Summary
Symptomatic cutaneous metastases are associated with the symptoms of discharge, malodor, and pain, all of which may negatively impact quality of life and cutaneous health. We conducted a retrospective chart review of patients referred to the Dermatology Service at Memorial Sloan Kettering Cancer Center between August 2006 and June 2015. We characterized the microbial flora and antimicrobial management of cutaneous metastases in 64 patients. We detected pathogenic and/or opportunistic bacteria in 50% of skin lesions. The most commonly isolated organisms were Staphylococcus aureus and Pseudomonas aeruginosa. Patients treated with oral antibiotics, alone or in combination with topical agents, had a statistically significant better improvement in infectious symptoms than those treated without oral antibiotics. Our findings suggest that the normal skin microbial flora is disrupted in patients with symptomatic skin metastases. Oral antibiotics may provide benefit when used as first-line therapy of infected skin lesions in patients with symptomatic cutaneous metastases.
Keywords: Microbial flora, microbiome, cutaneous metastasis, skin metastasis, fungating wound, breast cancer
Introduction
Cutaneous metastases (CM) are neoplastic lesions that arise from an internal malignancy or in-transit metastases from high-risk skin cancer1. In most patients, CM represents widely disseminated disease due to distant spread of the primary cancer1. Symptomatic CM can be associated with pain, malodor, ulceration, erosion, bleeding, and fungating wounds2. Recent reviews of the literature suggest that there is very little evidence to guide the therapeutic management of symptomatic wounds, indicating that only metronidazole, topically was able to reduce foul odor3,4.
In this study, we sought to characterize the microbial flora in skin lesions in patients with symptomatic cutaneous metastases. We observed that 50% of symptomatic lesions in CM harbor pathogenic and/or opportunistic bacteria. In addition, we found that the use of oral antibiotics led to better improvement in infection symptoms of skin wounds in patients with CM.
Report and discussion
We conducted an Institutional Review Board-approved retrospective chart review study of electronic medical records (EMR) of patients seen in the outpatient practice of the Dermatology Service at Memorial Sloan Kettering Cancer Center. We identified relevant EMRs containing the appropriate ICD-9 code and/or the search terms “cutaneous metastasis” and/or “cutaneous metastases.” Data were collected for patients seen between August of 2006 and June of 2015. We limited our analysis to patients in which 1) the diagnosis of cutaneous metastasis(es) was made by a provider in the Dermatology Service and, 2) a bacterial and/or fungal culture was obtained from one affected symptomatic skin lesion. A review of each Dermatology note was performed by the primary author. Descriptive statistical analysis and Pearson’s chi-square tests were performed using Microsoft Excel. P-value less than 0.05 was considered statistically significant. Bacterial and fungal swab cultures were analyzed as previously described5.
In all, 64 patients met our inclusion criteria. The demographic and clinical features of our study sample are described in Table 1. Tissue biopsy of an affected skin lesion was obtained in 45 (70.3%) patients. Histopathology results revealed that all 45 (100.0%) of these patients had neoplastic cutaneous lesions consistent with metastatic spread from the patient’s known primary malignancy. Representative images of CM arising from breast cancer (Fig. 1a) and melanoma (Fig. 1b) primary neoplasms from patients in this study are shown.
Table 1.
Demographic and clinical characteristics of the study sample.
| Feature | No. | (%) |
|---|---|---|
| Total | 64 | (100.0) |
| Gender | ||
| Male | 16 | (25.0) |
| Female | 48 | (75.0) |
| Mean age | 60.3 | |
| Cancer type or site | ||
| Breast | 36 | (56.3) |
| Skin | 12 | (18.8) |
| Gastrointestinal | 7 | (10.9) |
| Gynecologic | 2 | (3.1) |
| Lung | 2 | (3.1) |
| Other or unknown | 5 | (7.8) |
| Location of cutaneous metastases | ||
| Head/Neck | 9 | (14.1) |
| Trunk | 48 | (75.0) |
| Upper extremities | 1 | (1.6) |
| Lower extremities | 6 | (9.4) |
Figure 1.
Cutaneous metastases. Clinical presentation of cutaneous metastases wounds originating from breast cancer (a) and melanoma (b).
The culture swabs led to the identification of 17 distinct bacterial and fungal species (Fig. 2). Polymicrobial communities, after accounting for skin flora, were identified from 14 (21.9%) culture swabs. Pathogenic and/or opportunistic bacteria were isolated in 32 (50.0%) patients. Gram-positive bacteria included Enterococcus faecalis, beta-hemolytic group B streptococcus (Streptococcus agalactiae), group G streptococcus (Streptococcus dysgalactiae), Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus (MSSA), and methicillin-resistant Staphylococcus aureus (MRSA) (Fig. 2a). Gram-negative bacteria included Citrobacter freundii, Citrobacter koseri, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Morganella morganii, Neisseria sp., Proteus mirabilis, Proteus vulgaris, and Pseudomonas aeruginosa (Fig. 2b). Fungus included Aspergillus flavus and other unspeciated yeast.
Figure 2.
Gram-positive bacteria (a) and Gram-negative bacteria (b) isolated from affected tissue in patients with cutaneous metastases.
The most commonly prescribed topical antibiotics and antiseptics were mupirocin (42.2%), metronidazole (32.8%), bacitracin-polymyxin b (7.8%), silver sulfadiazine (7.8%), and hydrogen peroxide (4.7%). The most frequently prescribed oral antibiotics were cephalexin (9.4%) and ciprofloxacin (4.7%). Other common therapeutic modalities included topical steroids (4.7%), imiquimod (4.7%), and lidocaine (4.7%).
Thirty-four (53.1%) patients returned for follow-up in the outpatient clinic. Of these 34 patients, 19 (55.9%) reported improvement in symptoms. Of the 26 patients that did not use oral antibiotics (+/− topical antibiotics) and returned to clinic for follow-up, 12 (46.2%) reported improvement with symptoms. Of the 8 patients that were treated with oral antibiotics (+/− topical antibiotics), 7 (87.5%) reported improvement with symptoms in their skin lesions. This difference was statistically significant (Pearson’s chi-square statistic = 4.24, p-value = 0.04).
Pain, discharge, malodor, and psychosocial distress greatly impair quality of life in patients affected by symptomatic CM6,7. Modest evidence is available to guide the clinical management of these wounds3,4. Fungating wounds impair tissue oxygenation, lymphatic drainage, and skin homeostasis8,9. It has been hypothesized that this reduced tissue perfusion creates a rich environment where infectious microorganisms feed on necrotic tissue, produce malodor, and release exudate, which are the some of the main factors affecting patients with symptomatic CM8,9.
A recent study of exudates in breast cancer patients with malignant fungating wounds identified 12/20 (60%) patients with positive bacterial cultures from affected lesions10. In this particular study of the breast cancer patient population, S. aureus was isolated in 25.0% of cases, P. aeruginosa also in 25.0% of patients, and E. faecalis in 20.0% of cases10. Our findings confirmed these observations with similar values for percentage of opportunistic/pathogenic organisms present in symptomatic wounds and the identity of the most common offending infectious agents. Furthermore, our study provides a broader picture of the microbial flora present in malignant wounds originating from breast cancer and other underlying malignancies
The present study is the first to explore the microbial flora of cancer patients with CM originating from a wide range of distinct primary neoplasms. Indeed, 43.8% of patients in our cohort had primary malignancies other than breast cancer. This was possible due to the availability of EMRs from cancer patients and survivors seen at our Oncodermatology Clinic in a large cancer treatment center. The study was further strengthened by the fact that care for CM at this clinic includes routinely obtaining bacterial/fungal cultures and tissue biopsies from skin wounds. Limitations of our study include the retrospective design, inclusion of patients seen exclusively in the outpatient dermatology setting and from which a culture swab was obtained.
Future directions should include prospective multicenter studies to improve our understanding of the clinical characteristics, treatment modalities, and outcomes of cancer patients affected by CM. In addition, with new technologies becoming available in clinical microbiology, future research could potentially better define, quantitatively and qualitatively, the microbiota of cutaneous metastases.
Learning points.
Cutaneous metastases are associated with discharge, malodor, and pain, all of which negatively impact quality of life.
Pathogenic and/or opportunistic bacteria are frequently present in symptomatic cutaneous metastases.
The most commonly isolated organisms in symptomatic cutaneous metastases are Staphylococcus aureus and Pseudomonas aeruginosa.
Oral antibiotics may provide benefit when used as first-line therapy of infected skin lesions in patients with symptomatic cutaneous metastases.
Acknowledgements
We would like to thank the MSKCC Information Systems’ data delivery group (DataLine), especially Joseph Schmeltz and Stuart Gardos for assistance with data acquisition. Also, we thank Viswanath Reddy Belum, Kathryn Ciccolini, and Daphne Leon for help utilizing the MSKCC ePathbook database.
This study was partially funded by the National Institutes of Health Cancer Center Support Grant [P30-CA008748]. C.A.V. was supported by the American Academy of Dermatology Diversity Mentorship Program and the National Institutes of Health [T32-GM007198]. M.E.L. was supported by the RJR Oncodermatology Fund at Memorial Sloan Kettering Cancer Center.
Conflict of interest disclosures
C.A.V. declares that he has no conflict of interest. C.A.B. has a consultant/speaking role with Driver Group, Elekta, Patient Resource, RP Pharmaceuticals, Omniprex Group International, Regeneron, Pfizer, Novartis, AlphaTau Medical. C.A.B. receives/received funding from Australia and New Zealand Melanoma Trials Group, Merck, Amgen, University of California San Francisco, Elekta, Menssana, Esaote North America Inc., MesoScale Diagnostics, American Society of Radiation Oncology. C.A.B. is a committee member of the MSKCC Data Governance Council, American Society for Radiation Oncology (ASTRO) Radiation Therapy for Basal and Squamous Cell Cancer of Skin Guideline, National Comprehensive Cancer Network (NCN) Cutaneous Melanoma, NCCN Uveal Melanoma Subcommittee. M.E.L. has a consultant/speaking role with Legacy Healthcare Services, Adgero Bio Pharmaceuticals, Amryt Pharmaceuticals, Celldex Therapeutics, Debiopharm, Galderma Research and Development, Johnson and Johnson, Novocure Inc, Lindi, Merck Sharp and Dohme Corporation, Helsinn Healthcare SA, Janssen Research & Development LLC, Menlo Therapeutics, Novartis Pharmaceuticals Corporation, F. Hoffmann-La Roche AG, AbbVie Inc, Boehringer Ingelheim Pharma Gmbh & Co. KG, Allergan Inc, Amgen Inc, E.R. Squibb & Sons LLC, EMD Serono Inc, Astrazeneca Pharmaceuticals LP, Genentech Inc, Leo Pharma Inc, Seattle Genetics, Bayer, Manner SAS, Lutris, Pierre Fabre, Paxman Coolers, Adjucare, Dignitana, Biotechspert, Teva Mexico, Parexel, OnQuality Pharmaceuticals Ltd, Novartis, Our Brain Bank, and Takeda Millenium. M.E.L receives research funding from Berg, Bristol-Myers Squibb, Lutris, Paxman, Novocure, US Biotest, and Veloce, and is funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. M.E.L is a committee member of the Multinational Association of Supportive Care in Cancer (MASCC) News Planning Team, Palliative Care in Oncology Symposium, and Main Representative.
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