ARTICLE
Auteur(s) : Adina Thoelke,
Hans-Peter Schmid, Robert Figl, Dirk Schadendorf, Selma Ugurel
German Cancer Research Center, Skin Cancer Unit, University
Hospital Mannheim, Dept. of Dermatology, Theodor-Kutzer-Ufer 1-3,
D-68167 Mannheim
accepté le 18 Janvier 2006
Numerous reports and large population based studies, though not
unquestioned, have proposed an association between SSc and cancer,
especially breast, lung, ovarian, oral cavity and pharyngeal
carcinoma as well as non-Hodgkin’s lymphoma [1-3]. To explain this
correlation, a number of possible mechanisms have been discussed.
Common causative agents for both cancer and SSc like viral
infections, chemical substances, age, or linked disease
susceptibility-genes might be responsible for part of the cases [1,
4]; substances secreted by malignant cells, like transforming
growth factor beta can cause sclerodermatous changes in the skin
and account for other cases [5]. Furthermore, when malignancy
develops in tissues affected by sclerosis, these underlying changes
in biological structures may be responsible for malignant
degeneration [4]. Scleroderma-like diseases are reported after
administration of certain anti-cancer drugs like taxanes,
doxorubicin, cyclophosphamide, gemcitabine and bleomycin [6-8].
Frequently, in this subgroup of patients all relevant serum
autoantibodies (like ANA, anti Scl 70, anticentromere,
antifibrillarin, and anti RNA polymerase III) are found within
normal ranges, and symptoms start with extensive cutaneous edema of
the lower extremities, followed by sclerotic changes while
Raynaud’s phenomenon is typically absent [6, 9].
Clinical observation
In April 2002, a 39-year-old female presented with left axillary
lymph node metastases from melanoma of an unknown primary and
underwent complete lymph node dissection. In June 2002, she
recurred with bulky left supra- and infraclavicular non-resectable
lymph node metastases of 30 × 40 × 100 mm and was subsequently
assigned to our department. Here, routine laboratory assessments
revealed normal values besides an elevated serum ANA titer of
1:5120, displaying a speckled binding pattern. This finding was not
accompanied by clinical symptoms; neither her own nor her family’s
history revealed any autoimmune diseases, and technical assessments
revealed no evidence of organ involvement, i.e. computed tomography
(CT) of the chest showed no abnormalities. In August 2002, a
vaccination therapy with autologous peptide-pulsed dendritic cells
was started. At the first re-assessment in September 2002, the
bulky metastastatic mass showed a complete remission. In December
2002, the patient reported for the first time Raynaud’s phenomenon
of both hands ( (figure
1) ). A second reassessment of melanoma disease in January
2003 revealed a tumor recurrence of the supraclavicular lymph node
area, suspicious mediastinal and axillary lymph nodes, as well as a
new subcutaneous metastasis in the abdominal wall. Dendritic cell
vaccination was stopped, and the patient was assigned to a
chemoimmunotherapy regimen including interferon-alpha (IFN-a).
Laboratory assessments previous to treatment onset revealed that
the serum ANA titer had further increased to 1:10.240, and
antibodies against Jo-1 (histidyl-tRNA-synthetase) were detected.
Because at that time the patient’s symptoms of autoimmune disease
were mild, she was started on a regimen of temozolomide 200
mg/m2 days 1 through 5 and pegylated(PEG) IFN-a 150 μg
days 1, 8, 15 and 22 of each cycle, repeated after 28 days. Shortly
after treatment initiation, the patient complained of fever,
chills, bone pains, dyspepsia, dyspnea, depression, nausea and
fatigue. With the exception of nausea, which might also be caused
by temozolomide, all of these symptoms were attributed to
PEG-IFN-a. The first tumor reassessment after 2 therapy cycles in
April 2003 revealed a complete remission of all metastatic lesions.
In parallel, serum ANA titers had declined to 1:2560. A second
reassessment in July 2003 showed a minor recurrence of lymph node
metastases, which remained unchanged under additional treatment
cycles. In late August 2003, after completion of 6 cycles of
chemoimmunotherapy, the patient noted muscle and joint pains,
cough, chest pain, dysphagia, xerostomia, stiffening of her facial
expression, and the impossibility to close her fists. A newly
performed CT scan of the chest ( (figure 2) ) revealed
abnormalities, which were interpreted as fibrosing alveolitis with
a peripheral crescent of high attenuation in the lower lobes of the
lung by the radiologist. These changes are known as a
characteristic pattern of the pre-fibrotic stage of pulmonary
involvement of SSc [10]. The patient’s symptoms were re-evaluated
and with consideration of the serum antibody findings, progressive
SSc with pulmonary involvement was diagnosed.
Because of metastatic melanoma, no systemic immunosuppression
was administered. However, since IFN-a has been reported to induce
various autoimmune diseases, we discontinued PEG-IFN-a treatment in
our patient immediately after diagnosis of SSc. Temozolomide was
continued with tumor reassessments revealing a stabilization of
melanoma disease, and was withdrawn in December 2003 after 11
completed cycles. At that time point, the symptoms of SSc were
still present but tolerable. In February 2004, the patient
underwent palliative right axillary and left cervical lymph node
dissection in order to achieve a tumor mass reduction. However, in
April 2004 new metastatic lesions were diagnosed in the
mediastinum, retroperitoneum and right infraclavicular region. The
patient was started temozolomide again, but this time progressed
under treatment. In August 2004, she was started on an
investigational melanoma vaccine, but did not respond by October
2004, when the metastatic lesions had progressed in number and size
and a small solitary brain metastasis had appeared. The symptoms of
SSc, markedly dyspnea, had deteriorated in the meantime,
accompanied by an elevation of serum ANA titers on to 1:10.240.
Sclerosis of the skin progressed from the distal extremities to the
proximal extremities and the trunk, and a microstomia and
shortening of the frenulum of the tongue were observed. Nail fold
capillaroscopy demonstrated an irregular pattern with
teleangiectasia and hemorrhage, and the fingers were fixed in
flexure. Laboratory tests in October 2004 revealed anemia but
normal renal and thyroid function. On repeated immunologic testing,
antibodies against DNA, nucleosomes, histones, ribosomal P-protein,
U1-sn-RNP-Sm, Sm, SSA/Ro, SSB/La, Scl-70 and centromeres were
absent. Moreover, no cryoglobulines and cryofibrinogens could be
detected; only Jo1 antibodies were highly positive. The presence of
these antibodies is frequently associated with pulmonary
involvement of dermatomyositis and is rarely observed in patients
with scleroderma. Because of the newly detected brain metastasis,
the patient was started on fotemustine monochemotherapy in November
2004. Shortly after the first treatment cycle, she was hospitalized
due to dyspnea and extensive non-malignant pleural effusions. All
fingertips had become necrotic and sclerosis of the skin had
affected the whole body. Though high dose steroids were
administered, the patient died two weeks later due to the
complications of SSc. At this time she had multiple lymph node
metastases with a median size of 30 mm and one small brain
metastasis of 7 mm, none of which were life threatening.
Autopsy was refused by the patient’s relatives.
Discussion
Because of the correlation in clinical courses of melanoma and SSc
we regard this case of SSc as paraneoplastic in etiology. Unlike in
chemotherapy related scleroderma-like disease, our patient showed
high serum ANA titers, Raynaud’s phenomenon, and Jo1 antibodies.
Unfortunately, no assessments of serum ANA titers had been
performed before the diagnosis of melanoma. However, the patient
never experienced symptoms of autoimmune disease before December
2002, when tumor relapse occurred.
Jo1 antibodies are rarely expressed in SSc (5%), and here
particularly in patients with SSc/polymyositis overlap syndrome
[11]. In polymyositis, the detection of Jo1 antibodies has been
described to be associated with interstitial lung fibrosis and
arthritis. The combination of Jo1 antibody positivity, lung
fibrosis, arthritis, Raynaud’s phenomenon, sclerodactyly and mild
symptoms of myositis is also termed anti-Jo-1 (antisynthetase-)
syndrome. The pattern of fibrosing alveolitis with high attenuation
in the peripheral lower lobes of the lung in SSc and anti-Jo1
syndrome share similarities [10, 12]. The clinical picture in our
patient displayed an overlap between SSc and anti-Jo-1 syndrome.
Though melanoma is thought to be an immunogenic tumor, autoimmunity
is not a frequent phenomenon in melanoma patients. We are aware of
only one case in the literature reporting a case of melanoma
concurrent with SSc [13]. This patient was classified as
scleroderma-like syndrome by the authors because she denied
Raynaud’s phenomenon, had low serum ANA titers and showed
asynchronous courses of scleroderma and melanoma. Conclusively,
this case adds paraneoplastic etiology to the list of underlying
mechanisms in the interrelationship between SSc and cancer.
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