The Turkish Journal of Gastroenterology
Turk J Gastroenterol 2011; 22 (6): 621-625
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|Kaposiís sarcoma in patients with ulcerative
colitis receiving immunosuppressive drugs:
Report of a case
|BŁlent «ET›N1, SŁleyman B‹Y‹KBERBER1, IĢżlay Bilge YILMAZ2, Ramazan YILDIZ1, Uūur COřKUN1,
|Departments of 1Internal Medicine, Division of Medical Oncology and 2Pathology, Gazi University, School of Medicine, Ankara
|Keywords: Ulcerative colitis, Kaposiís sarcoma, immunosuppression, immunomodulatory agents.
Kaposiís sarcoma is an unusual tumor principally affecting the skin of the lower extremities. Although the association between Kaposiís
sarcoma and renal transplant has been well documented, there are few Kaposiís sarcoma cases in the literature associated
with ulcerative colitis or other inflammatory bowel diseases. This report presents a patient with ulcerative colitis who developed Kaposiís
sarcoma following treatment with long-term medium-dose azathioprine and additional corticosteroids. Kaposiís sarcoma is a
rare complication in inflammatory bowel diseases that may (or may not) be related to immunosuppression. Hence, immunomodulatory
agents should be planned carefully in the treatment of inflammatory bowel diseases and avoided if they are not essentially
necessary. Cases of colorectal Kaposiís sarcoma complicating inflammatory bowel disease should be managed with a conservative
approach and discontinuation of the immunosuppressive treatment.
Kaposiís sarcoma (KS) is an unusual tumor principally
affecting the skin of the lower extremities (1).
It occurs in four clinical forms: classic KS, human
acquired immunodeficiency syndrome (AIDS)-related
epidemic KS, African-type endemic KS, and
transplantation-associated (due to immunosuppression)
KS (2). There is a well-known relation
between KS and human immunodeficiency virus
(HIV) (3). KS was also reported in patients who
had immunosuppressive treatment in different
settings, such as rheumatoid arthritis, polymyositis/
dermatomyositis, vasculitis, systemic lupus
erythematosus, polymyalgia rheumatica, BehÁetís
syndrome, after renal/liver/cardiac transplantation, Wegenerís granulomatosis, and bullous pemphigoid
(4-6). In almost all of the cases, human herpesvirus-
8 (HHV-8) has a role in KS development
(7), and most of them have a history of high-dose
and/or long-term immunosuppressive treatment
(4). Although KS has been reported in such different
rheumatologic settings, it was rarely associated
with ulcerative colitis (UC) outside of AIDS or
post-transplant states. To our knowledge, only a
few cases with UC and KS have been reported.
A 42-year-old woman referred to our center with a
complaint of newly onset purple-colored lesions on
both arms and her face. A diagnosis of UC had been
made 13 years earlier, when she had presented
with proctitis, rectal pain and bloody stools. The
patient was followed regularly by a gastroenterologist.
Exacerbations of colitis approximately
every 4 to 6 months were treated with mesalamine
and intermittent oral corticosteroids; the most
recent episode had been treated with a threemonth
taper of prednisone that ended approximately
two months before admission. The patient had
been taking azathioprine 100 mg per day for five
years without interruption. The immunosuppressive
treatment had been given up two days before
admission to our hospital due to the sudden appearance
of lesions on her arms and face. Red-purple
papules were becoming confluent to form a large
plaque of 5x5 cm on the anterior side of her left
arm and face. The patient had another lesion on
her left ankle region that was a 2x2 cm bluishpurple
papule with erythema at the base (Figure
1). Physical and laboratory examinations were
normal. The patient reported no circumstance requiring
long-term sun exposure. No other simultaneous
precancerous skin lesions (i.e. nevi pigmentosus)
were found in this patient.
Pathologic examination of the lesion on the left
arm region revealed early stage KS. Hematoxylin
and eosin staining of a section from a biopsied nodule
showed moderate chronic inflammation and a
focal submucosal proliferation of spindle cells consistent
with KS. Immunolabeling for HHV-8 stained
the nuclei of the spindle cells (Figure 2).
An examination of serum samples for HIV by the
ELISA method was negative and other tests revealed
high titer of IgG antibodies to HHV-8.
Computed tomography (CT) of the thorax and abdomen
showed no visceral organ involvement.
Azathioprine treatment was stopped. External radiotherapy was planned for the lesions on the leg
and arm and face (Figure 1). The patient did not
receive any chemotherapy. After two weeks of treatment,
KS lesions completely regressed. Six
months after radiotherapy and following withdrawal
of immunosuppressive therapy, the patient
had no evidence of any disease and a normal abdominal
and thoracic CT scan.
There are four clinical variants of KS: classic, endemic,
AIDS-associated, and drug-related. Drugrelated
KS has been described in iatrogenic immunosuppressed organ transplant recipients and in a
wide spectrum of patients receiving chronic immunosuppressive
therapy. In patients with organ
transplantation, the incidence of KS is markedly
increased and estimated as 500- to 1000-fold greater
than in the general population (8).
Ulcerative colitis (UC) is a chronic inflammatory
disorder of the gastrointestinal tract that affects
the large bowel and is a major disorder under the
broad group of inflammatory bowel diseases
(IBDs). Current therapeutic strategies can be classified
broadly based on disease activity into those
that treat active disease (induction therapy) and
those that prevent recurrence of disease once remission
is achieved (maintenance therapy).
Of the various immunomodulatory agents, the
most widely used are azathioprine and 6-mercaptopurine
(6-MP). These two agents are purine analogs
that interfere with nucleic acid metabolism
and cell growth and exert cytotoxic effects on
lymphoid cells. Four controlled studies have demonstrated
the efficacy of azathioprine in the treatment
of active UC (9-12).
From the efficacy standpoint, patients with steroid-
dependent UC who are able to achieve remission
with azathioprine and mesalamine and discontinue
glucocorticoids can be maintained in remission
with azathioprine alone (13).
In addition to the effect of immune suppression,
however, there are specific characteristics of thiopurines
that may promote carcinogenesis. Thiopurines
work by incorporation of Ďrogueí thiopurine
nucleotides into DNA, but this subtly disrupts
DNA structure (14), interferes with DNA replication
and repair (14-16), creates unstable base pairs
(17), and codes ambiguously, promoting mutagenesis
Thiopurines also directly promote DNA damage
by rendering it highly sensitive to radiation, particularly
ultra-violet A (UVA) radiation, which accounts
for 95% of UV radiation from sunlight. When
thioguanine nucleotides are incorporated into
DNA, the action of radiation creates reactive oxygen
species, which attack both the DNA and its
surrounding proteins, promoting mutagenesis (17-
22). This is thought to account for the significant
excess of non-melanoma skin cancer seen in those
taking long-term thiopurines and the excess of
brain tumors seen when leukemia treatment with
MP was combined with cranial radiotherapy (23).
Recent work has demonstrated in vivo that individuals with IBD treated with thiopurines have higher
rates of somatic mutations in circulating white
cells than thiopurine-naive patients (24). The
rate of mutation was proportional to both the dose
and duration of treatment, and the pattern of mutations
formed a specific thiopurine signature (24).
Clinical data have linked the risk of malignancy
during thiopurine treatment to the total dose of
azathioprine received (25,26), thiopurine metabolite
levels and TPMT mutations (27-30).
Nonetheless, the majority of patients placed on
corticosteroids or immunosuppressive therapy do
not develop KS, and considering the number of patients
with UC disease requiring corticoids and/or
immunosuppressive drugs, KS is an extremely rare
complication. That has led many investigators
to invoke a genetic or an ethnic predisposition in
the development of this neoplasm because most
cases of drug-related KS overlap with populations
predisposed to classical KS. This rare neoplastic
complication of IBD is most likely related to the
immunosuppressive treatment. In light of the experience
in transplanted patients who receive aggressive
immunosuppression with several immunosuppressive
drugs and in whom drug-related
KS is relatively frequent, speculation suggests the
combination of several immunosuppressive drugs
increased the risk of KS in our patient. The optimal
duration of maintenance therapy with azathioprine
in patients with UC is currently unknown.
In patients with Crohn's disease, the maintenance
benefit of azathioprine or 6-MP can be observed
for at least five years (31,32). Based on these data
in Crohn's disease and the paucity of alternative
maintenance therapies, in patients with UC in
whom remission is maintained with azathioprine
or 6-MP, treatment is generally continued indefinitely
as long as there is no significant adverse side
effect. Our patient had been taking azathioprine
100 mg per day for five years without any side
Human herpesvirus (HHV)-8 is the main etiological
agent of the four clinical-epidemiological forms
of KS. That HHV-8 seems to be necessary but not
sufficient to induce KS was noticed in transplant
patients who were HHV-8-positive before transplantation,
though the tumor occurred only on
posttransplant immune suppression. HHV-8 is an
important cofactor in the development of the disease
in association with drug-related immunosuppression.
Drug-related KS could be the result
of viral reactivation by immunosuppressive drugs.
The clinical course of drug-related KS varies, depending
on the degree of immune suppression.
When immune suppression remains low, the
symptoms are reminiscent of classical KS, with
the lesions likely to resolve on suspension of treatment
with the drug and with a latency period estimated
at around one year. When the level of immune
suppression is greater, symptoms are more
aggressiveópossibly even fulminantóand the latency
period is shorter (33).
The natural history of cutaneous drug-related KS
is not fully known. Both regression and cure of KS
have been reported after withdrawal or reduction
of immunosuppressive therapy (34).
There is no consensus on the optimal tumor-directed
therapy for different classic KS manifestations.
Because many active treatments have been
described, therapeutic choices are often made based
upon the experience and medical discipline of
the treating clinician, but also include consideration
of patient preferences and comorbid conditions.
For patients who have limited volume disease causing
symptoms (e.g., bleeding or chafing against
clothes) or cosmetic disfigurement, we suggest local
treatment rather than observation or systemic
chemotherapy. The choice of modality (radiation
therapy, excision, cryotherapy, laser ablation) depends
on a number of factors, including the site
and extent of the disease involvement as well as
clinician and patient preference. In our patient,
steroids and azathioprine were discontinued. After
radiotherapy treatment, KS lesions completely
regressed and the patient did not receive any chemotherapy.
Six months after radiotherapy and following
withdrawal of immunosuppressive therapy,
the patient had no evidence of any disease
and a normal abdominal and thoracic CT scan.
The patient was started on 5-aminosalicylic acid
(5-ASA, mesalamine) after the disappearance of
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