ARTICLE
Auteur(s) : Regina
Renner1, Michael Sticherling2
1Clinic of Dermatology, Venereology und Allergology,
University of Leipzig Ph.-Rosenthalstr. 23-25, 04103 Leipzig,
Germany
2Clinic of Dermatology, University Hospital of Erlangen,
Erlangen, Germany
accepté le 21 Juillet 2008
Within the last decade a possible relationship of malignancy and
autoimmune chronic inflammatory diseases has been intensively
discussed. In this regard, evidence has been accumulating recently
for diverse rheumatological diseases. Lymphocyte monoclonality is
often described associated with rheumatoid arthritis [1, 2] or
Sjogren’s syndrome [3, 4] and similarly, in systemic lupus
erythematosus (SLE) an increased cancer risk was found [5-9].
Autoimmune phenomena or autoimmune diseases can precede, appear
concomitantly or follow malignancy, but in most cases, malignancy
develops after a long-standing autoimmune disease [7].
There are different hypotheses as to how malignancy in
autoimmunity develops. It may be a result i) of the chronic
inflammation process with chronic immune dysregulation, or may be
part ii) of the long standing immunosuppressive therapy, or iii) a
paraneoplastic phenomenon – particularly in cases with nearly
simultaneous occurrence, or iv) following a long standing local
proliferative and reparative process, mostly in cases with chronic
cutaneous lupus erythematosus. Some authors report elevated levels
of tumour-associated antigens in the sera of patients with
different rheumatic diseases e.g. rheumatoid arthritis or SLE.
These are expressed not only by cancer cells but also on the
surface of inflammatory cells and correlate with laboratory markers
of disease activity [10, 11]. On the other hand, non-specific and
specific autoantibodies can be found in the sera of patients with
different tumour entities. In the process of carcinogenesis,
antibodies occur naturally as a response to tumour antigens. In
this regard various autoantibodies such as anti-dsDNA, anti-RNP and
anti-Sm-antibodies are found to be significantly higher in patients
with different carcinomas and play a role in their improved
survival [12, 13]. Accordingly, autoantibodies reflect an increased
antineoplastic humoral immunity and thus may result in protective
autoimmune reactions [12].
In addition, drugs are known factors in triggering autoimmunity.
A couple of cases of so called post-chemotherapy rheumatism in
malignancies suggest that some chemotherapeutic or immunoregulatory
drugs like interferon used for the treatment of neoplastic
disorders activate autoimmune mechanisms and provoke features of
rheumatoid arthritis or systemic lupus erythematosus [14-16].
Here we review the literature regarding subacute cutaneous lupus
erythematosus (SCLE) and concomitant neoplasia and focus on
possible explanations of this coincidence on the basis of 3 short
case reports of patients with long-standing SCLE who developed
metastasizing solid organ cancers.
Case 1
CLE disease
The 55-year-old female patient suffered from a longstanding disease
over 13 years and explicit UV sensitivity. Skin lesions initially
presented as discoid lupus erythematosus and changed over the years
into more erythematous maculae or plaques reminiscent of SCLE
lesions which were verified by histological and direct
immunofluorescence examination. The patient complained about
recurrent arthralgias or arthritis in her knees, fingers and ankle.
Laboratory data
Routine laboratory investigations were within normal limits, but
antinuclear antibodies were elevated up to 1:1,280 with anti-SS-A-,
anti-RNP-antibodies and anti-β-glycoprotein-IgM-antibodies positive
at different titres without any previous thrombotic events. Other
specific autoantibodies have never been detectable. No other organ
manifestations besides skin lesions were found at any time during
regular annual clinical and serological check-ups.
Therapy of CLE
The patient was treated with topical corticosteroids and oral
chloroquine until 07/2004 with good clinical effects and never
received any other immunosuppressive drugs.
Breast cancer
In 1996, a ductal invasive mamma carcinoma of her right breast with
positive regional lymph nodes was detected. At this time, she had
suffered from SCLE for about 5 years. She underwent breast surgery,
radiation and adjuvant chemotherapy with apparent remission, but
developed a local tumour relapse 2 years later and was treated
afterwards with tamoxifen, later on with exemestane. Unfortunately,
she developed hepatic metastases 7 years after the first cancer
diagnosis and had to undergo different chemotherapeutic protocols
with epirubicin 35 mg/m2 BSA, doxetacel and later
on with vinorelbine 25 mg/m2 BSA, folic acid
500 mg/m2 BSA and 5-Fluorouracile
2,000 mg/m2 BSA. Her SCLE skin lesions exacerbated
during all the different protocols after about 6 cycles of
chemotherapy (figure 1A
and B before and during chemotherapy). Though metastases
were intermittently regressive and the skin condition improved, the
patient died at the age of 55 as a consequence of metastasing
cancer 8 years after first diagnosis.
Case 2
CLE disease
The 50-year-old female patient developed a SCLE at the age of 26.
She showed elevated antinuclear antibodies of 1:640 (normal range
< 1:160), anti-dsDNA-antibodies 136.9 IU/mL (normal range
<35-55 IU/mL), anti-SSA/Ro-antibodies 19.5 (normal range
< 1) and marginally elevated levels of anti-RNP-antibodies and
anti-Sm-antibodies.
Therapy of CLE
She was treated with chloroquine 250 mg/d starting in 1981 for
about 5 years. In 1982, this therapy was combined with oral
prednisolone or methylprednisolone respectively at 4-12 mg/d.
In 1986, medication was changed to oral (methyl) prednisolone and
azathioprine 100-200 mg/d until 2001. Despite this, she had
persistent activity of her SCLE over the years with skin lesions on
the face and upper trunk. Organ manifestation could not be totally
excluded because of pre-exisiting, but stable slight interstitial
disseminated fibrosis of the lung, as well as heart valve
degeneration which was interpreted as a consequence of earlier
endocarditis. Other organ manifestations could not be found at any
time. In 2001, she was treated with four cycles of adjuvant
intravenous immunoglobulins over 6 months at 2 g/kg BW each.
Following this therapy, the skin lesions disappeared almost
entirely and disease activity was reduced.
Breast cancer
In 1999 at the age of 47, she underwent surgery of her left breast
because of a benign tumour. At the age of 50, malignant breast
cancer was diagnosed in both mammae of invasive ductal (left side)
and invasive lobular breast cancer type on the right side.
Bilateral breast amputation and lymph node dissection of the
axillae were performed and followed by chemotherapy with
epirubicine 35 mg/m2 BSA in combination with
cyclophosphamide. At the time of diagnosis, she already had
disseminated metastases in her axial lymph nodes, bones, liver and
lung. Skin lesions were only slightly exacerbated during this time,
when azathioprine was reduced to 100 mg/d. Subsequently, the
patient died at the age of 50 as a consequence of metastasing
cancer.
Case 3
CLE disease
The 50-year-old female patient developed a SCLE in 1995 at the age
of 38. Autoimmune parameters were elevated for ANA (1:1,280, normal
range < 1:160), anti-histone-AK 35.7 IU/mL (15-30),
anti-SS-A/Ro-AK und -SS-B/La-AK.
Therapy of CLE
Since 1995, she was treated with chloroquine 250 mg/d and
since 2002 hydroxychloroquine intermittently in combination with up
to 5 mg oral prednisolone per day. In addition, she developed
Sicca symptoms of her eyes and mouth in 2002 and discrete lung
fibrosis of the right lobe of the lungs and slightly decreased
functional parameters were noticed.
Lung cancer
In 2004, small cell lung cancer was diagnosed in the right lobe of
her lungs although she had never smoked. Lung cancer was first
treated with radiation and chemotherapy with tapotecane. During
chemotherapy, the SCLE skin lesions worsened dramatically. Because
of metastasis of the brain, local radiation was performed and
resulted in a strong dermatitis on her head, which may also be
interpreted as SCLE induced by radiation. After a short time of
stable disease, her cancer relapsed in 2006. After a few cycles of
docetaxel, her skin lesions exacerbated again and were treated with
systemic and topical glucocorticosteroids. In 2007, the patient
died as a consequence of metastasing lung cancer after a disease
course of three years.
Discussion
The association of cancer and autoimmune chronic inflammatory
conditions has to be evaluated critically as coincidental or
causally related. Solid tumors of epithelial and stromal origin as
well as haematological malignancies have been described. Here we
discuss different theories: malignancy as a result of i) chronic
inflammation i.e. chronic immune dysregulation and induction of
lymphocyte monoclonality as shown for Sjogren’s syndrome, ii) long
standing immunosuppressive therapy, iii) paraneoplastic phenomenon,
iv) following long standing local proliferative and reparative
processes or v) as pure coincidence. While most data on any of
these ideas are based on case reports of patients with SLE or other
autoimmune diseases, studies on SCLE and solid cancers are still
lacking. It may be assumed that because of inflammation or chronic
stimuli relevant in SCLE as in other autoimmune diseases,
pathogenic pathways and the association to cancer are similar.
Chronic systemic inflammation
In rheumatic diseases, cancer may arise as a result of immune
dysregulation and chronic inflammation. Recent results clearly
indicate an association between the severity of chronic
inflammation and lymphoma risk in RA and Sjogren’s syndrome. Thus,
the average risk of lymphoma in RA is markedly increased in those
patients with most severe disease, whereas little or no increase is
found in those with mild or moderate disease [17]. According to
Naschitz et al. [5] long-standing rheumatic disorders may be
regarded as “premalignant conditions”, as shown for systemic lupus
erythematosus. Patients with Sjogren’s syndrome initially show
polyclonal antibody responses with the development of atypical
lymphocytes and monoclonality during further progress of the
disease. Patients have a 44-fold excess risk of developing a
non-Hodgkin-lymphoma [5]. A 4.1 fold increased risk for
haematological malignancies, namely non-Hodgkin-lymphoma, has also
been shown for SLE [18]. This increased risk was unrelated to the
extent of organ involvement but closely related to serological
inflammatory parameters like C-reactive protein.
Data from a large SLE cohort study [19] confirmed a slightly
increased risk in SLE for all cancer entities as a group,
especially for non-Hodgkin-lymphomas as well as hepatobiliary and
lung cancers. The increased incidence of lymphomas may be related
to long standing immunosuppressive therapy or additional stimuli
from chronic infections with Epstein-Barr, herpes simplex or other
oncogenic viruses [20, 21]. In addition, the chronic inflammatory
disease may result in constant B-cell-stimulation by chronic
antigenic exposure.
Bin et al. [22] tried to reproduce the published association of
lung cancer in SLE but they could not identify specific demographic
risk factors. Only 20% of affected patients have been exposed to
immunosuppressive drugs as seen in our patient in case 3.
Consequently the authors suggest an additional genetic link between
lung cancer and SLE. Some chromosomal loci are indeed implicated in
an increased lung cancer risk in the general population as well as
in SLE, such as 4p15.1-15.3 and 6p21 [22]. The authors hypothesized
that shared susceptibility loci predispose individuals to both SLE
and lung cancer.
Another hypothetical cause for an increased rate of lung cancer
in SLE is the higher incidence of fibrotic lung disease [23, 24].
Fibrosis may develop in SLE patients [25, 26], especially in those
with longstanding disease and chronic fibrotic lupus pneumonitis or
bronchiolitis obliterans with organizing pneumonia which may
eventually evolve into lung cancer. This may also result from
chronic local inflammatory and reparative stimuli. The patient
number 3 in our report also developed discrete lung fibrosis with
slightly decreased functional parameters two years before the
clinical diagnosis of small cell lung cancer (see further
discussion below).
Other suggestions are that autoimmunity rather reflects a
constant antineoplastic process. This is based on the ideas of
somatic mutation and clonal deletion where an intact immunity can
detect and eradicate transforming cells. Reines [27] postulated
that individuals suffering from autoimmunity have inherited
multiple foci of prematurely aging cells which are prone to
transform into cancer cells but are detected by the innate immune
system. The clinical outcome of initial neoplasia and immunity will
vary depending upon the individual degree of tumour-proneness as
polygenetic traits. Accordingly, HLA-linked autoimmune diseases may
be regarded as “chronic hypersensitivity syndromes” with the
constant and almost hidden efforts of the immune system to suppress
multiple incipient neoplastic microfoci. This concept is supported
by the fact that elevated autoantibodies can be found in cancer –
especially lymphoma – patients [12, 28, 29]. Our patients 2 and 3
presented elevated LE-specific autoantibodies, however, prior to
their malignant disease.
Long standing immunosuppressive therapy
The interval between the diagnosis of the rheumatological disease
and the diagnosis of associated malignancy may be up to 20 years
[30], as in our second patient with active SCLE for over 25 years
before the diagnosis of breast cancer.
Immunosuppressive drugs may increase the risk of developing
malignancies [31]. There is e.g. a higher cancer risk for patients
treated with cyclophosphamide with rheumatoid arthritis [32],
low-dose methotrexate [33], azathioprin or cyclosporine [34]. A
beneficial effect of antimalarial agents with regard to malignancy
in SLE has been suggested in some papers [35, 36], but recent
studies seem not to support this hypothesis [37].
Tarr et al. [7] reported the occurrence of malignancies in a
Hungarian LE population of 860 patients. Cancers appeared 13.4
years (mean) after diagnosis of LE. Breast cancer occurred most
frequently (n = 11) followed by gastro-intestinal malignancies (n =
9), cervical cancer, different hematological malignancies and
bronchial cancer. The relative risk of non-Hodgkin lymphoma and
cervical cancer was significantly increased when compared to the
general female population in Hungary. 62.2% of the patients had
received azathioprine and/or cyclophosphamide prior to cancer
development, as seen in our patient 2. This increase of malignant
diseases might result from mutagenic properties of the drugs used
for the treatment of autoimmune diseases and/or suppression of
anti-humoral and cellular immune reactions. With regard to the
theory of Reines [27], as discussed above, immunosuppressive
therapy may even be deleterious when constant autoimmune reactions
are necessary to suppress incipient neoplastic foci.
Paraneoplastic phenomenon
Paraneoplasia is defined, according to McLean’s criteria [38], by
the simultaneous occurrence of skin disorders and development of
the tumour, but may precede tumour diagnosis by no longer than 2
years. Several published cases of SCLE have been interpreted as
paraneoplastic conditions [39-41]. Laryngeal squamous cell
carcinoma, lung cancer and breast cancer have been described in
correlation to SCLE (see synopsis in [39]). Typically for
paraneoplastic syndromes, most of the patients showed regression of
SCLE after successful cancer therapy and persistence or relapse
during chronic or metastatic disease. The authors suggested that
this might be due to a direct beneficial immunosuppressive effect
of the chemotherapy on the dermatosis or the reduction of specific
tumor antigens which are able to stimulate the immune reaction and
will result in SCLE. These tumour antigens may be homologous or
related to the Ro/SS-A-antigens which are characteristically
involved in the SCLE disease process. One of our patients (case 3)
showed positive anti-Ro/SS-A-antibodies and SCLE
deteriorated during the chemotherapy cycles. A release of tumor
antigen during therapy might account for this effect.
Recently a case of lupus erythematosus gyratus repens has been
described which is clinically and histologically similar to the
annular variant of subacute cutaneous lupus erythematosus
associated with internal malignancies like lung cancer [42,
43].
Long standing local proliferative and reparative processes
Cases of squamous cell carcinoma (SCC) of the skin in patients with
long standing DLE may be related to persisting local proliferative
activity of keratinocytes or local chronic inflammatory stimuli
[44, 45]. Cohen et al. [46] reported an association between human
papillomaviruses infections (HPV), chronic immunosuppression with
azathioprine and prednisolone and SCC development in a patient with
non-scarring SCLE. In this case, the oncogenic potential of chronic
papillomavirus infection together with therapeutic
immunosuppression resulted in SCC development. However, in contrast
to DLE where the characteristic chronic scarring may account for
the occurrence of SCC, no such correlation has been described for
SCLE so far.
Similar ideas relate to chronic interstitial lung disease (ILD)
and cancer development: for this specific fibrotic and inflammatory
lung disease, an elevated risk for cancer has been found [47].
Inflammation, injury and chronic repair mechanism induced by ILD
may cause genetic errors and genetic alterations (microsatellite
instability and loss of heterozygosity) including mutations of e.g.
p53, which can lead to tumour genesis. However, other or additional
genetic predisposing factors associated with an autoimmune disease
may promote neoplasia as seen in systemic sclerosis [47].
Coincidence
On the other hand, pure coincidence of these diseases may be
discussed. Lung cancer is one of the most commonly diagnosed
cancers worldwide. The mean age of small cell lung cancer is
normally between 60-65 years with an incidence for females of 21:
100,000. LE or SCLE is more often seen in younger patients. Patient
3 was significantly younger than the mean age of lung cancer
manifestation and had no additional risk factors like smoking.
Increasing age and female sex are well-recognized risk factors
for breast cancer development [48], and indeed our patients were
all female and had an average age of 51.6 years at the time of
first diagnosis of their cancer disease. About 40% of women who
develop breast cancer do so before their 60th birthday. The
age-related incidence of breast cancer is estimated at 208.6:
100,000 for women between 50-54 years. In contrast, a recent review
suggests that there is no or only a minimally increased risk for
breast cancer in patients suffering from SLE [49].
Conclusion
The impact of a genetic susceptibility, treatment modalities and of
chronic inflammatory activity as well as differential relations of
the diverse autoimmune diseases and malignant entities remains to
be elucidated. Most published cases of SCLE and malignancies are
interpreted as paraneoplastic associations. In contrast, our cases
seem related to a long-term course of the autoimmune disease. None
of our patients suffered from one of the frequently described
non-Hodgkin lymphomas. As a consequence of the elevated risk of
developing neoplasias, all LE patients need to be regularly
screened for possible malignancies, especially in chronic courses
and long-standing immunosuppressive therapy.
Acknowledgements
This work is not supported by any funding sources and has not been
previously presented. The authors have no conflict of interest to
disclose.
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