J Oral Maxillofac Surg 61:1354-1358, 2003

Mucormycosis: Necrotizing Soft Tissue Lesion of the Face

Christoph Leitner, MD, BDS,* Jurgen Hoffmann, MD, DDS, PhD, Martin Zerfowski, MD, DDS, PhD, and Siegmar Reinert, MD, DDS, PhD
Spontaneous necrotizing soft tissue lesions of the face are seen rarely in a maxillofacial surgeons daily practice. Depending on the type of tissue involved, they can be differentiated into necrotizing cellulitis, fasciitis, and myonecrosis. Necrotizing cellulitis affects the skin and is usually caused by monomicrobial infection. Group A Streptococcus, Staphylococcus, aerobic coliforms, and Clostridia are known to be the main causal agents. Necrotizing fasciitis affects primarily the subcutaneous tissues, with little initial effect on the skin but necrosis in advanced stages of the disease. It occurs as the result of polymicrobial synergistic aerobic and anerobic gas-producing infection with streptococci and, less often, the mucormycosiscausing agents Rhizopus, Mucor, or Absidia. Myonecrosis primarily affects the muscle and is caused by Clostridium perfringens, Streptococcus pyogenes, or group B Streptococcus. Clinical differentiation between these types can cause problems because they can appear to be very similar. Although necrotizing soft tissue lesions are seen in healthy individuals, they most commonly occur in patients who are immunocompromised by degenerative diseases, abnormal metabolic states, malignant diseases, major burns, immunosuppressive drugs, acquired immune deciency syndrome, or prolonged antibiotic therapy.1 Necrotizing soft tissue infections are characterized by a high mortality rate, because many of these lesions are rapidly progressive infections that cause extensive necrosis of the subcutaneous tissues followed by gangrene of the skin and systemic toxicity.1 We present the case of a rarely seen spontaneous necrotic soft tissue lesion of the face caused by the mucormycosis-causing agent Absidia corymbifera in a patient who had undergone bone graft transplantation after she was diagnosed with acute myeloid leukemia.

Report of a Case
A 26-year-old woman was referred by her general practitioner in April 2000 to the Department of Haematology and Oncology of our hospital for further investigations with a suspected malignant hematologic disease after a complete blood count had revealed anemia (hemoglobin 6.8 g/dL) and leukopenia (880/ L). Further special investigations included a bone marrow puncture, cytochemistry, immunphenotyping, cytogenetics, and molecular biology. Taking into account the result of these examinations, the diagnosis of acute myeloid leukemia was made. The patient subsequently underwent 3 cycles of chemotherapy, which resulted in complete remission of the myoblasts within the bone marrow. Because the presence of the Philadelphia gene was proved, she was seen as a high-risk patient with regard to recurrence of the disease. Therefore, it was decided to carry out further treatment, consisting of an allogenic bone marrow transplantation. In October 2000, she received a bone marrow transplant. After no immediate complications, on the eighth day after the bone marrow transplantation, the patient developed a necrotic lesion on the left side of the chin that was initially small but rapidly increased in size (Fig 1). There was no known trauma in that region previously. Clinical examination also revealed signs of cellulitis of the neck. The C-reactive protein level increased to a maximum of 32 mg/dL. An emergency computed tomography scan of the face and neck excluded bone involvement and showed that the infection was limited to the subcutaneous/epifascial soft tissue. No other lesions were found. Because the cause of the necrotic lesion was unclear, an incisional biopsy was carried out and the tissue was sent off for histopathologic examination. Parafn-embedded skin specimens of 5- m thickness were stained with hematoxylin-eosin and investigated with light microscopy. This examination revealed a widespread infection with ribbon-like aseptate hyaline hyphae that were found to be located primarily within smaller vessels, resulting in thrombosis. In addition, fungal elements were observed within extensive areas of necrosis (Fig 2). To identify the genus and species of the fungal pathogen in

Received from the Department of Oral and Maxillofacial Surgery, University Hospital of Tubingen, Tubingen, Germany. *Specialist Registrar. Consultant Oral and Maxillofacial Surgeon. Consultant Oral and Maxillofacial Surgeon. Professor, Head, and Consultant Oral and Maxillofacial Surgeon. Address correspondence and reprint requests to Dr Leitner: Specialist Registrar, Department of Oral and Maxillofacial Surgery, University Hospital of Tubingen, Osianderstr 2-8, 72076 Tubingen, Germany; e-mail: Christoph.Leitner@med.uni-tuebingen.de
2003 American Association of Oral and Maxillofacial Surgeons

0278-2391/03/6111-0020$30.00/0 doi:10.1016/S0278-2391(03)00740-7

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FIGURE 1. Initial appearance of the necrotic lesion on the left side of the chin.

FIGURE 3. Clearly circular demarcation of the lesion developed just before it was excised.

more detail, a polymerase chain reaction (PCR) analysis was performed with the parafn-embedded skin specimens. After isolation of DNA using a nonionic detergent and proteinase K, PCRs were performed as described by Walsh et al.2 A PCR product was succesfully amplied from the 18S rRNA gene common to all medically important opportunistic fungi. Further analysis of the PCR product by direct sequencing resulted in the identication of A corymbifera. Considering the diagnosis and the immunocompromised condition of the patient, further treatment consisted of sytemic application of the antifungal drug liposomal amphotericin B and excision of the entire 3.5 3 cm necrotic lesion. Interestingly, just before the excisional biopsy was carried out, the lesion had clearly demarcated from the surrounding healthy tissue (Fig 3). Two weeks later, while

the patient was still undergoing antifungal treatment, further resection at the initial site of surgery was carried out to exclude progress of the disease. Histopathologic examination revealed chronic necrotizing inammatory reaction without clear evidence for fungal spores and hyphae. Molecular pathologic examination did not show any further evidence of A corymbifera. Under the systemic antifungal treatment with liposomal amphotericin B, the clinical signs of cellulitis of the neck subsided and the wound did not reveal any further signs of inammation. Because the patient was in a poor general condition, the denitive wound closure was delayed until 2 months later, when the patient had fully recovered. The surgical wound closure was carried out under general anesthesia and consisted of a transpositional ap (Fig 4). The postoperative wound healing was uneventful. Nine months later, at review, the patient was recurrence free and very satised with the aesthetic outcome of the surgical wound closure (Fig 5).

Discussion
Necrotizing soft tissue infections can be caused by either a single or a variety of organisms. These organisms are most commonly bacteria such as group A and B streptococci, staphylococci, aerobic coliforms, and Clostridia. Less commonly, the causal agents are fungi. Although fungal infections can occur among healthy individuals, they most commonly affect immunocompromised hosts, particularly in those with hematologic diseases that cause neutropenia.3-11 Nosari et al6 found evidence of mycotic infections in 31% of cases among 153 postmortem examinations of patients who had a hematologic malignancy. The

FIGURE 2. Hematoxylin-eosinstained section from the specimen revealed a widespread infection with ribbon-like aseptate hyaline hyphae (arrow). These were located primarily within blood vessels, resulting in thrombosis and tissue necrosis.

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MUCORMYCOSIS

FIGURE 4. Surgical wound closure 2 months after removal of the necrotic lesion. The size of the defect had decreased considerably through secondary wound healing. A, Lines indicate the outline of the transpositional ap used to close the defect. B, Raising the ap. C, Result immediately after the ap had been sutured in.

most commonly found fungal species are Aspergillus, followed by Candida and, more rarely, mucormycosis is present.6,12 In a review of 1,186 patients who underwent bone marrow transplantation between 1974 and 1989 at the University of Minesota Hospital, mucormycosis accounted for only 2% of noncandidal fungal infections.13 Penalver et al14 found mucormycosis in 0.8% of 345 patients undergoing bone marrow transplantation, which is an even lower incidence rate. Mucormycosis, caused by the species of the genera Rhizopus, Mucor, or Absidia, is recognized as the most rapidly progressive and lethal form of fungal infection in humans.1 Clinical presentation includes the rhinocerebral, pulmonary, gastrointestinal, cutaneous, and disseminated types.6,15-18 There also are case reports of mucormycosis affecting the heart, kidney, or palate.9,19,20 Adam18 analyzed 116 cases that were a combination of his patients and those in other literature. The most common type he found was the rhinocerebral type (39%), followed by the pulmonary type (22%), the disseminated and cutaneous type

FIGURE 5. Appearance of the patient 9 months after surgical wound closure.

LEITNER ET AL

1357 the progress of the infection and control infection in regions where vital tissues cannot be completely resected and therefore is an essential part of the treatment of cutaneous mucormycosis. Liposomal amphotericin B is considerably less nephrotoxic but has the same therapeutic effect as conventional amphotericin B and therefore should be used whenever the renal function is impaired as it was in our patient. This case report highlights the importance of considering mucormycosis as a possible diagnosis in spontaneous necrotic soft tissue lesions of the face. Although it occurs rarely, it is characterized by a high mortality if not diagnosed and treated appropriately. Early and adequate treatment, which includes urgent local debridement of all necrotic tissue as well as simultaneous systemic application of amphotericin B, not only increases the chance of survival but also reduces the size of the defect caused by local debride ment.

(16% each), the gastrointestinal type (4%), and types at other locations (3%). Considering the overall low percentage of mucormycosis among fungal infections and the low percentage of the cutaneous type among all the different types of mucormycosis, our case report highlights the rarity of cutaneous mucormycosis of the face. The mucormycosis-causing agents Rhizopus, Mucor, and Absidia are widespread in nature. They can grow on bread, fruit, leaves, and soil and are also found in the hospital environment. In addition to systemic risk factors such as degenerative diseases, abnormal metabolic states, malignant diseases, major burns, immunosuppressive drugs, acquired immunodeciency syndrome, prolonged antibiotic therapy, and neutropenia, there also are local risk factors such as burns, the use of needles, knife wounds, insect or spider bites, and other types of trauma or skin lesions.18 Marchevsky et al21 and Gartenberg et al4 found contaminated adhesive bandages to be the main causal agent of cutaneous mucormycosis. However, if no local risk factor can be found, as in our case, it could be assumed that the pathogenic agents are passed onto the patients skin by the medical staff or directly from the air and penetrate the skins surface through an injury invisible with the naked eye. Clinically, the presentation of cutaneous mucormycosis is variable and ranges from rather indolent nonhealing ulcers to other rapidly growing necrotizing lesions. Culture and histologic examinations are imperative in providing the correct diagnosis, whereas blood cultures are always negative and therefore useless.6 Histologic examination typically reveals broad nonseptate hyphae invasion of the blood vessels and their walls, resulting in vascular thrombosis and tissue necrosis.21 Although conventional histologic examination may suggest mucormycosis, the diagnosis must always be conrmed by molecular pathologic examination or a mycologic culture. It is important to bear in mind that culture examination of surface swab specimen can be negative for mucormycosis as it tends to invade deeply into the tissues. Therefore, it is mandatory to obtain a histologic specimen as well as a culture specimen from necrotic wound surfaces. Despite early treatment, mortality remains high. Adam et al18 found a mortality rate of 16% for cutaneous mucormycosis. This contrasts to a mortality rate of 67% for rhinocerebral, 83% for pulmonary, and 100% for gastrointestinal and disseminated mucormycosis.18 To avoid the extension of the infection into vital regions where complete resection would be impossible, early radical surgical intervention in the form of local de bridement of the infected and necrotic tissue is essential. Systemic application of amphotericin B can slow

References
1. Patino JF, Castro D: Necrotizing lesions of soft tissues: A review. World J Surg 15:235, 1991 2. Walsh T, Francesconi A, Kasai M, et al: PCR and single-strand conformational polymorphism for recognition of medically important opportunistic fungi. J Clin Microbiol 33:3216, 1995 3. Adriaenssens K, Jorens PG, Meuleman L, et al: A black necrotic skin lesion in an immunocompromised patient: Diagnosis: Cutaneous mucormycosis. Arch Dermatol 136:1165, 2000 4. Gartenberg G, Bottone EJ, Keusch GT, et al: Hospital-acquired mucormycosis (Rhizopus rhizopodiformis) of skin and subcutaneous tissue: Epidemiology, mycology and treatment. N Engl J Med 299:1115, 1978 5. Maertens J, Demuynck H, Verbeken EK, et al: Mucormycosis in allogeneic bone marrow transplant recipients: Report of ve cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant 24:307, 1999 6. Nosari A, Oreste P, Montillo M, et al: Mucormycosis in hematologic malignancies: An emerging fungal infection. Haematologica 85:1068, 2000 7. Pruitt BA Jr: Biopsy diagnosis of surgical infections. N Engl J Med 310:1737, 1984 8. Carpenter CF, Subramanian AK: Images in clinical medicine: Cutaneous zygomycosis (mucormycosis). N Engl J Med 341: 1891, 1999 9. Moraru RA, Grossman ME: Palatal necrosis in an AIDS patient: A case of mucormycosis. Cutis 66:15, 2000 10. Sheldon DL, Johnson WC: Cutaneous mucormycosis: Two documented cases of suspected nosocomial cause. JAMA 241: 1032, 1979 11. Sugar AM: Mucormycosis. Clin Infect Dis 14:S126, 1992 (suppl 1) 12. Herbrecht R, Neuville S, Letscher-Bru V, et al: Fungal infections in patients with neutropenia: Challenges in prophylaxis and treatment. Drugs Aging 17:339, 2000 13. Morrison VA, McGlave PB: Mucormycosis in the BMT population. Bone Marrow Transplant 11:383, 1993 14. Penalver FJ, Romero R, Fores R, et al: Mucormycosis and hemopoietic transplants. Haematologica 83:950, 1998 15. Bigby TD, Serota ML, Tierney LM Jr, et al: Clinical spectrum of pulmonary mucormycosis. Chest 89:435, 1986 16. Thomson SR, Bade PG, Taams M, et al: Gastrointestinal mucormycosis. Br J Surg 78:952, 1991

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17. Mizutari K, Nishimoto K, Ono T: Cutaneous mucormycosis. J Dermatol 26:174, 1999 18. Adam RD, Hunter G, DiTomasso J, et al: Mucormycosis: Emerging prominence of cutaneous infections. Clin Infect Dis 19:67, 1994 19. Davila RM, Moser SA, Grosso LE: Renal mucormycosis: A case report and review of the literature. J Urol 145:1242, 1991
J Oral Maxillofac Surg 61:1358-1361, 2003

PRIMARY BILIARY CIRRHOSIS AND SJOGRENS SYNDROME

20. Virmani R, Connor DH, McAllister HA: Cardiac mucormycosis: A report of ve patients and review of 14 previously reported cases. Am J Clin Pathol 78:42, 1982 21. Marchevsky AM, Bottone EJ, Geller SA, et al: The changing spectrum of disease, etiology, and diagnosis of mucormycosis. Hum Pathol 11:457, 1980

Primary Biliary Cirrhosis and Sjogrens Syndrome: Case Report

Louis Mandel, DDS,* and Noah Dehlinger, DDS
Primary biliary cirrhosis (PBC) is a chronic progressive and frequently fatal cholestatic liver disease that seems to be autoimmune in origin. It is characterized by a destruction of the bile ducts, both the septal and smaller intralobular ducts; portal inammation with scarring; and extension of the inammatory process into the liver parenchyma, causing hepatocyte destruction and extensive brosis. Ultimately, liver cirrhosis and liver failure ensue.1-3 The large majority of patients with PBC are middleaged woman,4 of whom many have no subjective symptoms. Routine laboratory studies can raise suspicions regarding the presence of the disease. Signicant elevations in liver enzymes, particularly alkaline phosphatase, and serum bilirubin mandate further investigation. Because antimitochondrial antibodies (AMA), reacting particularly to the E2 component of the mitochondrial antigen pyruvate dehydrogenase5,6 have been identied in a titer of 1:320 or more in 90% of the PBC patients, they function as a specic diagnostic serum marker.4,7 The symptomatology of PBC patients varies. Often patients are totally asymptomatic, with suspicion of the diseases presence being aroused only as result of aberrations in the blood chemistry. Such a relatively benign state may last for many years, with a median duration of 10 to 15 years.8 However, progression in 2 to 4 years is recognized in most patients when fatigue, itching, and jaundice develop. Failure to treat symptomatic patients portends a dire outcome, with a median survival rate of 7 years.9 An enlarged liver is often found as a presenting physical nding. Osteoporosis can be present and may result from the suppression of osteoblastic activity by the high serum bilirubin levels.10 Esophageal bleeding, reecting the presence of varices secondary to portal hypertension, may also be encountered. The appearance of these signs of hepatic pathology signals a likely progression to liver cirrhosis and a diminished survival rate.8 Irreversible disease and a failing liver, best indicated by marked alteration in serum bilirubin, mandate a liver transplant.

Sjogrens Syndrome in Primary Biliary Cirrhosis

Sjogrens syndrome (SS), an autoimmune disease, exists in 2 clinical forms: primary and secondary. Primary SS involves decreased lacrimal and salivary gland secretions with no associated systemic autoimmune disease. Secondary SS is clinically diagnosed when dry eyes and dry mouth coexist with a systemic autoimmune disease. The systemic disease is usually rheumatoid arthritis, but it can be lupus erythematosus, systemic sclerosis, polymyositis, or, occasionally, PBC. The criteria for an objective diagnosis of SS have been established.11 Ocular symptoms may include an awareness of dry eyes associated with a sensation of sand or gravel in the eye. Evidence for ocular involvement can also be derived objectively from a positive Schirmer test, a tear volume study, or a rose Bengal test that reveals the corneal ulcerations that result from lacrimal dysfunction. Oral symptoms include a dry mouth, which can necessitate frequent drinking to aid in the swallowing of food. Salivary gland swell-

*Director, Salivary Gland Center; Assistant Dean, Clinical Professor (Oral and Maxillofacial Surgery), Columbia University School of Dental and Oral Surgery, New York, NY. Research Assistant, Salivary Gland Center, Columbia University School of Dental and Oral Surgery, New York, NY. Address correspondence and reprint requests to Dr Mandel: School of Dental and Oral Surgery, 630 W 168th St, New York, NY 10032; e-mail: lm7@columbia.edu.
2003 American Association of Oral and Maxillofacial Surgeons

0278-2391/03/6111-0021$30.00/0 doi:10.1016/S0278-2391(03)00741-9