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Journal of Surgical Oncology 2004;88:21–26
Invasive Cutaneous Fungal Infections Requiring RadicalResection in Cancer Patients Undergoing Chemotherapy
RAVI RADHAKRISHNAN, MD,1 MICHELE L. DONATO, MD,2 VICTOR G. PRIETO, MD, PhD,3
STEVEN R. MAYS, MD,4 ISSAM I. RAAD, MD,5 AND HENRY M. KUERER, MD, PhD1*
1Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas2Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center,
Houston, Texas3Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
4Department of Dermatology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas5Department of Infectious Diseases, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Invasive fungal infections have emerged as a significant problem in patients withcancer with the development of better systemic therapies for malignancy and moreeffective antibacterial agents. The currently available world published medical litera-ture was reviewed on invasive fungal infections in cancer patients with specificattention devoted to the multidisciplinary role of surgery in refractory cutaneous cases.Infections can develop on the forearm where peripheral intravenous catheters had beeninserted in cancer patients undergoing cytotoxic chemotherapy. Curative intent beginswith systemic contemporary anti-fungal therapy. Following resolution of neutropenia,patients may require radical surgical debridement with negative margins of resectionfor complete eradication of the fungal infection. Although invasive fungal infectionsrefractory to antifungal systemic therapy in immunocompromised patients undergoingchemotherapy are a rare event, it is critical for surgeons and other multidisciplinaryclinicians to recognize these potentially life-threatening infections that may neces-sitate radical surgical resection for cure.J. Surg. Oncol. 2004;88:21–26. � 2004 Wiley-Liss, Inc.
KEY WORDS: mucormycosis; aspergillosis; chemotherapy; surgery; fasciitis
INTRODUCTION
Primary cutaneous invasive fungal infections are rare.Most commonly, they are a result of direct trauma to theskin, such as occurs when intravenous access is esta-blished, or application of bandages to the skin [1,2]. Themajority of cases of primary invasive cutaneous fungalinfections have been reported in patients with compromis-ed immune responses due to a variety of factors, includ-ing AIDS, hematologic malignancy, diabetes mellitus,receipt of an organ transplant, or treatment with corti-costeroids, antibiotics, or other cytotoxic drugs.
Patientswith neutropenia secondary to cytotoxic chemo-therapy are particularly at risk for life-threatening in-vasive fungal infections. Mortality rates from theseinfections currently remain in the 50–90% range [3].Here we review the presentation, diagnosis, and treat-ment of these infections in patients with cancer receivingchemotherapy. Special emphasis is devoted to specific
cases in which radical surgical resection may be requiredfor eradication of disease.
RECENT M. D. ANDERSON CANCERCENTER EXPERIENCE
The impetus for complete review of this clinical entitywas the identification and multidisciplinary managementof two recent patients at M. D. Anderson Cancer Centerwith acute myelogenous leukemia who required radicalskin and subcutaneous excision following the develop-ment of persistent isolated invasive fungal infections
*Correspondence to: Dr. Henry M. Kuerer, MD, PhD, Department ofSurgical Oncology, The University of Texas M. D. Anderson CancerCenter, Box #444, 1515 Holcombe Blvd., Houston, TX 77030. Fax: (713)792-4689. E-mail: hkuerer@mdanderson.org.
Accepted 22 July 2004
DOI 10.1002/jso.20115
Published online in Wiley InterScience (www.interscience.wiley.com).
� 2004 Wiley-Liss, Inc.
unresponsive to standard medical management duringchemotherapy. These specific cases illustrate the typi-cal presentation of patients with isolated invasive fungalinfections refractory to medical management, thecourse of disease, and types of therapies that should beinstituted.Both of these patients had acute leukemia. The first
patient was a 23-year-old White man who was diagnosedwith acute myelogenous leukemia. Initial treatment ofthe disease with cytarabine and idarubicin resulted incomplete remission. The patient then received four cyclesof consolidation therapy and proceeded to high-dosechemotherapy followed by matched unrelated-donor bonemarrow transplantation. The patient’s course was compli-cated by graft-versus-host disease that necessitated high-dose steroid therapy with methylprednisolone. Thepatient developed a parainfluenza syndrome with rhinor-rhea and associated pancytopenia. The patient wasreferred for a surgical consultation because of an approxi-mately 4 cm� 4 cm painful subcutaneous nodule on theleft forearm with a small area of central necrosis thatwas increasing in size despite intravenous antifungaltherapy with itraconazole. Biopsy of the lesion revealedfilamentous nonseptate fungi throughout the specimen,consistent with mucormycosis. The patient was treatedwith radical excision of the lesion, including removal ofsurrounding skin and the underlying muscular fascia
(Fig. 1), which resulted in a 12 cm� 8 cm defect on hisleft forearm. The wound was closed by skingrafting.Intraoperative frozen section evaluation of the specimenrevealed that the margins were negative for disease. Thepatient had no further development of mucormycosis, andfurther chemotherapy was not delayed.The second recent patient was a 67-year-old White
woman who developed recurrent acute myelogenousleukemia, which was treated with induction chemother-apy with cytarabine and clofarabine. Following removalof a peripheral intravenous catheter that had been in placefor a few days, multiple small black spots were notedaround the area where the catheter had been inserted.Over the course of 7 days, these spots grew larger andcoalesced into a 3 cm� 5 cm eschar with underlyingbeefy red tissue and an erythematous border. Ten daysof therapy with vancomycin, meropenem, ciprofloxacin,itraconazole, mupirocin, caspofungin, and liposomalamphotericin B brought about little or no clinicalimprovement in the area of the eschar. At the end ofthe 10 days, biopsy of the area revealed invasive septatehyphae with acute branching consistent with aspergillosisor Fusarium. Culture of the eschar failed to grow fungus.At surgery, an approximately 5 cm� 7 cm area on thepatient’s left forearm was excised to the muscular fascia,necessitating placement of a split-thickness skin graftfor closure (Fig. 2). The adequacy of the margins was
Fig. 1. Patient with invasive mucormyocosis of the left forearm. A: Extent of resection necessary to remove infected area. B: Gross view ofcentrally necrotizing subcutaneous mucormycosis. C: High-powered microscopic view of lesion demonstrating hyphae involving a dermal vessel(hematoxylin-eosin). D: 1-year follow-up image showing healed split-thickness skin graft. [Color figure can be viewed in the online issue,available at www.interscience.wiley.com.]
22 Radhakrishnan et al.
established by intraoperative frozen section evaluation.The patient recovered without further sequelae from thisinfection and subsequently completed her chemotherapy.
CLINICAL PRESENTATION AND DIAGNOSIS
Broadly speaking, the organisms that most likely causeinvasive skin and soft tissue invasive fungal infectionsinclude Aspergillus, Fusarium, Mucor, Rhizopus, andCandida in cancer patients with neutropenia. Primary
invasive cutaneous invasive fungal infections may mani-fest as cellulites, paronychia, eschars, i.v. site infections,subcutaneous nodules, and abscesses. After examiningthe literature over the past 18 years on patients withcutaneous fungal infections and cancer, a few inferencescan be made (Table I). First, in those patients withdocumented wide surgical debridement of the fungallesion, eradication of disease can be seen. It should benoted that many of the cases of eradication of diseaseoccurred after resolution of the patient’s neutropenia.Cure rates in patients with neutropenia on medical orminimal surgical management may still remain low evenwhen radical debridement is performed.
While there are very few cases of invasive fungalcutaneous infections in cancer patients, the data suggestthat the treatment of choice may need to include widesurgical debridement of the lesion when the patient’sneutropenia has resolved, and perioperative antifungaltherapy. In this regard, it has been suggested that removalof the eschar does not promote healing in the absence ofneutropenia and may even result in a larger more difficultwound to manage [4].
In addition, it is interesting to note that many of thesecases occurred at peripheral IV sites. This data shouldprompt increased vigilance from the physicians andnursing staff to monitor peripheral IV sites in theirimmunocompromised patients and highlights the poten-tial risk of any invasive catheter. Primary cutaneousaspergillosis has also been reported to be associated withcentral venous catheters in patients with hematologicmalignancy [4].
TYPES OF INVASIVE FUNGAL LESIONS
Aspergillus is a fungus that can be isolated from vege-tation, decaying organic matter, air, and soil. The fungusis spread via aerosolization of the conidia. In hospitalsettings, Aspergillus may colonize the air vents and be-come airborne during times of construction. Commonly,the fungus causes infections of the lung, nasal sinuses,and orbital cavities. In certain situations, Aspergillusconidia may directly implant on hospital supplies orduring operative procedures and result in invasive cuta-neous aspergillosis [5]. Infection is no longer believed tobe related to occupational exposure; it is now believedto be related to compromised immune function [3,6].Antifungal chemoprophylaxis as well as high-efficiencyparticulate air (HEPA) filter systems have been shownto prevent infection by Aspergillus species in some neutro-penic cancer patients [7]. Diagnosis can be complex andis established with cultures and visualization of acuteangled branched septate hyphae on microscopy [1]. Itshould also be noted that hyphae are easily identified withstandard frozen-section analysis. This is an important
Fig. 2. Patient with invasive aspergillosis of the left forearm.A: Pre-operative view. B: Extent of resection needed for completeremoval of infected area. C: Appearance of split-thickness skin graft,approximately 5 cm� 5 cm, immediately after placement of graft.[Color figure can be viewed in the online issue, available atwww.interscience.wiley. com.]
Fungal Infections During Chemotherapy 23
TABLEI.
InvasiveCutaneousFungalInfectionsin
Patients
WithCancer
Year
Institution
Author
Age
Primarycancerdiagnosis
Organism
IVsite
Widesurgical
resection/debridem
ent
Outcome
1985
Columbia-Presbyterian
Grossman
etal.
4Acute
lymphocyticleukem
iaAspergillus
Yes
No
Early
death,other
cause
5Acute
myelogenousleukem
iaAspergillus
Yes
No
Eradicated
7Acute
lymphocyticleukem
iaAspergillus
Yes
No
Eradicated
7Acute
lymphocyticleukem
iaAspergillus
Yes
No
Eradicated
9Acute
lymphocyticleukem
iaAspergillus
Yes
No
Eradicated
13
Acute
lymphocyticleukem
iaAspergillus
Yes
No
Fungal
liver
abscess
1987
JohnsHopkins
Alloet
al.
41
Acute
myelogenousleukem
iaAspergillus
Yes
No
Eradicated
17
Lymphoblastic
lymphoma
Aspergillus
Yes
No
Eradicated
74
Acute
erythrocyticleukem
iaAspergillus
Yes
No
Unrelateddeath
33
Acute
myelogenousleukem
iaAspergillus
Yes
Yes
Eradicated
23
Acute
lymphoblastic
leukem
iaAspergillus
Yes
No
Eradicated
72
Acute
non-lymphoblastic
leukem
iaAspergillus
Yes
No
Death
pulm
onaryAspergillus
50
Acute
myelogenousleukem
iaAspergillus
Yes
Yes
Eradicated
53
Acute
myelogenousleukem
iaAspergillus
Yes
Yes
Eradicated
53
Aplastic
anem
iaAspergillus
Yes
No
Death
disseminated
Aspergillus
1989
MayoClinic
Umbertet
al.
21
Acute
myelogenousleukem
iaMucorm
ycosis
Yes
Yes
Eradicated
1993
GunmaUniversity
SOM
Shitaraet
al.
3Myelodysplastic
syndrome
Aspergillus
No
No
Death
from
intracranialbleed
withoutcure
18
Acute
myelogenousleukem
iaAspergillus
No
No
Early
death,other
cause
1996
Iowa
Trigget
al.
10
Acute
lymphocyticleukem
iaMucorm
ycosis
No
Yes
Eradicated
14
Acute
myelogenousleukem
iaMucorm
ycosis
Yes
Yes
Eradicated
1997
France
Bretagneet
al.
29
Acute
myelogenousleukem
iaAspergillus
No
No
Death
fungal
sepsis(notsurgical
candidate)
2002
National
CancerCenter,Tokyo
Nakai
etal.
19
Myelodysplastic
syndrome
Aspergillus
No
No
Death
fungal
sepsis
2002
Children’sHospital,RochesterNY
Loseeet
al.
1Acute
myelogenousleukem
iaMucorm
ycosis
Yes
Yes
Eradicated
2002
M.D.AndersonCancerCenter
Boday
etal.
57–79
Acute
lymphocyticleukem
iaFusarium
No
No
2eradicated
afterrecoveryfromneutropenia
Acute
myelogenousleukem
iaFusarium
No
No
1recurrence
aftersurgery
Acute
myelogenousleukem
iaFusarium
No
No
1death
other
cause
Acute
myelogenousleukem
iaFusarium
No
No
2persistentinfection
Lymphoma
Fusarium
No
No
Other
cancer
Fusarium
No
No
2003
M.D.AndersonCancerCenter
Mattiuzziet
al.
50
AML/m
yelodysplastic
syndrome
Aspergillus
No
No
Eradicated
afterrecoveryfrom
neutropenia
69
AML/m
yelodysplastic
syndrome
Candida
No
No
Eradicated
afterrecoveryfrom
neutropenia
2003
M.D.AndersonCancerCenter
Radhakrishnan
etal.
23
Acute
myelogenousleukem
iaMucorm
ycosis
Yes
Yes
Eradicated
67
Acute
myelogenousleukem
iaAspergillus
Yes
Yes
Eradicated
point because the diagnosis of an invasive fungal infec-tion can be achieved rapidly with punch-biopsy andfrozen section analysis. When radical surgical resection isnecessary because lesions are refractory to antifungaltherapy, it is critical that frozen sections be obtained fromboth peripheral and deep margins. In this way, additionalsurgical procedures to eradicate the fungal lesion willusually not be necessary.
Mucormycosis is the clinical name for fungal in-fections caused by Rhizopus, Rhizomucor, and Absidiaspecies. These fungi are ubiquitous and are necessary toinitiate decay of organic material. Mucormycosis hastraditionally been divided into six syndromes: rhino-cerebral, pulmonary, cutaneous, gastrointestinal, centralnervous system, and disseminated. In addition, thesesyndromes are commonly seen in particular patientpopulations—e.g., rhinocerebral in patients with dia-betes, cutaneous in patients with trauma to the skin, andgastrointestinal in patients with kwashiorkor [8].Thesusceptible patient is exposed to the sporangiospores byinhalation but also by direct contact. Diagnosis is esta-blished by culture and visualization of irregularly shapedbroad nonseptate hyphae with right angle branching.These organisms are usually found along with a neutro-philic infiltrate and within vessels [9].
Fusarium is a soil saprophyte known to produce infec-tions of the sinuses, skin, nails, lung, and blood. Typi-cally, Fusarium species enter the body through the lungs,sinuses, and skin. While onychomycosis from Fusariuminfection is documented in healthy patients, disseminatedFusarium infections are seen only in severely immu-nocompromised patients such as neutropenic patientsundergoing chemotherapy or bone marrow transplanta-tion. Onychomycosis from Fusarium infections canprogress to disseminated infection in immunocompro-mised patients, highlighting the need for vigilance by thephysician. Clinically, primary Fusarium skin infectionspresent at areas of skin breakdown, i.e. IV catheter sites,surgical wounds, or at insect bites. Typically, primaryFusarial skin infections are found in the extremities.Diagnosis is established by culture and visualization ofseptate hyphae with branching at 45 degree angles.
There are many similarities between Aspergillus andFusarium that can make diagnosis difficult. On histo-pathologic exam, Fusarium and Aspergillus are difficultto distinguish from each other. In addition, both fungi canbe cultured from the air, soil, and plants. Also, bothAspergillus and Fusarium most commonly infect thelungs and sinuses. Finally, both fungi invade bloodvessels, causing infarct or thrombosis. While there aremany similarities, there are characteristic differences thatcan aid in distinguishing the two fungi from one another.While the two fungi are similar on histopathology, onecan distinguish the two by culture. While it is uncommon
to isolate Aspergillus in blood cultures of patients withdisseminated infection, Fusarium can be isolated in 70%of patients with disseminated infection. Finally, dis-seminated Fusarium typically (75–90%) produces skinlesions while they are uncommon in disseminatedAspergillus [5,9].
Candida are normal flora of humans. The human bodyis the natural reservoir for Candida species producing thehigh rates of invasive fungal infections that we see inneutropenic cancer patients. On microscopic examina-tion, Candida species have budding yeasts, pseudohy-phae, and hyphae. Most Candida species have thepotential to be pathogenic in patients with severe neu-tropenia. However, distinction between these species isvery important because antifungal therapy differs be-tween species. While Candida albicans, the mostcommon species, is susceptible to many antifungals in-cluding the current azole antifungals, Amphotericin B,and the echinocandins; non-albicans species have shownsome resistance to the current azole medications. Typi-cally, Candida species invade the respiratory, gastro-intestinal tract, genitourinary tract, skin, and othermucous membranes secondary to breakdown of thenormal mucosal and cutaneous barriers. Disseminationoccurs most commonly in patients who are immunocom-promised. Candida species may disseminate through theblood to almost any organ including the urinary tract,peritoneum, lungs, GI tract, and eye.
Clinically, fungal soft-tissue infections resemble theirbacterial counterparts: both are associated with charac-teristic skin discoloration or necrosis, foul-smelling fluid,or subcutaneous crepitus. In addition, it may be difficultto assess the borders of the lesion, which may affecttreatment. A high index of suspicion for a fungal etiologymust be maintained when cutaneous and soft-tissue in-fections do not respond to appropriate antibiotic therapy[8,10]. A diagnosis can be established by histopathologicskin biopsy, fungal culture, and/or immediate potassiumhydroxide examination of a biopsy specimen.
ANTIMICROBIAL THERAPY
Treatment of localized invasive cutaneous fungal infec-tions involves a concerted surgical and medical approach.While immunocompetent patients may be treated withpre-operative antifungal therapy and radical surgicaldebridement alone, immunocompromised patients willrequire pre- and post-operative intravenous antimicro-bials in addition to radical surgical debridement. Theideal post-operative antifungal regimen has not beendetermined.
While most advocate amphotericin B at 1 mg/kg/dayor its lipid formulation (liposomal amphotericin B, orABLC, or amphotericin B colloidal dispersion), some
Fungal Infections During Chemotherapy 25
have also used the new triazoles, such as itraconazole orvoriconazole in patients who cannot tolerate the toxicityof amphotericin B, such as elderly patients, renal trans-plant recipients, or patients with borderline creatinineclearance [1,11,12].More recently, caspofungin (an echinocandin) has been
shown to be efficacious in the treatment of aspergillosis[13]. The echinocandins, like the newer triazoles, have anequivalent efficacy but a better safety profile whencompared to amphotericin B or its lipid formulations inthe treatment of mold infections [13–15]. However, theechinocandins (such as caspofungin and micafungin), aswell as voriconazole, have not been shown to be clini-cally active against invasive mucormycosis. Additionally,the echinocandins agents are effective only for Aspergil-lus infections and not other mold infections.A novel investigational triazole agent (posaconazole)
has been shown to be clinically active against invasivemucormycosis, as well as aspergillosis [16]. Like othertriazoles (itraconazole and voriconazole), posaconazoleis an oral antifungal agent and, in that regard, has anadvantage over amphotericin B and the echinocandins,which can only be given intravenously. Therefore, ther-apy for rare cases of invasive fungal infections that occurat the central venous catheter insertion sites may include:catheter removal, surgical debridement, and a 3–4 weekcourse of oral triazole therapy. Further clinical studies areneeded in the future to determine the optimal therapy inthis immunocompromised patient population [10].
SURGICAL MANAGEMENT OF PERSISTENTISOLATED INVASIVE FUNGAL LESIONS
As evidenced by the review of the literature, radicalsurgical debridement may be necessary for resolution ofinvasive fungal infections. In the patients treated by theauthors, a wide excision in the operating room, with in-traoperative evaluation of the surgical margins was usedwith accurate, rapid, and effective results. While surgerywith perioperative antifungal therapy is the treatment ofchoice, the underlying disease process does not alwaysallow the patient to withstand the surgery. In suchpatients, antifungal therapy must be instituted with ag-gressive measures to control or correct the patient’s neu-tropenia and overall condition so that they may be able toundergo surgery to treat their fungal infection.
SUMMARYAND CONCLUSIONS
Our experience indicates that favorable results can beachieved in patients who develop invasive cutaneous
fungal infections while they are immunocompromisedduring chemotherapy. Resolution of neutropenia is asso-ciated with a higher chance of successful complete eradi-cation of invasive fungal lesions. However, to obtainfavorable results, refractory infection must be diagnosedearly to enable the most minimal radical surgical debri-dement to eradicate these life-threatening infections.
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