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Severe osteomyelitis of the jaw in long-term survivors of multiple myeloma: A new clinical entity
CORRESPONDENCE SEVERE OSTEOMYELITIS OF THE JAW IN LONGTERM SURVIVORS OF MULTIPLE MYELOMA: A NEW CLINICAL ENTITY To the Editor: Multiple myeloma is a common lymphoproliferative disorder of the plasma cell, with a median survival of 30 months when untreated (1). Therapy includes chemotherapy, antiangiogenesis and immunomodulating agents, and bone marrow transplantation. Monthly biphosphonate therapy improves survival and quality of life (2). Severe and life-threatening infectious complications remain a major threat to patients with multiple myeloma (3). We report 3 patients with multiple myeloma who developed osteomyelitis of the jaw during chronic biphosphonate therapy for bone disease prevention. The first patient, a 65-year-old man, was referred because of trismus and pain in the left mandibular area for the past week. Eleven years prior to admission, he was diagnosed with smoldering multiple myeloma. He had been treated with monthly intravenous injections of 90 mg pamidronate for 3 and a half years (total dose, 3420 mg), with 4 mg zoledronate for the last 18 months (total dose, 72 mg), and with pulse therapy with melphalan and prednisone. Intraoral examination revealed an exposed necrotic bone at the left retromolar mandibular area with a secretion of pus from the gingiva. Intravenous clindamycin was given and local decortication and débridement were performed. Histopathologic examination revealed inflammatory exudates containing fragments of necrotic bone. No improvement was noted and the exposed necrotic bone grew larger. Hyperbaric treatment was then initiated, with rapid clinical improvement: the size of the lesion decreased, and healthy granulation tissue grew over the bone. Four months later, the patient is 440
© 2004 by Elsevier Inc. All rights reserved.
asymptomatic with no local sign of infection. The second patient, a 58-year-old woman, was referred in 1996 because of pain in the right side of her face. She had been diagnosed with multiple myeloma in 1991 and was being treated with monthly intravenous pamidronate infusions and pulse therapy with melphalan and prednisone. Intraoral examination revealed two ulcers provoked by the patient’s dentures. The denture’s flanges were shortened and there was clinical improvement. In October 2000, while on pamidronate therapy (total dose, 4320 mg), she complained of pain in her lower jaw that radiated to the upper jaw. A sinus tract that secreted pus extended from the mandibular bone to the gingiva. An incisional biopsy of the infected bone was performed. The histopathologic examination showed abundant purulent material, necrotic bone, and numerous Actinomyces colonies. Local alveoloplasty was performed, followed by antibiotherapy. In September 2001, we performed sequestrectomy and alveoloplasty for similar complaints and clinical findings in this patient. Histopathologic examination revealed necrotizing acute osteomyelitis with extensive Actinomyces infestation (Figure). The infection resolved completely after prolonged penicillin therapy, with no recurrence after a 24-month follow-up. The third patient, a 76-year-old man, was admitted in January 2003 because of fever, swelling, and severe pain in the right mandible a few days after tooth extraction. Six years previously, he had been diagnosed with multiple myeloma with severe diffuse bone lesions and massive proteinuria and was treated with monthly pulses of oral melphalan and prednisone. In April 1998, monthly infusions of 90 mg of intravenous pamidronate were initiated and given until August 2002 (total dose, 4680 mg), when it was replaced by monthly infusions of 4 mg of zoledronate (total dose, 16 mg).
Examination revealed trismus and right submandibular lymphadenopathy. Intraorally, the alveolar bone at the extraction site was exposed, and a purulent discharge was observed in the mucosa. A biopsy of the area showed a hyperplastic squamous epithelium with severe inflammation, evidence for acute osteomyelitis, and the presence of colonies of Actinomyces. Antibiotherapy with massive doses of penicillin G was initiated. Clinical response was good, with progressive healing of the infection. One year after diagnosis and treatment of osteomyelitis, there was no local sign recurrent infection. Although the biphosphonates used to treat osteoporosis (etidronate, residronate) have not been associated with bone necrosis, recent reports have alerted physicians to a “growing epidemic” of pamidronate- and zoledronate-induced avascular necrosis of the jaw. Marx (4) reported 36 such patients, 24 of whom had been treated with monthly pamidronate, 6 with zoledronate, and 6 with both drugs successively. In 78% of patients, avascular necrosis was provoked by tooth extraction. Migliorati (5) described 5 patients with intraoral cavity, avascular bone necrosis while being treated with either zolendronate or pamidronate. In 2 patients, bone necrosis was preceded by tooth extraction. Both pamidronate and zoledronate have very strong antiosteoclastic activity with prolonged action (6). Moreover, zoledronate is an antiangiogenic agent, which may contribute to the development of bone necrosis. Since the jaws are the only bones of the skeleton exposed to the external environment, with frequent traumatisms, local inflammations, and abcesses, the association of bone necrosis with secondary chronic infections may lead to osteomyelitis, especially among patients suffering from severe and prolonged immunosuppression, such as in our 3 patients. 0002-9343/04/$–see front matter
Letters to the Editor
PRESSURE-INDUCED BULLAE AND SWEAT GLAND NECROSIS FOLLOWING CHEMOTHERAPY INDUCTION
Figure. Patient 2: fragment of necrotic bone surrounded by actinomyces colonies (magnification ⫻400).
The local presence of Actinomyces was demonstrated in 2 patients. Actinomyces is an indolent infection that colonizes the mouth and, following disruption of the mucosal barrier, may lead to hematogeneous spread with possible general dissemination. Clinically, infections with Actinomyces occur most frequently in the oral, cervical or facial areas, with a special predilection for the angle of the jaw (7). Osteomyelitis of the jaw in longterm survivors of multiple myeloma who are on chronic biphosphonate therapy may be a new clinical entity. Although it is not possible to prove beyond doubt an etiological link between biphosphonate therapy and the occurrence of osteomyelitis of the jaw, the association of multiple myeloma with severe immunosupression, the prolonged biphosphonate therapy, and the localization to the jaw all are in favor of a relation. With the expected life prolongation of multiple myeloma patients due to recent therapeutic breakthroughs and the rising use of antiangiogenic agents, it is crucial to be aware of the possibility of a substantial rise in the number of cases of osteomyelitis of the jaws in this category of patients. Tooth extraction should be performed in specialized centers with emphasis on infection preven-
tion. Our limited, but positive, experience with hyperbaric oxygen in 1 patient should convince physicians to try this therapeutic method after everything else has failed. Gilles Lugassy, MD Rachel Shaham, DMD Anatoly Nemets, MD David Ben-Dor, MD Oded Nahlieli, DMD Barzilai Medical Center, Ashkelon Ben Gurion University of the Negev Beer Sheva, Israel 1. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21–33. 2. Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood. 2004;103:20 –32. 3. Lugassy G, Platok I, Schlesinger M. Hypocomplementemia in multiple myeloma. Leuk Lymphoma. 1999;33:365–370. 4. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J OralMaxillar Surg. 2003;61:1115–1118. 5. Migliorati CA. Biphosphonates and oral cavity avascular bone necrosis. J Clin Oncol. 2003;21:4253– 4254. 6. Fournier P, Boissier S, Filleur S. Biphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res. 2002;15:6538 – 6544. 7. Russo TA. Actinomycosis. In: Principles and Practice of Infectious Diseases. 5th ed. GL Mandell et al (eds). New York, New York; Churchill Livingstone: 1999. September 15, 2004
To the Editor: Pressure-induced bullae and sweat gland necrosis is a rare entity described with a variety of conditions involving impaired consciousness. We present a patient who developed this entity following chemotherapy. A 43-year-old man with acute myelogenous leukemia was admitted for chemotherapy induction. He was afebrile, neutropenic (absolute neutrophil count, ⬍200/mm3) and thrombocytopenic (platelet count, ⬍12,000/mm3). Four days after receiving idarubicin and cytosine arabinoside, he became hyperthermic (39.7°C). Empiric antibiotic coverage including vancomycin and cefipime was initiated. He remained febrile and on day 10 developed an erythematous macular eruption on his trunk and extremities believed to be from antimicrobic therapy. This eruption resolved with discontinuation of the medication. The patient was transferred to the intensive care unit on day 18 with respiratory distress and hypoxemia. He was diagnosed with septic shock and subsequently developed respiratory failure requiring mechanical ventilation. He was treated with vasopressors for blood pressure support and continuous hemodialysis for renal failure. Antibiotic coverage at that time included vancomycin, imipenem/cilastin, ciprofloxacin, and liposomal amphotericin B. Several days following intubation, the patient remained febrile and developed multiple dusky, erythematous, annular macules and patches on the dorsal aspect of his hands, accompanied by centrally seated, flaccid, tan-to-yellow bullae on the dorsum of his right hand (Figure 1). Erythematous blanching macules and patches
THE AMERICAN JOURNAL OF MEDICINE威
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© 2004 by Elsevier Inc. All rights reserved.
asymptomatic with no local sign of infection. The second patient, a 58-year-old woman, was referred in 1996 because of pain in the right side of her face. She had been diagnosed with multiple myeloma in 1991 and was being treated with monthly intravenous pamidronate infusions and pulse therapy with melphalan and prednisone. Intraoral examination revealed two ulcers provoked by the patient’s dentures. The denture’s flanges were shortened and there was clinical improvement. In October 2000, while on pamidronate therapy (total dose, 4320 mg), she complained of pain in her lower jaw that radiated to the upper jaw. A sinus tract that secreted pus extended from the mandibular bone to the gingiva. An incisional biopsy of the infected bone was performed. The histopathologic examination showed abundant purulent material, necrotic bone, and numerous Actinomyces colonies. Local alveoloplasty was performed, followed by antibiotherapy. In September 2001, we performed sequestrectomy and alveoloplasty for similar complaints and clinical findings in this patient. Histopathologic examination revealed necrotizing acute osteomyelitis with extensive Actinomyces infestation (Figure). The infection resolved completely after prolonged penicillin therapy, with no recurrence after a 24-month follow-up. The third patient, a 76-year-old man, was admitted in January 2003 because of fever, swelling, and severe pain in the right mandible a few days after tooth extraction. Six years previously, he had been diagnosed with multiple myeloma with severe diffuse bone lesions and massive proteinuria and was treated with monthly pulses of oral melphalan and prednisone. In April 1998, monthly infusions of 90 mg of intravenous pamidronate were initiated and given until August 2002 (total dose, 4680 mg), when it was replaced by monthly infusions of 4 mg of zoledronate (total dose, 16 mg).
Examination revealed trismus and right submandibular lymphadenopathy. Intraorally, the alveolar bone at the extraction site was exposed, and a purulent discharge was observed in the mucosa. A biopsy of the area showed a hyperplastic squamous epithelium with severe inflammation, evidence for acute osteomyelitis, and the presence of colonies of Actinomyces. Antibiotherapy with massive doses of penicillin G was initiated. Clinical response was good, with progressive healing of the infection. One year after diagnosis and treatment of osteomyelitis, there was no local sign recurrent infection. Although the biphosphonates used to treat osteoporosis (etidronate, residronate) have not been associated with bone necrosis, recent reports have alerted physicians to a “growing epidemic” of pamidronate- and zoledronate-induced avascular necrosis of the jaw. Marx (4) reported 36 such patients, 24 of whom had been treated with monthly pamidronate, 6 with zoledronate, and 6 with both drugs successively. In 78% of patients, avascular necrosis was provoked by tooth extraction. Migliorati (5) described 5 patients with intraoral cavity, avascular bone necrosis while being treated with either zolendronate or pamidronate. In 2 patients, bone necrosis was preceded by tooth extraction. Both pamidronate and zoledronate have very strong antiosteoclastic activity with prolonged action (6). Moreover, zoledronate is an antiangiogenic agent, which may contribute to the development of bone necrosis. Since the jaws are the only bones of the skeleton exposed to the external environment, with frequent traumatisms, local inflammations, and abcesses, the association of bone necrosis with secondary chronic infections may lead to osteomyelitis, especially among patients suffering from severe and prolonged immunosuppression, such as in our 3 patients. 0002-9343/04/$–see front matter
Letters to the Editor
PRESSURE-INDUCED BULLAE AND SWEAT GLAND NECROSIS FOLLOWING CHEMOTHERAPY INDUCTION
Figure. Patient 2: fragment of necrotic bone surrounded by actinomyces colonies (magnification ⫻400).
The local presence of Actinomyces was demonstrated in 2 patients. Actinomyces is an indolent infection that colonizes the mouth and, following disruption of the mucosal barrier, may lead to hematogeneous spread with possible general dissemination. Clinically, infections with Actinomyces occur most frequently in the oral, cervical or facial areas, with a special predilection for the angle of the jaw (7). Osteomyelitis of the jaw in longterm survivors of multiple myeloma who are on chronic biphosphonate therapy may be a new clinical entity. Although it is not possible to prove beyond doubt an etiological link between biphosphonate therapy and the occurrence of osteomyelitis of the jaw, the association of multiple myeloma with severe immunosupression, the prolonged biphosphonate therapy, and the localization to the jaw all are in favor of a relation. With the expected life prolongation of multiple myeloma patients due to recent therapeutic breakthroughs and the rising use of antiangiogenic agents, it is crucial to be aware of the possibility of a substantial rise in the number of cases of osteomyelitis of the jaws in this category of patients. Tooth extraction should be performed in specialized centers with emphasis on infection preven-
tion. Our limited, but positive, experience with hyperbaric oxygen in 1 patient should convince physicians to try this therapeutic method after everything else has failed. Gilles Lugassy, MD Rachel Shaham, DMD Anatoly Nemets, MD David Ben-Dor, MD Oded Nahlieli, DMD Barzilai Medical Center, Ashkelon Ben Gurion University of the Negev Beer Sheva, Israel 1. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21–33. 2. Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood. 2004;103:20 –32. 3. Lugassy G, Platok I, Schlesinger M. Hypocomplementemia in multiple myeloma. Leuk Lymphoma. 1999;33:365–370. 4. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J OralMaxillar Surg. 2003;61:1115–1118. 5. Migliorati CA. Biphosphonates and oral cavity avascular bone necrosis. J Clin Oncol. 2003;21:4253– 4254. 6. Fournier P, Boissier S, Filleur S. Biphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res. 2002;15:6538 – 6544. 7. Russo TA. Actinomycosis. In: Principles and Practice of Infectious Diseases. 5th ed. GL Mandell et al (eds). New York, New York; Churchill Livingstone: 1999. September 15, 2004
To the Editor: Pressure-induced bullae and sweat gland necrosis is a rare entity described with a variety of conditions involving impaired consciousness. We present a patient who developed this entity following chemotherapy. A 43-year-old man with acute myelogenous leukemia was admitted for chemotherapy induction. He was afebrile, neutropenic (absolute neutrophil count, ⬍200/mm3) and thrombocytopenic (platelet count, ⬍12,000/mm3). Four days after receiving idarubicin and cytosine arabinoside, he became hyperthermic (39.7°C). Empiric antibiotic coverage including vancomycin and cefipime was initiated. He remained febrile and on day 10 developed an erythematous macular eruption on his trunk and extremities believed to be from antimicrobic therapy. This eruption resolved with discontinuation of the medication. The patient was transferred to the intensive care unit on day 18 with respiratory distress and hypoxemia. He was diagnosed with septic shock and subsequently developed respiratory failure requiring mechanical ventilation. He was treated with vasopressors for blood pressure support and continuous hemodialysis for renal failure. Antibiotic coverage at that time included vancomycin, imipenem/cilastin, ciprofloxacin, and liposomal amphotericin B. Several days following intubation, the patient remained febrile and developed multiple dusky, erythematous, annular macules and patches on the dorsal aspect of his hands, accompanied by centrally seated, flaccid, tan-to-yellow bullae on the dorsum of his right hand (Figure 1). Erythematous blanching macules and patches
THE AMERICAN JOURNAL OF MEDICINE威
Volume 117 441