictivo independiente del estado del
ganglio centinela.
Rev Oncol 2004;6(5):283-8
283
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PIÑERO MADRONA A, MARTÍNEZ-ESCRIBANO J, MARTÍNEZ-BARBA E, ET AL. ARE THERE FACTORS THAT PREDICT THE RESULT OF
SELECTIVE SENTINEL LYMPH-NODE BIOPSY IN MELANOMA?
Conclusiones. El análisis de los datos de nuestra serie muestra que, además del índice de Breslow, la
presencia de invasión linfática en el tumor primario, el tamaño del melanoma y la presencia de ulceración, son factores predictivos independientes
para el resultado positivo de la biopsia selectiva del
ganglio centinela en el melanoma cutáneo y, por
tanto, a falta de estudios prospectivos, estas variables deben tenerse en cuenta a la hora de indicar la
realización de dicha biopsia aun con espesores tumorales pequeños.
Palabras clave: melanoma, ganglio centinela.
INTRODUCTION
To date the most frequently studied prognostic factors
in patients with melanoma have been clinical and,
particularly, histological, with lymph node involvement and the Breslow index being the most important prognostic factors in the evolution of patients
with melanoma1. The most commonly used classification system for staging cutaneous melanoma is the
AJCC (American Joint Committee on Cancer), and
the main clinical and pathological features of melanoma that predict the risk of metastasis and survival
have recently been reviewed by the Committee, who
propose a new classification system for patients with
melanoma2.
In the management of melanoma various studies
show that there are no differences in either survival
or disease-free time between patients undergoing
elective lymphadenectomy and those receiving lymphadenectomy therapeutically3,4. Moreover, lymphadenectomy, as occurs in the treatment of breast cancer,
is the surgical intervention that associates most morbidity in the treatment of patients, to the extent that it
can interfere significantly in their life quality5. If to
this we add the validation by numerous study groups
of selective sentinel lymph node biopsy to define the
status of lymph node involvement6,7 it is not surprising that this technique is proposed in cases of melanoma, in order to avoid unnecessary lymphadenectomies and provide a better knowledge of the lymphatic
drainage routes of the different anatomical regions,
which do not always adjust to classical patterns8.
Having acknowledged its utility, it would be convenient to increase the efficacy and efficiency of the
technique, for which we could intervene, principally, on two fronts: on the one hand by reducing
the rate of false negatives with techniques using immunohistochemistry and even molecular biology
(PCR of thyrosinase and other proteins); on the other hand, it might be a case of selecting patients for
whom an optimum cost-benefit relationship is obtained.
284
The aim of this paper is to study the existence of clinical and histopathological parameters related to primary tumours (cutaneous melanoma) which could
be predictors of sentinel lymph node involvement
and therefore help improve sentinel lymph node
biopsy results in terms of efficacy and efficiency.
PATIENTS AND METHODS
We studied 142 patients diagnosed with and undergoing surgery for cutaneous melanoma at the Melanoma Unit of the “Virgen de la Arrixaca” University
Hospital, in whom a selective sentinel lymph node
biopsy proved successful in terms of both scintigraphic location and detection and surgical removal. The
search for sentinel lymph nodes was carried out in
all cases using a radioactive tracer (Lymphoscint®,
Nycomed Amersham Sorin, Milan, Italy), without colouring, by the same surgical team.
The following data were recorded in the patients: age,
sex, histological type of melanoma, site, Breslow index and lesion size. In the 95 cases referring directly
to our health care centre, i.e. not referred from other
centres, and in whom we had the possibility of having them assessed independently by the same two
pathologists, we also studied the presence or not of
ulceration, signs of regression (defined by the presence of vacular fibrous tissue with or without melanophages, and a variable lymphocytic infiltrate), lymphovascular invasion and/or inflammatory infiltrate in
the primary lesion.
The mean age of the patients was 50.78±15.22 years
(range: 13-82); 81 were females (57%) and 61 were
males (43%). The most frequent histopathological
diagnosis was superficial spreading melanoma (74%);
the anatomical distribution is shown in table 1. The
number of lymphatic drains per lesion ranged from
one to three: single in 116 cases (81.7%), double in 23
cases (16.2%) and triple in 3 cases (2.1%).
TABLE 1. Anatomical distribution of the primary lesion
Site
Trunk
Lower extremity
Upper extremity
Head and neck
Cases (%)
55 (38.73)
51 (35.91)
20 (14.08)
16 (11.27)
The mean size of the primary lesion was 12.41±7.68
mm (range: 3-46), with a mean Breslow index of
1.81±1.77 mm (range: 0.2-10.3). Sixty-three cases
(44.4%) have a Breslow index lower than 1 mm, 28
cases (19.7%) between 1 and 2 mm, 38 (26.7%) between 2 and 4 mm, and 13 cases (9.1%) higher than 4
mm. There was ulceration of the primary lesion in
Rev Oncol 2004;6(5):283-8
36
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PIÑERO MADRONA A, MARTÍNEZ-ESCRIBANO J, MARTÍNEZ-BARBA E, ET AL. ARE THERE FACTORS THAT PREDICT THE RESULT OF
SELECTIVE SENTINEL LYMPH-NODE BIOPSY IN MELANOMA?
20 of the 95 cases (21%). In 36 (37.9%) there were
signs of regression and in 15 (15.8%) evidence of
lymphovascular invasion. Focal inflammatory infiltrate was observed in 47 cases (49.5%) and diffuse in
31 (32.6%).
In all the cases a histological (hematoxilin-eosine)
and immunohistochemical (S-100 and HMB-45) studies of the sentinel node were made. The patients
were divided according to whether or not they were
positive for sentinel lymph node in the immunohistochemical study (S100, HMB-45); a total of 19 positive
cases were found (13.4%), and these were followed
up with a lymphadenectomy of the affected area. Of
these patients only two have other affected nodes
(three and nine more) in addition to the sentinel one.
We found three cases of micrometastases that were
diagnosed by immunohistochemical techniques. Both
metastases and micrometastases were considered positive.
A statistical study was conducted to analyse the relationship of each variable to the histopathological and
immunohistochemical result of the sentinel lymph
node. After verifying adjustment to normality we performed, by way of a univariate analysis, a means
comparison with the Student t test for quantitative variables and chi-squared test for qualitative variables.
A level of statistical significance was considered for
p<0.05. We also performed a multivariate analysis
using a logistic regression analysis and calculated the
relative risk for the variables with independent predictive value.
RESULTS
Univariate analysis (table 2):
Clinical data (age, sex, site and number of drains per
lesion)
No differences were found with regard to age or sex
between patients with metastatic spread to the sentinel
lymph node and those without. Nor did the site of the
primary melanoma or the number of lymphatic drains
per lesion show differences between the groups.
Histopathological data (histological type, lesion size,
Breslow index, ulceration, signs of regression,
inflammatory infiltrate)
The most frequently diagnosed histopathological
form was superficial spreading melanoma, seen in
74% of the cases, and although nodular melanoma
showed a greater probability of presenting a positive
sentinel lymph node, no statistically significant differences were found (p=0.1353).
Differences did appear for size (p=0.046) and, particularly, Breslow index (p=0.0001). It must be said here
that the minimum values for these parameters, from
which positive sentinel lymph nodes were found, were 9 mm Breslow and 9 mm maximum diameter.
TABLE 2. Univariate analysis of the different parameters for sentinel lymph node positivity
Age (years, mean ± SD)
Sex (%)
Males
Females
Size (mm, mean ± SD)
Site (%)
Trunk
Leg
Arm
Head & neck
No. drains (mean ± SD)
Diagnosis (%)
SSM
NM
LAM
LMM
Breslow (mm, mean ± SD)
Ulceration (%)
Regression (%)
Inflammation (%)
Focal
Diffuse
Lymphatic invasion (%)
Negative sentinel
lymph node (n=123)
Positive sentinel
lymph node (n=19)
p
51.25±14.84
47.78±17.65
0.8327
43.90
56.09
11.95±7.50
36.84
63.16
15.65±8.18
0.5628
38.21
36.58
13.82
11.38
1.19±0.45
42.10
31.58
15.79
10.52
1.30±1.47
75.60
16.26
2.44
5.69
1.56±1.69
16.45
40.5
36.84
63.16
0
0
3.29±1.49
43.75
25
53.16
29.11
3.79
31.25
50
75
0.046
0.9717
0.302
0.1353
0.0001
0.0146
0.2436
0.2146
0.00005
SSM: superficial spreading melanoma; NM: nodular melanoma; LAM: lentiginous acral melanoma; LMM: lentigo malignant melanoma;
SD: standard deviation.
37
Rev Oncol 2004;6(5):283-8
285
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PIÑERO MADRONA A, MARTÍNEZ-ESCRIBANO J, MARTÍNEZ-BARBA E, ET AL. ARE THERE FACTORS THAT PREDICT THE RESULT OF
SELECTIVE SENTINEL LYMPH-NODE BIOPSY IN MELANOMA?
As for the presence in the melanoma of signs of ulceration, regression of lymphatic invasion or inflammatory infiltrate, differences were found for the presence of ulceration in the primary lesion (p=0.0146)
together with a greater likelihood that the sentinel
lymph node is positive when there is evident lymphovascular invasion in the primary lesion (p=0.00005).
As for the existence of inflammatory signs, no differences were found, not even when divided into focal
and diffuse (p=0.2146).
Multivariate analysis (table 3)
The logistic regression of the variables showed parameters with an independent predictive value for sentinel lymph node involvement to be Breslow index
(p=0.001), existence of lymphatic invasion (p=0.0005),
size of the primary lesion (p=0.003) and, like size,
presence of ulceration (p=0.023).
TABLE 3. Results of the multivariate analysis using logistic
regression
Parameter
Breslow index*
Lymphatic invasion
Size**
Ulceration
p
Odds ratio
0.001
0.0005
0.003
0.023
128.7
8.718
2.458
1.987
* Analysis done in relation to the median of the series (0.62 mm).
** Analysis done in relation to 10 mm in diameter.
DISCUSSION
On the strength of the results in our patients we will
comment on the various aspects of the variables studied and whether or not they coincide with findings
in other series.
Superficial spreading melanoma and nodular melanoma were the two most common histological types,
in that order. Although a higher frequency of diagnosed nodular melanoma was observed among patients
with a positive sentinel lymph node, the differences
were not significant, nor was it a notable independent
variable in the multivariate analysis. These results
coincide with those reported in other multivariate
studies, which do not find histological type to have
any independent predictive value; this is because
when analysed together with tumour thickness, to
which it is closely related, it is seen to have no prognostic value for the same thickness, and the greater
aggressiveness of nodular melanomas simply results
in thicker lesions9.
The anatomical site of the lesion has independent
prognostic value in studies conducted with multivariate analyses10,11 and, generally, lesions located in
286
the extremities and, among them, those situated in
the upper extremities have a better prognosis than
those located in the head, neck, trunk and palmoplantar and subungual areas12. To explain this different prognosis it has been suggested that melanomas
located axially may have a later diagnosis, drain to
more than one lymphatic territory and have a greater
irrigation, which would favour the appearance of metastasis. All the same, our patients did not reveal differences in lymph node involvement according to the
site of the primary lesion.
In 1970, the thickness of the melanoma began to be
quantified using the so-called Breslow index or thickness, considering as such the thickness of the melanoma measured vertically with an ocular micrometer
from the highest part of the granulous layer to the deepest part of the tumour13. Numerous multivariate
studies have shown that the positive predictive value
of other histological parameters is dependent on tumour thickness, especially in stage I melanomas14.
This thickness is directly correlated with the likelihood of regional and distant metastases, as well as with
survival15. As for the possibility of lymph node spread, our results ratify the importance of tumour thickness, the Breslow index being an independent predictive factor, and establishing at 0.9 mm the minimum
value for which sentinel lymph node involvement
was found. To give an idea, the risk of lymph node involvement in our series is multiplied by more than
128 when the Breslow index exceeds the median
(0.62 mm).
With regard to the size of the melanoma, some authors find that tumour volume, calculated from the
combination of diameter and Breslow thickness, has
a prognostic importance both for overall survival16
and disease-free survival17, and even as a predictive
parameter for response to radiation therapy18. In our
series, tumour size, represented by the maximum
diameter of the primary lesion, had a predictive value
for lymph node involvement independent of the other
parameters, including thickness.
Melanoma ulceration has been reported as a variable
related to metastatic lymph node involvement19. It
was shown in a series of 8,500 melanomas that the
10-year survival rate in AJCC stage I and II patients
with ulcerated lesions was 50%, compared to 70%
when there was no ulceration. It was also observed
that ulceration, although strongly associated with tumour thickness, had an independent prognostic
value10. Moreover, the wider the area of tumour ulceration the worse the prognosis: only 5% of melanoma
patients with ulcers larger than 6 mm survive at 5 years, compared to 44% if the ulceration is less than 6
mm20. A relationship was seen in our patients between sentinel lymph node involvement and ulceration,
which like tumour size had an independent predictive value.
Rev Oncol 2004;6(5):283-8
38
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PIÑERO MADRONA A, MARTÍNEZ-ESCRIBANO J, MARTÍNEZ-BARBA E, ET AL. ARE THERE FACTORS THAT PREDICT THE RESULT OF
SELECTIVE SENTINEL LYMPH-NODE BIOPSY IN MELANOMA?
The spontaneous regression of a tumour is defined as
the partial or complete disappearance in the absence
of treatment and has been reported in 10%-58% of
melanomas. This variability has been attributed to
the different criteria used to define it21. Regression is
associated with a poor prognosis in melanomas less
than 0.76 mm thick, since more than 20% develop
metastasis after a 6-year follow-up, compared to just
2% of those without signs of regression22. One explanation might be that the lesions are thicker before the
onset of the regression phenomena. It has been observed that the frequency of histological regression is
inversely correlated with the thickness of the lesion:
46% in melanomas with less than 1.5 mm Breslow
index, 32% if the index is between 1.5 and 3 mm, and
9% if the thickness is greater than 3 mm23. Shaw et
al24 reported that thin melanomas with extensive areas of regression usually had regional lymph node
metastases at the time of diagnosis. The same authors
speculated that stimulus of the host immune system
by malignant cells at the lymphatic tissue could cause the immunological response responsible for the
regression of the primary lesion. However, others did
not find significant differences for the appearance of
metastasis between thin melanomas with or without
regression25. We found no relationship between regression in primary cutaneous melanomas and involvement of sentinel lymph nodes.
It has classically been accepted that the presence of a
mononuclear inflammatory infiltrate at the base of the
tumour is a good prognostic factor. However, multifactorial studies have shown that the intensity of the inflammatory response decreases as the thickness of the
lesion, with which it is closely and inversely related26,
increases, which is why it would not have any independent prognostic value27. The thickness may, at least in part, be conditioned by the infiltrate, i.e. when
there is no infiltrate the consequent inability to limit
tumour growth may enable it to become thicker. Clemente et al28 find a strong predictive value for survival of the inflammatory infiltrate, with 5- and 10-year
rates of 77% and 55% for significant infiltrates, compared to 37% and 27% respectively for the absence of inflammatory infiltrate. In our series regression does
not have any predictive value for sentinel lymph node
status; in fact, we found a diffuse inflammatory infiltrate associated with a more frequent sentinel lymph
node positivity, whereas the presence of a weak focal
inflammatory infiltrate was more common in patients
with negative sentinel lymph nodes, although in no
case were there significant differences.
Lastly, lymphatic or blood vessel invasion, defined as
the presence of tumour cells in endothelium-lined
cavities, is closely related to the existence of satellosis, and although its presence is not invariably linked
to the appearance of metastasis, it has been traditionally considered an important predictive factor for
39
the existence of lymph node metastasis29. Its predictive value has recently been shown for lymph node involvement in breast cancer30. Our results confirm
these findings and show that the presence of lymphatic invasion or permeation multiplies by 8.7 the risk
of sentinel lymph node involvement.
In conclusion, analysis of the data in our series
shows that apart from Breslow index, the presence of
lymphatic invasion in the primary tumour, the size
of the melanoma and the presence of ulceration are
independent predictive factors for the positive result
of selective sentinel lymph node biopsy in cutaneous
melanoma, and, although prospective studies are still
necessary, these variables must be taken into account
when indicating such biopsies with even smaller tumour thicknesses.
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SELECTIVE SENTINEL LYMPH-NODE BIOPSY IN MELANOMA?
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