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Mondello et al. SpringerPlus 2014, 3:123
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Necrotizing fasciitis as a rare complication of
osteonecrosis of the jaw in a patient with
multiple myeloma treated with lenalidomide:
case report and review of the literature
Patrizia Mondello1,5*, Vincenzo Pitini1, Carmela Arrigo1, Stefania Mondello2, Michael Mian3,4 and Giuseppe Altavilla1
Bisphosphonates (BPs), potent inhibitors of osteoclast-mediated bone resorption, play a major role in the
management of patients with multiple myeloma (MM). However, in the case of dental infections, they can lead to
bisphosphonate related osteonecrosis of the jaw (BRONJ). This process can be worsened by concomitant
antineoplastic therapy. Herein, we present a case of a life-threatening necrotizing fasciitis (NF) as a rare and severe
complication of BRONJ after three cycles of lenalidomide and dexamethasone in an MM patient treated with
corticosteroid therapy and Ibandronate for 5 years. The patient presented swelling on the right part of the neck,
difficulty in swallowing and acute pain, so a magnetic resonance of the head and neck region was performed. It
revealed the presence of an NF with a massive extension. Due to the large necrotic area and a rapid progression of
the infection, the necrotic tissue had to be removed surgically. Furthermore, a specific antimicrobial treatment as
well as 12 sessions of hyperbaric oxygen therapy were needed to cure the patient.
Herein, we highlight the potential serious adverse events associated with the use of bisphosphonates and
antiangiogenetic drugs in patients with MM. Future studies are needed to evaluate the potential synergistic effects
of BPs, corticosteroids and antiangiogenetic drugs.
Keywords: Necrotizing fasciitis; BRONJ; Bisphosphonate; Multiple myeloma; Lenalidomide
Bisphosphonates (BPs) are important drugs in the treatment of neoplasia involving the bones. Particularly in
multiple myeloma (MM) they are able to inhibit disease
progression and even to prolong survival (Coleman et al.
2012). BPs are usually administered on a regular basis
and often concomitantly with antineoplastic drugs such
as thalidomide ore lenalidomide. However, in patients
with infections involving the jaw, the administration of
BPs can be complicated by a bisphosphonate related
osteonecrosis of the jaw (BRONJ), a localized death of
bone tissue with minor soft tissue involvement (Lee
et al. 2014). Rarely, this severe complication can be further worsened by a necrotizing fasciitis (NF), a rapidly
* Correspondence: [email protected]
Department of Medical Oncology, University of Messina, Messina, Italy
Via Lodi is. 47 b, 98124 Messina, Italy
Full list of author information is available at the end of the article
progressing infection characterized by extensive necrosis
of subcutaneous tissue and fascia (Sultan et al. 2012;
Tsitsilonis et al. 2013). If not promptly diagnosed and
treated it can lead to a life-threatening condition.
Case description
A 59-year-old woman was diagnosed with a Stage III
MM IgA kappa. First line treatment consisted of three
cycles of VAD (vincristine, doxorubicin and dexamethasone) followed by autologous stem cell transplant. Since
the patient achieved only a partial remission, 5 months
later she underwent 6 cycles of bortezomib monotherapy
followed by radiation therapy of the whole dorsal column and pelvis. Having achieved a very good partial remission, monthly Ibandronate 6 mg and weekly 20 mg
dexamethasone were delivered as maintenance treatment. Before and during BP treatment, the patient
underwent a dental examination.
© 2014 Mondello et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction
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Mondello et al. SpringerPlus 2014, 3:123
Two years later she presented with M-component in
serum and urine, anemia and multiple lytic lesions.
Therefore, second line treatment consisting of lenalidomide 25 mg/die, day 1–21 q28 and dexamethasone
25 mg/die p.o., Days 1–4, 8–11, 18–21) was initiated
(Weber et al. 2007; Dimopoulos et al. 2007), while the BP
was continued. After three cycles the patient presented
swelling on the right part of the neck (from Robbinson
level I to IV), difficulty in swallowing and acute pain.
Intra-oral exploration revealed palato-pharyngeal paralysis on the right side and an ulcer of the right genuamandibular mucosa with exposure of the surrounding
alveolar bone. Within 24 to 48 hours from onset, local
erythema, pain and edema quickly worsened. The skin
appeared shiny and tense. The patient developed signs of
systemic infection as well as atrial fibrillation. Routine laboratory tests revealed high levels of white blood cell
count, creatine, C-reactive protein (CRP), and creatine
kinase (CK). Magnetic resonance imaging (MRI) study of
head and neck showed an increased signal of the right
mandibular body, consistent with the diagnosis of right
jaw osteonecrosis (Figure 1A), and a second highintensity area characterized by gas formation spread for
about 10 cm with involvement of the right parapharyngeal space and with extension to skin and muscle, suggestive of a gas-forming necrotising fasciitis of the neck
(Figure 1B). Extension of the abscess was measured by
computed tomography (CT) and ranged from the right
side of the neck midline located at almost 1.5 cm from
the cranial base to the upper edge of the right clavicle.
The mediastinum was not involved. Surgical debridement
with radical excision of necrotic tissues was necessary
Page 2 of 5
and histological examination revealed a lymphohistocytic
infiltrate of the dermis, suppuration, necrosis of the superficial fascia, and edema in the fascial planes. Microbiological
tissue cultures were positive for Streptococcus Mitis, a facultative anaerobe gram positive coccus that inhabits the human mouth. Combined antibiotic and antifungal therapy
associated with nonsteroidal anti-inflammatories was initiated. Despite opioid-based pain therapy, total parenteral
nutrition was necessary. In order to accelerate the healing
process and because of the anaerobic infection, she underwent 12 sessions of hyperbaric oxygen therapy (OTI).
Three months later pain was completely resolved and she
was able to eat normally.
BRONJ is a severe complication of BPs therapy, not depending on the type of drug but on the duration of therapy since it accumulates in the bone tissue. Despite
several cases of BRONJ having been reported (Lee et al.
2014), the pathophysiology of this complication is still
unknown. However, a multifactorial genesis is strongly
suggested. Recently, Vermeer et al. (2013) have shown
that osteoclasts of the jaw and their precursors
internalize a greater quantity of BPs compared to those
of other bones. Since the inhibition of osteoclasts is
dose dependent (Lam et al. 2007), bone remodeling is
more reduced in the jaw than elsewhere in the body.
Another effect of BPs is to promote a premature senescence of the oral keratinocytes (Kim et al. 2011a),
impairing mucosal wound healing. Moreover BPs have
antiangiogenic activity (Wood et al. 2002; Vincenzi et al.
2003) due to the reduction of circulating endothelial
Figure 1 Magnetic resonance imaging (MRI) study of head and neck. A, Axial MRI scan showing a significantly increased signal of the bone
marrow lesion (yellow arrow) when compared with left mandibular body (asterisk), with bone edema indicative of an inflammatory process
taking place in the right mandibular body and gas tracking along the two pterygoid muscles (white arrows). B, A coronal T2-weighted image of
the submandibular region showing a wide mass with very high signal intensity from the parapharyngeal space to the inferior cervical region with
associated edema.
Mondello et al. SpringerPlus 2014, 3:123
cells (Allegra et al. 2007) and by lowering VEGF serum
levels (Santini et al. 2002). Beside BPs therapy, also corticosteroids, immunomodulatory drugs and chemotherapeutic agents have been implicated in the development of
BRONJ (Saad et al. 2012) since most patients who have
developed BRONJ have been treated with one or both.
For example, thalidomide, an efficient antimyeloma agent,
(Bamias and Dimopoulos 2005; Goranova-Marinova et al.
2009) has not only immunomodulary effects but also
antiangiogenic activity contributing to impaired wound
healing. Overall, the immunosuppressive effects of
chemo- and radiotherapy, impaired bone remodeling
due to corticoid therapy, and reduced vascularization
due immunomodulatory drugs (IMiDs) are BRONJ favoring conditions (Goranova-Marinova et al. 2009).
In the present case, BRONJ was further complicated by
NF, probably due to an over-infection of the necrotic tissue with successive extension to the surrounding structures. NF is a rare, rapidly progressing infection,
characterized by extensive necrosis of subcutaneous tissue and fascia, usually accompanied by severe systemic
symptoms (Sultan et al. 2012). It can occur de novo after
inoculation of bacteria or as a complication of surgery or
other traumas. Most frequent infectious agents are group
A β-hemolytic streptococci, hemolytic staphylococcus,
and Pseudomonas (Tsitsilonis et al. 2013). Although NF
can occur in young and healthy patients, it usually afflicts
elderly and/or immunocompromised patients. Early recognition of NF may be difficult because the initial clinical
presentation is not specific and often resembles that of
cellulitis (Chelsom and Halstensen 1994). An appropriate
differential diagnosis between these two pathological
conditions is critical for an effective clinical management.
Indeed, while cellulitis, which is restricted to the subcutaneous tissue and can be cured in most cases with antibiotics alone, NF instead frequently requires an additional
surgical intervention. The gold standard for the diagnosis
of NF is a biopsy before surgery (Stamenkovic and Lew
1984). However, this procedure is invasive and can be associated with complications, therefore MR seems to be a
valid alternative (Kim et al. 2011b). Both cellulitis and NF
present a high signal intensity of subcutaneous tissue on
T2-weighted images and a moderate to high contrast enhancement of the subcutaneous fat, but only in NF is
there a deep fascia involvement identified in T2-weighted
and contrast-enhanced T1-weighted images (Kim et al.
2011b). Moreover, as was the case with the herein presented patient, laboratory parameters such as CRP and
CK could aid in early NF recognition since levels are
higher in patients with NF than in those with cellulitis
(Simonart et al. 2001). As in BRONJ, the combination of
BPs anti-angiogenetic activity and lenalidomide, as well
as the immunomodulatory effect of the latter could predispose the patient to NF. The vascular impaired and
Page 3 of 5
reduced viability of oral keratinocite slow down the reparative processes in the oral cavity and appear as predisposing factors in mucosal breakdown, facilitating
bacteria infiltration. Moreover, patients with MM undergoing lenalidomide have an altered function of the immune system, promoting the extension of the infection.
Indeed, Hsu et al. demonstrated that lenalidomide, in
combination with dexamethasone (Len-Dex), leads to
progressive reduction in the function of NK cells during
the course of therapy (Hsu et al. 2011). As recently reported and similarly to our case, lenalidomide induced
alterations of physiologic mechanisms can occur within a
few days of the beginnig of treatment (Danbara et al.
The herein presented patient suffered from BRONJ
followed by NF, both rare complications. Up to now their
pathogenetic causes are not fully understood but a multifactorial genesis is strongly suggested. Available data implicates a major role of altered bone remodeling, reduced
angiogenesis and therefore defective tissue repair mechanisms, altered microenviroment and immunodeficiency
caused by antimyeloma therapy as well as the disease
Written informed consent was obtained from the patient
for the publication of this report and any accompanying
BPs: Bisphosphonates; BRONJ: Osteonecrosis of the jaws; NF: Necrotizing
fasciitis; MM: Multiple myeloma; VAD: Vincristine, doxorubicin and
dexamethasone; CK: Creatine kinase; CRP: C-reactive protein; MRI: Magnetic
resonance imaging; CT: Computed tomography; OTI: Hyperbaric oxygen
therapy; IMiDs: Immunomodulatory drugs; Len-Dex: Lenalidomide and
Competing interests
The authors have no conflicts of interests.
Authors’ contributions
MP collected the data, revised the literature and wrote the manuscript; PV
and MS were involved in revising the manuscript critically for important
intellectual content; CA participated in the acquisition of data and in the
manuscript layout; AG participated in the coordination of the study and
gave final approval of the version to be published. All authors read and
approved the final manuscript.
Authors’ information
Patrizia Mondello, MD, graduated with mark 110/110 cum laude in
Medicine and Surgery at the University of Messina (Italy) in 2009 defending
an experimental thesis entitled “Primary Lymphoma of the central nervous
system” and is currently attending the fourth year of the post-graduate
specialization in Oncology. She pursues different cancer specializations,
focusing on the hematoncology field. She has received many awards and
spent long periods in Germany and the USA, furthering her medical and
anguage knowledge. She is currently spending a year at the Memorial Sloan
Kettering Cancer Center in New York working in the laboratory of Dr. Anas
Younes as research fellow and furthering her knowledge of translational
research in the lymphomas field. She is also co-author of scientific papers
published in national and international peer-review journals. Her main fields
Mondello et al. SpringerPlus 2014, 3:123
of research focus on pathophysiology in onco- and hematology fields and
translational research.
Vincenzo Pitini, MD and Chief of “High dose chemotherapy and Stem cell
transplantation department” at Universitary Hospital “G. Martino” in Messina.
He graduated in Medicine and Surgery in 1977 with 110/110 cum laude.
After graduation, he specialized in Renal, haematological diseases, and
metabolic disorders in 1980. He specialized in Oncology in 1983. Since
August 1980, he has been University Researcher at the Institute of Oncology
at the University of Messina, and is still in service at the Department of
Human Pathology. Since 1987 he has obtained the qualification of Aid. Since
the academic year 1990/91 he has also given lesson cycles on the use of
Molecular Biology in Oncology. Since 1995, he has developed the
procedures for the collection and subsequent reinfusion of circulating stem
cells in the high-dose antiblastic therapy, thereby contributing to the
accreditation of the Division of Medical Oncology at the Italian Group for
Bone Marrow Transplantation (GITMO) CIC 669. He also attended an
updating course in Oncohematology at the University of Texas M.D.
Anderson Cancer Center in Houston, Texas (USA). He is also author of
scientific papers published on national and international peer-review journals
focusing on hematology and oncology fields.
Carmela Arrigo, lab manager of Stem of “High dose chemotherapy and
Stem cell transplantation department” at Universitary Hospital “G. Martino” in
Messina. She graduated in Natural Science in 1975 and in 1986 in Medical
Biology at the University of Messina. She specialized in “Medical Genetics” in
1993 at the University of Catania. She is also co-author of scientific papers
published in national and international peer-review journals.
Stefania Mondello, MD, MPH, PhD, is a trained neurointensivist with an
extensive experience in critical care, biomarker research and statistical
analysis methods. She received her medical degree and completed her
residency at the University of Messina. Afterwards she obtained her Master’s
in Public Health at the University of Florida and then continued studies with
a Ph.D. degree focusing on assessments of the clinical utility of brain
damage biomarkers to assist in the management of severe traumatic brain
injury patients. For the past 5 years she has been attending the Division of
Critical Care Medicine at the University of Florida. Her clinical and PhD training
qualified her to assume the responsibility of Director of Clinical Research at the
biotech company, Banyan Biomarkers, Inc. Her research focuses on the use of
biochemical markers to improved management, diagnosis and prognosis of
patients including clinical validation and assessment of the relationships with
clinical variables and physiologic monitoring. These research projects are being
carried out in collaboration with NIH and DoD grants. Her intellectual
contributions are documented in peer reviewed manuscripts, book chapters,
abstracts, and presentations at international scientific meetings. She has been
invited to serve on national and international grant review panels and has
received a number of awards recognizing her contributions to the field. She
was also recognized by the prestigious journal Nature.
Michael Mian graduated in Medicine at the University of Innsbruck in 2004.
In 2005 he worked as resident at the University of Salzburg. In 2009 he
specialized in hematology at the University of Verona. From 2009 to 2010 he
was a research fellow at the the Institute of Oncology Research of the
Istituto Oncologico della Svizzera Italiana for 1.5 years. During this ellowship
he developed methods to interpret single nucleotid polimorphism array data
together with clincal data. Since then, he has been working as a physician at
the General Hospital of Bolzano. In collaboration with the International
Extranodal Lymphoma Study group he provided new insights into the
clinical behaviour of rare extranodal lymphoid malignancies.
Giuseppe Altavilla Full Professor and Director of Medical Oncology
department at Universitary Hospital “G. Martino” in Messina and a current
member of the national executive of the Italian Association of Medical
Oncology (AIOM). He graduated in Medicine and Surgery in 1975. He
specialized in Cardiovascular Diseases, Catholic University (Rome) in 1979
and in Oncology at the Catholic University of Rome in 1979. Since 1980 he
has been Researcher at the Unit of Medical Oncology. He is Professor of the
College of PhD in Neurooncology (cycles XXVIII to XXI). He is Professor of
Medical Oncology at the School of Specialization in Oncology, Toxicology,
Geriatrics, Radiotherapy, Physics, Nuclear Medicine, Internal Medicine, and
Genetics. He is interested in the assessment of diagnostic and therapeutic
protocols and the study of prognostic factors of various solid tumours and,
recently in the pharmacogenomics of cancer. He is also author and
co-author of numerous scientific papers published on national and
international peer-review journals.
Page 4 of 5
The authors thank Michele Gaeta and Giorgio Ascenti respectively for MRI
and CT images.
No authors have any funding sources.
Author details
Department of Medical Oncology, University of Messina, Messina, Italy.
Department of Neurosciences, University of Messina, Messina, Italy.
Department of Hematology & CTMO, Hospital of Bolzano, Bolzano, Italy.
Department of Hematology & Oncology, Medical University of Innsbruck,
Innsbruck, Austria. 5Via Lodi is. 47 b, 98124 Messina, Italy.
Received: 14 November 2013 Accepted: 3 March 2014
Published: 5 March 2014
Allegra A, Oteri G, Nastro E, Alonci A, Bellomo G, Del Fabro V, Quartarone E, Alati
C, De Ponte FS, Cicciù D, Musolino C (2007) Patients with bisphosphonatesassociated osteonecrosis of the jaw have reduced circulating endothelial
cells. Hematol Oncol 25(4):164–169
Bamias A, Dimopoulos MA (2005) Thalidomide and immunomodulatory drugs in
the treatment of cancer. Expert Opin Investig Drugs 14(1):45–55
Chelsom J, Halstensen A (1994) Necrotising fasciitis due to group A streptococci
in westernNorway: incidence and clinical features. Lancet
Coleman R, Gnant M, Morgan G, Clezardin P (2012) Effects of bone-targeted
agents on cancer progression and mortality. J Natl Cancer Inst
Danbara M, Tadera N, Togano T, Katayama T, Aoki T, Miyazaki K, Higashihara M
(2013) Lenalidomide-induced acute lung injury in case of multiple myeloma.
Int J Clin Pharmacol Ther 51(6):513–6
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A,
San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M,
Yu Z, Patin J, Zeldis JB, Knight RD, Multiple Myeloma (010) Study
Investigators (2007) Lenalidomide plus dexamethasone for relapsed or
refractory multiple myeloma. N Engl J Med 357(21):2123–2132
Goranova-Marinova VS, Pechalova-Petrova PF, Goranov SG (2009) Osteonecrosis
of the jaw in patients on bisphosphonate treatment. review of literature with
contribution of a case of multiple myeloma. Folia Med (Plovdiv) 51(4):53–57
Hsu AK, Quach H, Tai T, Prince HM, Harrison SJ, Trapani JA, Smyth MJ, Neeson P,
Ritchie DS (2011) The immunostimulatory effect of lenalidomide on NK-cell
function is profoundly inhibited by concurrent dexamethasone therapy.
Blood 117(5):1605–1613
Kim RH, Lee RS, Williams D, Bae S, Woo J, Lieberman M, Oh JE, Dong Q, Shin KH,
Kang MK, Park NH (2011a) Bisphosphonates induce senescence in normal
human oral keratinocytes. J Dent Res 90(6):810–816
Kim KT, Kim YJ, Won Lee J, Kim YJ, Park SW, Lim MK, Suh CH (2011b) Can
necrotizing infectious fasciitis be differentiated from nonnecrotizing
infectious fasciitis with MR imaging? Radiology 259(3):816–824
Lam DK, Sándor GK, Holmes HI, Evans AW, Clokie CM (2007) A review of
bisphosphonate-associated osteonecrosis of the jaws and its management.
J Can Dent Assoc 73(5):417–422, Review
Lee SH, Chan RC, Chang SS, Tan YL, Chang KH, Lee MC, Chang HE, Lee CC (2014)
Use of bisphosphonates and the risk of osteonecrosis among cancer
patients: a systemic review and meta-analysis of the observational studies.
Support Care Cancer 22(2):553–560
Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, Diel IJ,
Takahashi S, Shore N, Henry DH, Barrios CH, Facon T, Senecal F, Fizazi K, Zhou
L, Daniels A, Carrière P, Dansey R (2012) Incidence, risk factors, and outcomes
of osteonecrosis of the jaw: integrated analysis from three blinded activecontrolled phase III trials in cancer patients with bone metastases. Ann Oncol
Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M, Salerno A,
Denaro V, Tonini G (2002) Pamidronate induces modifications of circulating
angiogenetic factors in cancer patients. Clin Cancer Res 8(5):1080–1084
Simonart T, Simonart JM, Derdelinckx I, De Dobbeleer G, Verleysen A, Verraes S,
de Maubeuge J, Van Vooren JP, Naeyaert JM, de la Brassine M, Peetermans
WE, Heenen M (2001) Value of standard laboratory tests for the early
recognition of group A beta-hemolytic streptococcalnecrotizing fasciitis. Clin
Infect Dis 32(1):E9–E12
Mondello et al. SpringerPlus 2014, 3:123
Page 5 of 5
Stamenkovic I, Lew PD (1984) Early recognition of potentially fatal necrotizing
fasciitis: the use of frozen-section biopsy. N Engl J Med 310(26):1689–1693
Sultan HY, Boyle AA, Sheppard N (2012) Necrotising fasciitis. BMJ 345:e4274
Tsitsilonis S, Druschel C, Wichlas F, Haas NP, Schwabe P, Bail HJ, Schaser KD
(2013) Necrotizing fasciitis: is the bacterial spectrum changing? Langenbecks
Arch Surg 398(1):153–159
Vermeer JA, Jansen ID, Marthi M, Coxon FP, McKenna CE, Sun S, de Vries TJ,
Everts V (2013) Jaw bone marrow-derived osteoclast precursors internalize
more bisphosphonate than long-bone marrow precursors. Bone
Vincenzi B, Santini D, Rocci L, Tonini G (2003) Bisphosphonates: new
antiangiogenic molecules in cancer treatment? Ann Oncol 14(5):806–807
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D,
Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M,
Zeldis JB, Knight RD, Multiple Myeloma (009) Study Investigators (2007)
Lenalidomide plus dexamethasone for relapsed multiple myeloma in North
America. N Engl J Med 357(21):2133–2142
Wood J, Bonjean K, Ruetz S, Bellahcène A, Devy L, Foidart JM, Castronovo V,
Green JR (2002) Novel antiangiogenic effects of the bisphosphonate
compound zoledronic acid. J Pharmacol Exp Ther 302(3):1055–1061
Cite this article as: Mondello et al.: Necrotizing fasciitis as a rare
complication of osteonecrosis of the jaw in a patient with multiple
myeloma treated with lenalidomide: case report and review of the
literature. SpringerPlus 2014 3:123.
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