Gemcitabine-Related “Pseudocellulitis”: Report of 2 Cases and Review of the Literature
- 1Division of Infectious Diseases, University Health Network, Toronto
- 2Department of Medicine, University of Toronto, Toronto
- Reprints or correspondence: Dr. Darrell H. S. Tan, Div. of Infectious Diseases, University Health Network, EN13-213, 200 Elizabeth St., Toronto, ON, M5G 2C4 (darrell.tan{at}gmail.com).
Abstract
Gemcitabine is a chemotherapeutic agent whose cutaneous toxicities are easily mistaken for infections. We describe 2 patients, 1 with gemcitabine-induced radiation recall dermatitis and 1 with gemcitabine-related erysipeloid reaction, who received misdiagnoses of infectious cellulitis and were given empirical antibiotics. Recognition of these syndromes is important to avoid unnecessary antibiotic use.
Case report 1. A 53-year-old woman was referred to the Infectious Diseases Clinic at the University Health Network (University of Toronto; Toronto, Ontario, Canada) for a 4-month history of recurrent cellulitis over the anterior chest wall. Her past medical history was notable for stage III, grade 1 micropapillary ovarian cancer, which had been diagnosed 11 years earlier and was initially managed with surgery and adjuvant cyclophosphamide-carboplatinum chemotherapy. After 10 years of disease remission, the patient experienced a relapse of disease in the pelvis, and painful metastases developed on her anterior chest wall and in her supraclavicular lymph nodes. Eight cycles of carboplatinum were given with moderate clinical effect. A 10-day course of local radiation therapy was administered to the upper thorax 10 months prior to presentation. Four months prior to presentation, chemotherapy was reinitiated with gemcitabine because of progression of the disease.
The morning after her initial cycle of gemcitabine, the patient awoke with low grade fever and severe erythema, pain, and swelling over the anterior chest wall. Cephalexin was prescribed for presumed cellulitis, but her symptoms worsened, prompting presentation to the emergency department. Physical examination revealed marked erythema and swelling over the anterior chest wall. The WBC count was 4.8 × 109 cells/L, the polymorphonuclear cell count was 4.0 × 109 cells/L, routine cultures of blood and urine samples revealed no growth, and chest radiograph findings were normal. Intravenous vancomycin and ceftriaxone were administered for 7 days, followed by 14 days of oral cephalexin, for a diagnosis of presumptive bacterial cellulitis, and the patient's symptoms gradually resolved. She subsequently received 5 additional cycles of gemcitabine, each of which was associated with the development of similar signs and symptoms. Each episode was treated with empirical oral antibiotics. On 2 of these occasions, the patient also received intravenous antibiotic therapy. Blood cultures performed during each episode repeatedly showed no growth. Signs and symptoms resolved within ∼1 week after the onset of each episode.
Further questioning revealed that the erythema always occurred in the same rectangular distribution, consistent with the area of prior radiation therapy. On the basis of this information, a diagnosis of gemcitabine-associated radiation recall dermatitis was considered. For the patient's subsequent cycle of chemotherapy, gemcitabine was administered at one-half of her usual dose, and a 3-day course of prophylactic oral dexamethasone and dimenhydrinate was prescribed. The patient developed only minimal erythema and swelling and did not require antimicrobial therapy.
Case report 2. A 57-year-old man presented with a 2-day history of a painful rash involving his abdomen and groin, without associated fever, chills, or antecedent trauma. His past medical history was significant for a left-sided malignant pleural mesothelioma, treated with pneumonectomy, radiation therapy, and chemotherapy, initially with cisplatin-based regimens. Recently, his chemotherapy had been changed to gemcitabine because of metastatic recurrence in the form of malignant ascites. His first dose of gemcitabine was administered 4 days prior to presentation with his rash. Physical examination revealed a tender, erythematous, blanchable rash involving the abdomen, genitalia, and medial thighs but sparing his waistline (figure 1). The patient's WBC count was 4.9 × 109 cells/L, his polymorphonuclear cell count was 4.5 × 109 cells/L, his platelet count was 188 × 109 platelets/mL, and blood culture results were negative. Cefazolin therapy was initiated for treatment of presumptive bacterial cellulitis. However, because of the atypical features of the case, including the absence of fever and the unusual location and noncontiguous nature of the rash, a noninfectious etiology was considered, and antimicrobial therapy was discontinued the following day. The rash resolved completely over the next 2 weeks.
Figure 1
Noncontiguous erysipeloid reaction over the abdomen
Discussion. Chemotherapeutic agents have been associated with a variety of cutaneous reactions, including radiation recall dermatitis, erysipeloid reactions, hypersensitivity reactions, and hyperpigmentation. Distinguishing the many noninfectious causes of skin inflammation from infectious cellulitis is challenging, because their clinical features may overlap, and because a specific pathogen is not isolated in most cases of uncomplicated skin and soft-tissue infection [1]. However, accurate diagnosis of such conditions is important to avoid unnecessary exposure to antibiotics, thereby decreasing the risk of antibiotic-associated adverse effects and hastening the implementation of appropriate therapy.
In this article, we describe 2 patients who developed noninfectious cellulitis ("pseudocellulitis") complicating cancer chemotherapy with gemcitabine and who were treated with antimicrobial therapy for presumed bacterial cellulitis. Gemcitabine (2′,2′-difluorodeoxycytidine) is a nucleoside analogue prodrug currently used in the treatment of a number of solid malignancies, including carcinoma of the lung (non—small cell carcinoma), breast, pancreas, ovary, gall bladder, and bladder, as well as malignant mesothelioma, sarcomas, and some hematologic malignancies. As the therapeutic use of gemcitabine expands to include treatment of a wider range of cancers, awareness of its potential cutaneous toxicities by infectious diseases clinicians is increasingly important.
Radiation recall reactions are typically characterized by an inflammatory reaction in an area previously treated with radiotherapy that develops hours to days after the first exposure to a precipitating agent. The skin is most frequently involved, and of the 24 cases of gemcitabine-induced radiation recall reaction that have previously been reported in the English-language literature, 13 involved patients who presented with a dermatitis, including 2 cases that occurred in the context of clinical trials (table 1) [2,3,4,5,6,7,8,9,10–11]. Two of these patients were reported to have initially received empirical antibiotic therapy. Affected skin may display maculopapular, vesicular, desquamative, or ulcerative features that range in severity from a mild rash to severe skin necrosis, sometimes in a radiation dose—dependent fashion. However, internal organ involvement, occurring either with or without dermatitis, has increasingly been recognized as a manifestation of radiation recall, including myositis, lymphangitis, gastritis, colitis, typhlitis, pneumonitis, optic neuritis, brainstem radionecrosis, and pericardial effusions [5, 9, 14,15,16,17,18–19]. Fever is an uncommon feature and was present in only 3 of the cases included in this review. Its presence may increase the clinical suspicion of an infectious cause, although patients with cancer may have other important causes of fever, such as medications and underlying malignancy.
Table 1
Cases of radiation recall and erysipeloid reactions associated with receipt of gemcitabine therapy.
Although the elapsed time between the initial administration of radiation therapy and the development of the recall reaction can range from 8 days to 15 years, most cases occur when the inciting agent is administered within several months after the radiation therapy, with a median interval of ∼40 days [20]. First described in 1959 after the administration of actinomycin-D [21], radiation recall has now been recognized in cases associated with a wide range of chemotherapeutic agents and other drugs (table 2) [20, 22].
Table 2
Drugs implicated in radiation recall reactions.
Corticosteroid therapy is considered to be the mainstay for management of radiation recall on the basis of anecdotal evidence [2, 4, 8, 9, 11, 14, 15, 17,18,19–20]. One case of gemcitabine-related dermatitis developed despite coadministration with dexamethasone [10]. Other authors have described clinical improvement with diphenhydramine [4, 20] or nonsteroidal antiinflammatory agents [8, 9, 19], as well, although the benefit of all of these therapies remains unproven.
Gemcitabine has also been reported to cause erysipeloid reactions, often in areas of preexisting lymphedema, generally in patients who have not previously received radiation therapy (table 1) [12, 13]. These patients have generally presented without fever or systemic symptoms of infection. Lesions usually arise within 24–48 h of exposure to gemcitabine and fade without specific therapy over 5–14 days, as in our second case. Skin findings are reportedly difficult to distinguish from those of infectious erysipelas, and 1 patient identified in this review received empirical antibiotics. Further adding to the difficulty of distinguishing gemcitabine-associated erysipeloid reactions from infectious erysipelas is the known association of streptococcal skin disease with impaired lymphatic drainage.
The pathophysiology of gemcitabine-induced radiation recall and erysipeloid reactions remains unclear. Some authors propose that the highly idiosyncratic nature of radiation recall supports a non—immune-mediated hypersensitivity mechanism in previously sensitized irradiated tissue [20]. A cytotoxic etiology has also been hypothesized, because the majority of causative agents are cytotoxic drugs [23]. Hypotheses relating to vascular damage and epithelial stem cell inadequacy have also been suggested (reviewed in Camidge and Price [20]). Erysipeloid reactions may occur preferentially in areas of lymphedema because of drug permeation into interstitial fluid, local drug accumulation caused by impaired lymphatic drainage, and inadequate drug inactivation in subcutaneous tissue [12]. However, not all patients with this syndrome have preexisting lymphedema.
In summary, we have described 2 patients who presented with gemcitabine-induced cutaneous toxicities that mimic 2 different infectious disease syndromes: cellulitis and erysipelas. Prior to recognition of these entities, both patients were treated empirically with antimicrobial therapy for a presumed infectious etiology. Radiation recall dermatitis and erysipeloid reactions caused by gemcitabine may masquerade as and be indistinguishable from cases of infectious cellulitis and should be considered in the differential diagnosis of acute inflammatory conditions of the skin in patients who have been administered this drug. Recognition of this entity may prevent the unnecessary administration of antimicrobial therapy.
Acknowledgments
Potential conflicts of interest. All authors: no conflicts.
- Received February 1, 2007.
- Accepted April 25, 2007.
- © 2007 Infectious Diseases Society of America
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