Keywords
tamoxifen-induced vasculitis - breast cancer - endocrine therapy - side effects of
tamoxifen
Introduction
Tamoxifen is a selective estrogen receptor modulator and has agonistic as well as
antagonistic actions on the estrogen receptors (ERs), depending on the organ site.
It binds to the ER of the tumor, preventing the binding of estrogen and hence interrupting
the tumor proliferation pathways, leading to cell death.[1] It is the backbone of hormonal therapy in premenopausal women in the adjuvant as
well as metastatic settings and is one of the landmark discoveries in the treatment
of hormone receptor positive breast cancer, providing a significant benefit in disease
free and overall survival.[2]
[3]
[4]
It is usually well tolerated. In addition to antitumor responses, tamoxifen can also
exert antiangiogenic effects.[5] The common side effects seen are vasomotor symptoms (hot flushes), vaginal dryness,
and menstrual irregularities with venous thrombosis, and endometrial carcinoma being
less common. Cutaneous side effects account for 19% of the patients being treated
with tamoxifen, including the vasomotor symptoms, and other less common effects like
urticaria, rarely hypersensitivity-type reactions, including angioedema.[4] These are well documented and hence easily recognized by clinicians over the world.
However, skin rash in current literature is documented less than 1%,[2] and cutaneous vasculitis is a rare and lesser-known reaction, hence may be overlooked
and under treated.
As in most drug-induced vasculitis, there are antibodies produced against the drug
molecule, which result in immune complex formation. Cutaneous vasculitis is a small‐vessel
hypersensitivity vasculitis, due to the deposition of these immune complexes in the
vessel walls and activation of the inflammatory pathways. Typically, it presents as
symmetric palpable purpura and affects dependent areas of the body. The clinical manifestation
ranges from a mild cutaneous rash to a severe fatal reaction. It is important to recognize
the offending agent, as usually discontinuation of tamoxifen leads to a rapid resolution
of symptoms.[6] We report a case of a 38-year-old woman presenting with cutaneous vasculitis while
on maintenance tamoxifen in the adjuvant setting.
Case Report
A 38-year-old premenopausal lady, with no family history and no comorbidities, presented
with locally advanced carcinoma of the left breast, stage cT4bN2aM0. It was an infiltrating
ductal carcinoma grade 3, which was hormone receptor positive (ER, progesterone receptor
Allred score 8/8) and HER2neu negative. She received neoadjuvant chemotherapy with
four cycles of adriamycin and cyclophosphamide, following which she had a modified
radical mastectomy. The pathological stage was ypT2 ypN3a. She then received four
cycles of paclitaxel, followed by radiation to chest wall and supraclavicular fossa
along with which she was started on tamoxifen 20 mg once daily (OD) and leuprolide
11.25 mg once in3 months. Three months later she presented with maculopapular rashes
on all four limbs, on her legs more than her hands ([Fig. 1]). This rash was non blanching, erythematous, pruritic, and was not associated with
any other systemic or infectious symptoms. Patient had no history of insect bite,
or previous allergic reaction or family history of the same. Other causes of cutaneous
vasculitis such as antineutrophilic cytoplasmic antibody (ANCA)-associated or autoimmune
vasculitis were differential diagnosis; however, patient could not get the perinuclear-ANCA
serum test done due to financial constraints. Using the Naranjo scale for causality
assessment, this patient scored 6, which indicated a probable adverse drug reaction
to tamoxifen.[7] This rash was Common Terminology Criteria for Adverse Events grade 1.
Fig. 1 Bilateral lower leg showing maculopapular rash.
A dermatology opinion was taken, and skin biopsy was done from the left leg, in which
perivascular mononuclear inflammation in superficial and deep dermis was found, with
red blood cell extravasation and neutrophilic infiltration in the vessel walls. A
diagnosis of small vessel vasculitis secondary to tamoxifen was then done ([Fig. 2]). Tamoxifen was stopped, and she was given letrozole 2.5 mg OD along with the ovarian
suppression. She was given antihistamines (cetirizine) and fusidic acid for a week,
after which she was prescribed halobetasol 0.05% for topical application, along with
vitamin C and moisturizing lotions, for a period of 2weeks. The symptoms resolved
completely within 1 month and the patient was continued on letrozole with leuprolide.
Fig. 2 Skin biopsy micorphotographs: (A) Dense perivascular inflammation around upper and mid-dermal vessels (hematoxylin
and eosin [H&E] x100); (B) inflammatory infiltrate of lymphocytes, neutrophils, eosinophils, and plasma cells.
Red blood cell extravasation with hemosiderin staining (golden brown). Vascular outlines
not clear (H&E, x400); (C) vessel wall fibrinoid necrosis (white arrow) and eosinophil (black arrow).
Discussion
Drug-induced vasculitis is a reaction known to occur with many drugs documented in
literature. The manifestation may vary, commonly from mild cutaneous vasculitis to
rarely, severe systemic vasculitis with organ failure (Stevens-Johnson syndrome).
Withdrawal of the drug often leads to resolution, which suggests a reversible pathogenesis.
Vasculitis causes inflammation, fibrosis, weakening, and narrowing of the blood vessels.
It is often difficult to distinguish between idiopathic and drug-induced vasculitis,
but the temporal association with drug intake along with its resolution on withdrawal
helps cinch the diagnosis and hence prevent further episodes. It has been noted that
a timely withdrawal of the drug leads to complete relief of symptoms, but a delay
in diagnosis may lead to persistent symptoms with the need for immunosuppressive agents.[8]
Drug-induced vasculitis may be small vessel, medium vessel, large vessel, or cerebral.
Small vessel vasculitis is the most common type, and may be further classified into
three types, namely cutaneous leukocytoclastic vasculitis (CLCV), immunoglobulin A
(IgA), and ANCA-associated vasculitis. CLCV is the most frequently seen and is associated
with drug intake 31% of the time, mostly with antibiotics and anti-inflammatory drugs.
CLCV may be associated with a significant number of patients having a synchronous
involvement of internal organs, gastrointestinal tract, renal system, and musculoskeletal
system.[9] In one study, nearly half of the patients required immunosuppressive therapy despite
stopping the causative drug.[10] Other drugs known to cause CLCV are allopurinol, thiazides, phenytoin, sulfonamides,
as well as drugs used in oncology like levamisole and ceritinib.[11] Other small vessel vasculitis (IgA and ANCA associated), as well as medium vessel
vasculitis (often seen with tetracyclines, affecting renal and mesenteric vessels)
and large vessel vasculitis (reported with bevacizumab and lenograstim, causing aortitis
and periaortitis) are extremely rare forms and have only been reported anecdotally.
The pathogenesis of drug-induced cutaneous vasculitis involves immune complex formation
and deposition in the cutaneous capillaries. This causes endothelial injury and the
beginning of the inflammatory cascade, via activation of the complement system.[10] Due to the scarce available literature on the phenomenon, the exact pathogenesis
of tamoxifen-induced vasculitis is not known. ANCA may also play an important role
in drug-induced vasculitis, and many studies have established the association between
ANCA positive vasculitis and prior drug use. The majority of ANCA-positive vasculitis
related to drugs has been associated with perinuclear-ANCA pattern, in which myeloperoxidase
is the most frequently related antigen.
Estrogen is agonistic in breast tissue and consequently in malignant breast cells
and blood vessels. Tamoxifen blocks this action at the breast tissue level, and hence
acts as an antagonist to estrogen. It is the mainstay of hormonal therapy in breast
cancer in premenopausal women. It is given to all women with hormone receptor positive
tumors due to its excellent tolerability and lower adverse effect profile. It has
shown a benefit in adjuvant setting, metastatic setting, and also in preventing recurrence
in the ipsilateral as well as contralateral breast. The benefit of extending tamoxifen
therapy up to 10 years has been proven in multiple trials,[12]
[13] making its extended use more common, and subsequently its side effects with the
knowledge of their management, more pertinent.
In our case, cessation of the offending agent along with symptomatic treatment using
anti histamines and topical steroids led to a complete resolution of the symptoms
within 3 to 4 weeks. Our patient did not require any further treatment or immunosuppressants,
and was switched to letrozole along with ovarian suppression therapy, using gonadotropins.
Joseph et al found a similar reaction and discontinued the use of tamoxifen too, after
which the patient had a rapid resolution of symptoms.[6] Kulkarni et al observed a similar case and used dapsone in the treatment, while
the tamoxifen was continued and vasculitis persisted.[14]
The strengths of this approach are that an early diagnosis exists of a rare but curable
condition while preventing its complications, by quick and timely identification and
intervention. The limitations include the fact that the use of tamoxifen is on a decline
worldwide due to the introduction of newer agents, and the use of ovarian suppression
with aromatase inhibitors is practiced commonly, for its survival benefit over tamoxifen.
Conclusion
Tamoxifen-induced cutaneous vasculitis is a rare complication manifesting as a simple
drug-induced rash. While hot flushes, pruritus, mild rashes, and vaginal dryness are
known common side effects of tamoxifen, it is important to distinguish them from cutaneous
vasculitis. Prompt diagnosis of this infrequent condition may lead to a timely intervention
and avoid immunosuppressants with their associated morbidity and complications in
our patients. The intervention is simple, involves cessation of tamoxifen and its
replacement with other endocrine therapies. It is, therefore, essential that all oncologists
be aware of this ailment and its management.
