FOCIS Centers of Excellence Review
Cutaneous vasculitis in breast cancer treated with chemotherapy

https://doi.org/10.1016/j.clim.2008.07.001Get rights and content

Abstract

A patient from the University of California Los Angeles Medical Center who developed cutaneous vasculitis during the course of treatment for metastatic breast cancer is presented (status: post-lumpectomy and radiation therapy). Since the onset of vasculitis occurred during the course of therapy for the neoplasm, it was difficult to differentiate between drug-induced vasculitis and paraneoplastic vasculitis. The patient had been exposed to medications including gabapentin, methimazole, trastuzumab, fulvestrant, and letrozole — which could cause endothelial cell toxicity. Drug-induced small vessel vasculitis usually attacks the skin or subcutaneous parts of the skin. In cancer therapy, there have been case reports that hormonal drugs such as estrogen receptor antagonists, aromatase inhibitors, and epidermal growth factor receptor (EGFR) inhibitors can induce cutaneous vasculitis. On the other hand, paraneoplastic syndromes manifested as cutaneous vasculitis have been documented, possibly mediated by unknown immunological mechanisms associated with the tumor such as formation of immune complexes, direct antibody-mediated effects on endothelial cells, or direct effects of tumor cells on the vascular wall. Some patients with drug-induced cutaneous vasculitis have antineutrophil cytoplasm antibodies (ANCA) directed to one or more neutrophil cytoplasm antigens — the most common being granule protein myeloperoxidase (MPO), human leukocyte elastase (HLE), cathepsin G and lactoferrin. Some patients also have antibodies against histones and antiphospholipid. Serologic testing and measurements suggest an influence of therapy on vasculitis, yet the lack of sensitivity and specificity for a biomarker in endothelial injury indicate the need to search and evaluate new markers for improved predictive value of the tests, and to provide guidance in therapy.

Introduction

A 63 year old black female with a history of breast cancer presented to the UCLA Medical Center in 2004 with a rash in her lower extremities for two months. She had been diagnosed with intraductal breast carcinoma in 1992. Her status post left lumpectomy with radiation therapy and tamoxifen therapy for two years showed no signs of relapse. She had also been diagnosed with toxic multinodular goiter in 1996, and following treatment with 131I therapy and methimazole, she had been euthyroid since then. She had previously been on estrogen replacement therapy until her diagnosis with breast carcinoma in 1992, and had past history of idiopathic thrombocytopenia.

Her symptoms in 2004 began as a draining wound in her right lower extremity, which rapidly progressed to large ulcerations at both lower extremities. Systemic symptoms included mild weight loss, but no fever or joint problems. She had not used over-the-counter medications or herbal supplements in the recent past, and had not been exposed to corticosteroids. On exam, diffuse superficial, irregular, indurated purpura was localized in her lower extremities. Those lesions were painful, raised, confluent, erythematous patches with a burning sensation.

Blood exams indicated an erythrocyte sedimentation rate (ESR) of 96 mm/h. Positive serological tests included: anti-cardiolipin IgM antibody (Ab): 19 MPL (normal: < 10), β2-glycoprotein IgA: 10 U/ml (normal: < 10), immunofluorescent perinuclear ANCA (p-ANCA): 1:80 (she was negative for myeloperoxidase), thyroglobulin (TG) Ab: 40.5 IU/ml (normal: < 2.5), thyroperoxidase (TPO) Ab): 675.7 IU/ml (normal: < 2.0), parietal cell Ab: 1:80. The cytokine profile was unremarkable: tumor necrosis factor (TNF)-α: < 0.1 pg/ml (normal is 1.2–15.3), interleukin (IL)-1β: < 3.9 pg/ml (normal is < 3.9), IL-2 receptor: 716 U/ml (normal is 406–1100), IL-6: 3.81 pg/ml (normal is 0.31–5.0). Tests for rheumatoid factor, antinuclear Ab (ANA), antihistone Ab were negative. The carcinoembryonic antigen (CEA) level was 2.0 ng/ml (normal range is 0–2.5 ng/ml in non-smokers).

Full thickness biopsy of the skin on the right calf showed vacuolar alteration of the dermoepidermal junction, with superficial and deep perivascular and peradnexal lymphocytic infiltrate extending to the subcutis in a lobular pattern, consistent with a connective tissue disease (Fig. 1).

The medication gabapentin that had been started a month before the onset of her lesions was discontinued, and her lesions stopped progression and improved gradually, the ulcerations resolving with wound care.

In the tumor surveillance exam taken in 2006, whole-body PET CT scan revealed a focus of increased 18-fluro-2-deoxyglucose (FDG) activity in the medial segment of the left lobe of the liver (Fig. 2). MRI of the abdomen showed two ill-defined lesions in the left lobe of the liver — which were hypointense to the normal liver tissue on precontrast T1-weighted images, isointense on early postcontrast images with portal venous phase enhancement (that persisted on delayed images), and increased T2 signal (Fig. 3). At the same time, cystoscopy was done because of a persistent bladder infection, and a bladder mass was found. After bladder biopsy, fluorescence in situ hybridization (FISH) for the expression of the HER-2/neu gene showed an abnormal signal pattern, with a HER-2/D17z1 ratio of 6.3 (a ratio ≥ 2 indicates a gene amplification) (Fig. 4).

The patient was diagnosed with a stage IV estrogen receptor-positive (ER+), HER2+ breast cancer, and she was immediately started on anastrazole. Since she developed arthralgia with this medication, therapy was switched to letrozole. However, arthralgia persisted and, at the same time, skin lesions recurred in both lower extremities. Letrozole was discontinued and the patient was started on trastuzumab and fulvestrant, but the skin lesions continued to progress in both number and size over the next six months, during which she received chemotherapy. During this time of progression of the lesions, her CEA remained low at < 2.5 ng/ml, and her level of CA27.29 was unremarkable. A full thickness skin biopsy at her right shin showed parakeratosis and vacuolar alteration along the dermoepidermal junction, with superficial and deep perivascular and interstitial mixed infiltrate composed of lymphocytes, eosinophils and neutrophils. Both lymphocytes and neutrophils were present within the vessel walls, with signs of leukocytoclasis, suggesting a drug eruption.

The patient was started on colchicine 0.6 mg/ml bid while she remained on trastuzumab, and her skin lesions gradually improved. Glucocorticoid was not given due to concerns of negative interactions with ongoing cancer treatment. Her subsequent tumor surveillance exams were unremarkable.

Section snippets

Discussion

Cutaneous vasculitis is a small-vessel systemic vasculitis characterized by the involvement of the skin as palpable purpura. It can range in severity from benign, self-limited, short-lived cutaneous eruption to a life-threatening disease with multiple organ failure. Systemic manifestations include, most frequently, fever, arthralgias and arthritis and, less commonly, renal, neurological or gastrointestinal involvement [1], [2]. The disorder is caused by mechanisms of hypersensitivity associated

Conclusions

In our patient, it may be not possible to distinguish between a case of drug-induced cutaneous vasculitis and paraneoplastic cutaneous vasculitis, due to overlap of events and confounding factors. The two factors that might suggest a paraneoplastic etiology of the vasculitis could be the outbreak of vasculitis during the year before the diagnosis of the relapse of her stage IV breast cancer — which fits with the mean time necessary to develop the disease, and the age of the patient and onset of

Acknowledgments

Supported in part by the National Institutes of Health (NIH) grants AR53463 (to M.W.), AI 46776 (to B.H.H.), and AR53239 (to A.L.C.). The contents of this work are solely responsibility of the authors and do not necessarily represent the official views of the NIH.

References (46)

  • T. Kitahara

    Case of propylthiouracil-induced vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA); review of literature

    Clin. Nephrol.

    (1997)
  • A. Wiik

    Drug-induced vasculitis

    Curr. Opin. Rheumatol.

    (2008)
  • S. ten Holder et al.

    Cutaneous and systemic manifestations of drug-induced vasculitis

    Ann. Pharmacother.

    (2002)
  • H. Thong et al.

    Methimazole-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and lupus-like syndrome with a cutaneous feature of vesiculo-bullous systemic lupus erythematosus

    Acta. Derm. Venereol.

    (2002)
  • T. Herlin

    Anti-neutrophil cytoplasmic autoantibody (ANCA) profiles in propylthiouracil-induced lupus-like manifestations in monozygotic triplets with hyperthyroidism

    Scand. J. Rheumatol.

    (2002)
  • H. Sato

    High prevalence of antineutrophil cytoplasmic antibody positivity in childhood onset Graves' disease treated with propylthiouracil

    J. Clin. Endocrinol. Metab.

    (2000)
  • D. Slamon

    Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

    Science

    (1989)
  • T. Cooke

    HER2 as a prognostic and predictive marker for breast cancer

    Ann. Oncol.

    (2001)
  • L. Castillo

    Pharmacological background of EGFR targeting

    Ann. Oncol.

    (2004)
  • Y. Yarden

    The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities

    Eur. J. Cancer.

    (2001)
  • F. Ciardiello et al.

    EGFR antagonists in cancer treatment

    N. Engl. J. Med.

    (2008)
  • M. Pagano

    Cyclin A is required at two points in the human cell cycle

    EMBO. J.

    (1992)
  • P. Ridgway et al.

    Chromatin assembly and organization

    J. Cell. Sci.

    (2001)
  • Cited by (36)

    • Cutaneous and Gastrointestinal Leukocytoclastic Vasculitis Induced by Palbociclib in a Metastatic Breast Cancer Patient: A Case Report

      2018, Clinical Breast Cancer
      Citation Excerpt :

      Some case reports described some immunologic disorders and vasculitis during aromatase inhibitor therapy, with shorter time to disorder onset, from days to months.10,12-14 However, we report 1 case of leukocytoclastic vasculitis that might be induced by fulvestrant,3 but the relation between treatment and vasculitis remains unclear because of overlapping events and several confounding factors. In France, pharmacovigilance procedure has declared one patient who presented a vasculitis that might be induced by fulvestrant but with other potentially suspect factors: chemotherapy (fluorouracil, vinorelbine) and zoledronate.

    • Paraneoplastic cutaneous small-vessel vasculitis as a presentation of recurrent metastatic breast cancer

      2018, JAAD Case Reports
      Citation Excerpt :

      Several case reports of CSVV in breast cancer were related to chemotherapy or hormonal therapy, such as aromatase inhibitors.4-7 We found 1 case report of recurrent metastatic breast cancer presenting as paraneoplastic cutaneous vasculitis.8 However, the vasculitis was likely antineutrophil cytoplasmic antibody associated.

    View all citing articles on Scopus
    View full text