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.

REFERENCES

1. Chakrabarti A, Gupta V, Biswas G, et al.: Primary cutaneousaspergillosis: Our experience in 10 years. J Infect 1998;37:24– 27.

2. Sugar AM. Mucormycosis. Clin Infect Dis 1992;14(Suppl 1):S126–S129.

3. Bow EJ, Laverdiere M, Lussier N, et al.: Antifungal prophylaxisfor severely neutropenic chemotherapy recipients: Meta-analysisof randomized-controlled clinical trials. Cancer 2002;94:3230–3246.

4. Allo MD, Miller J, Townsend T, et al.: Primary cutaneousaspergillosis associated with Hickman intravenous catheters. NEng J Med 1987;317:1105–1108.

5. Francis P, Walsh TJ. Approaches to management of fungalinfections in cancer patients. Oncology 1992;5 133–148.

6. Dunn DL. Diagnosis and treatment of opportunistic infections inimmunocompromised surgical patients. Am Surg 2000;66:117–125.

7. Lortholary O, Dupont B. Antifungal prophylaxis during neutro-penia and immunodeficiency. Clin Microbiol Rev 1997;10:477–504.

8. Johnson MA, Lyle G, Hanly M, et al.: Aspergillus: A rare primaryorganism in soft-tissue infections. Am Surg 1998;64:122–126.

9. Bodey GP, Boktour M, Mays S, et al.: Skin lesions associatedwith fusarium infection. J Am Acad Dermatol 2002;5:659–666.

10. Henriquez M, Levy R, Raja RM, et al.: Mucormycosis in a renaltransplant recipient with successful outcome. JAMA 1979;242:1397–1399.

11. Hoffman HL, Rathbun RC. Review of the safety and efficacy ofvoriconazole. Expert Opin Investig Drugs 2002;11:409–429.

12. Denning DW, Ribaud P, Milpied N, et al.: Efficacy and safety ofvoriconazole in the treatment of acute invasive aspergillosis. ClinInfect Dis 2002;34:563–571.

13. Maertens J, Raad I, Petrikkos G, et al.: Update of multicenternoncomparative study of caspofungin (CAS) in adults withInvasive aspergillosis (IA) refractory1 or intolerant (I) to otherantifungal agents: Analysis of 90 patients. In: Proceedings ofthe 42nd Annual Meeting of the Interscience Conference onAntimicrobial Agents and Chemotherapy (abstract #M-868),September 27–30. San Diego, California: ICAAC, 2002.

14. Walsh TJ, Pappas P, Winstonn DJ, et al.: Voriconazole comparedwith liposomal amphotericin B for empirical antifungal therapy inpatients with neutropenia and persistent fever. N Engl J Med2002;346:225–234.

15. Herbrecht R, Denning DW, Patterson TF, et al.: Voriconazoleversus amphotericin B for primary therapy of invasive aspergil-losis. N Engl J Med 2002;347:408–415.

16. Hachem RY, Raad II, Afif C, et al.: An open, non-comparativemulticenter to evaluate efficacy and safety of posaconazole (SCH56592) in the treatment of invasive fungal infections (IFI)refractory1 to or intolerant (I) to standard therapy (ST). In:Proceedings of the 40th Interscience Conference on Antimicro-bial Agents and Chemotherapy (ICAAC), Abstract #1109September 17–20. Toronto, Ontario, Canada: ICAAC, 2000.372p.

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