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Cloxacillin

Cloxacillin is a semisynthetic antibiotic in the same class as penicillin. It is sold under a number of trade names, including Cloxapen® and Orbenin®.

Cloxacillin is for use against staphylococci that produce beta-lactamase.

Molecular formula: C19H17ClN3O5S*Na*H2O

Molecular weight: 475.9

CAS registry no.: 7081-44-9

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Delayed diagnosis of Ewing's sarcoma of the right humerus initially treated as chronic osteomyelitis: A case report
From Journal of Orthopaedic Surgery, 4/1/05 by Tow, B P B

ABSTRACT

We report a case of limited stage Ewing's sarcoma which was initially treated as chronic osteomyelitis for 3 years. A 24-year-old man presented with a one-week history of pain in the right arm and fever, with histology suggestive of osteomyelitis of the affected humerus. He developed multiple relapses of pain and fever; each episode responded to antibiotic treatment. A second biopsy was performed 3 years later and confirmed a diagnosis of Ewing's sarcoma. Despite a 3-year delay in diagnosis, the disease remained localised. This case report highlights an atypical facet of the natural history of Ewing's sarcoma: a response to antibiotic and anti-inflammatory agents, and the limited stage of the disease despite a misdiagnosis of 3 years. This suggests the possibility that anti-inflammatory agents exert an inhibitory effect on the tumour growth. We also highlight the newer histologie and immunologic staining used in the diagnosis of Ewing's sarcoma.

Key words: anti-inflammatory agents; osteomyelitis; prostaglandin-endopemxide synthase; sarcoma, Ewing's

INTRODUCTION

Ewing's sarcoma is a fairly rare, distinctive, small round cell sarcoma. It is considered one of the most lethal of all bone tumours.1 It is believed to arise from undifferentiated mesenchymal stem cells with a propensity for neural lineage, and its histologic characteristics are non-specific. The presenting symptoms include pain, swelling, fever, and pathological fractures, where fever is associated with disseminated disease.2 Radiographs feature lytic destruction and subperiosteal new bone formation akin to Onion skinning'. These non-specific findings may be present in many conditions such as metastatic carcinoma, malignant lymphoma, and osteomyelitis, necessitating open biopsy to confirm the diagnosis.1 Poor prognosis is associated with tumours that are in the axial skeleton, tumours of large volume (more than 100 cm^sup 3^), the presence of metastasis, histologic characteristics, a poor response to chemotherapy, and older patients.3-5

We present a case of a 24-year-old man who presented with symptoms and investigations suggestive of osteomyelitis. This case also revealed histology suggestive of chronic osteomyelitis and was negative for malignancy. Despite negative microbiologie cultures, treatment was commenced on a presumptive diagnosis of osteomyelitis. The patient's condition responded to antibiotic therapy and improved.

Several relapses of pain and fever occurred over the following 3 years, which led to a second biopsy that revealed Ewing's sarcoma. Strangely, the sarcoma had remained localised over such a long period of time and apparently showed repeated responses to antibiotic therapy. We highlight the pitfalls in the diagnosis of this case of Ewing's sarcoma.

CASE REPORT

In April 1999, a 24-year-old man presented to the Singapore General Hospital with a one-week history of right arm pain and fever. Radiographs revealed a radiolucent lesion in the proximal medullary canal of the lower humerus (Fig. 1). Magnetic resonance imaging (MRI) and bone scan findings were consistent with an active localised lesion of the bone. Open biopsy was performed and histology revealed reactive osteogenesis with interconnecting trabeculae of woven bone, osteoblasts assuming epithelioid cytology and mucin negative cytoplasmic vacuolation, immunoreactivity for vimentin, and negative staining for cytokeratin. There was no evidence of spindle cell hypercellularity, nuclear atypia, or mitotic activity suggestive of sarcoma. The findings were consistent with chronic inflammation and negative malignancy. Special staining for CD99, leukocyte common antigen, myeloperoxidase, CD3, CD1A, CD20, CD56, desmin, neuron specific enolase, chromogranins, and synaptophysin was not performed. Tissue culture revealed no bacterial growth. The patient was treated for 6 weeks with antibiotics-ampicillin, cloxacillin, and clindamycin-and with anti-inflammatory analgesics. He responded well and had a complete resolution of the symptoms.

Five months later the patient had a recurrence of symptoms. Radiographs showed multiple radiolucencies with poorly defined outlines in the shaft, and areas of cortical radiolucency. His C-reactive protein level was raised. He was treated with another course of ampicillin and cloxacillin with analgesics. His symptoms resolved and C-reactive protein levels returned to normal. He developed a total of 5 episodes of similar recurrences in a period of 34 months since initial presentation. At each follow-up, the radiographs showed changes of increased rarefaction on the diaphysial bone. A review of the histologic specimen by the same pathologist did not suggest malignancy, and a second opinion was not sought. By April 2002, the radiographs revealed a rarefied, moth-eaten appearance of the humeral shaft (Fig. 2). MRI revealed a heterogeneous hyperintensity in the proximal humerus on T2-weighted studies, with cortical erosions and surrounding muscle oedema (Fig. 3). These features were consistent with an aggressive bony tumour.

A second open biopsy and curettage was carried out 35 months after the initial presentation. Histology showed a malignant, small round cell tumour with features of Ewing's sarcoma: positive for PAS and CD99, and negative for leukocyte common antigen, myeloperoxidase, CD3, CDlA, CD20, CD56, desmin, neuron specific enolase, chromogranins and synaptophysin. Tissue cultures grew coagulase-negative Staphylococci. Staging studies, including bone scan and computed tomography, revealed no metastatic spread of the tumour to the thorax. The patient underwent wide local resection of the tumour and reconstruction with a vascularised fibular graft, followed by adjuvant chemotherapy. The post-reconstruction radiographs are shown in Figure 4.

On retrospective analysis of the first biopsy, a histopathologic review of the first specimen did yield a positive CD99 reactivity. Therefore, it is clear in hindsight that the later diagnosis of Ewing's sarcoma could have been made with the first specimen.

DISCUSSION

Ewing's sarcoma, first described in 1921, is now known as a distinct round cell sarcoma of the bone that occurs predominantly in the long bones of skeletally immature patients. The tumour is composed of undifferentiated round cells rich in glycogen, exhibiting a karyotypic abnormality representing reciprocal translocation t(11;22)(q24;q12) and resulting in the expression of a new chimeric EWS/FL-1 protein. This abnormality occurs in 90% of tumours classified as Ewing's sarcoma. The cell of origin is believed to be the undifferentiated mesenchymal stem cell with a propensity for neural lineage.6,7 Ewing's sarcoma belongs to the category of the most aggressive tumours and has a high propensity for local recurrence and distant metastases, which occur predominantly in the lung.4,6 90% of patients are below 20 years of age, and it is extremely rare for patients over 30 years.6,8,9 Its presentation in 70% of patients is a solitary tumour with extra-osseous extent.4 25% of cases are diagnosed with metastasis at presentation.10 Fever is present in patients with disseminated disease.9 The prognosis for Ewing's sarcoma is unfavourable, with a less than 10% chance of survival in 5 years if untreated; however, with chemotherapy, the survival rate is over 60%.4,8 The prognosis is also worse with increasing age.4,5

The presentation of this case was atypical and its clinical and histological features were suggestive of osteomyelitis. The patient's clinical and biochemical parameters responded to antibiotics and anti-inflammatory agents. Three years later, he was diagnosed with Ewing's sarcoma on a second biopsy. We attempt to explain the findings, and take the opportunity to highlight the difficulties in the diagnosis of Ewing's sarcoma and the newer methods employed in confirming the diagnosis.

Misdiagnosis of Ewing's sarcoma as osteomyelitis has been reported in several cases.11,12 Reasons reported for the misdiagnoses include a low level of suspicion, occurrence at an atypical site, and the lack of or insufficient histologic specimens.

Ewing's sarcoma is an undifferentiated primitive tumour lacking any specific markers, and requires its diagnosis to be made largely by exclusion. Recent techniques in histochemical analysis have improved the diagnosis rate in Ewing's sarcoma and similar small round cell neoplasms. Histologic characteristics of Ewing's sarcoma include the presence of broad sheets of uniform small round cells, coagulative necrosis, and reactive new bone formation. In addition, the presence of glycogen and scant amounts of reticulin helps to differentiate Ewing's sarcoma from lymphoma and rhabdomyosarcoma.7 Immunohistochemistry-a technique for identifying tissues by means of antigen-antibody interactions-is useful in ruling out other morphological mimics consisting of small round cells. CD3, CD43, CD20, CD45, Rho, and leukocyte common antigen are negative in Ewing's sarcoma but positive in lymphoma, leukaemia, angiosarcoma, and metastatic neuroblastoma. CD99 immunoreactivity is sensitive but not specific for Ewing's sarcoma. CD99 has been shown to be positive in peripheral blood monocytes, bone marrow precursors, natural killer cells, and T-lymphocytes.13 Vimentin is an intermediate filament and a marker for mesenchyme-derived tumours, including sarcomas, melanomas, lymphomas, seminomas, and neural tumours. It is also, however, almost always present in tissue segments because of its presence in background stromal elements; this renders vimentin of limited usefulness as a stand-alone test, and the absence of vimentin after staining may be more useful as a diagnosis of exclusion for the aforesaid tumours.14 Markers for neural differentiation show variable results; neuron specific enolase, leu-7, S-100 protein, and synaptophysin may be positive in some cases. A recently developed 013 antibody stain, which is directed against the MIC-2 antigen expressed by Ewing's sarcoma, is sensitive, but not specific, for Ewing's and primitive neuroectodermal tumours.11

Cytogenetic studies have demonstrated reciprocal translocation t(11;22)(q24;q12) and t(21:22)(q22:q12) of Ewing's sarcoma. Fluorescent in situ hybridisation for the fusion transcripts EWS/FLI-1 and EWS/ERG, with DNA probes and reverse transcriptase polymerase chain reactions, allow highly specific diagnoses of Ewing's sarcoma.7 Many of the abovementioned tests are not routinely done and are only ordered when the index of suspicion is high.

This patient presented with arm pain and fever at the age of 24. His radiologic and biochemical investigations, including histology, were consistent with that of osteomyelitis. He also had a clinical and biochemical response to antibiotics and anti-inflammatory agents. The sterility of the biopsy specimens did not rule out osteomyelitis as there are no tests that independently confirm infection in the absence of a positive culture. Only 36% of patients with osteomyelitis have a positive blood culture; 38% have positive cultures obtained from tissue, wound, or joint aspirate.15,16 As many as 26% of cases of osteomyelitis are diagnosed without culture confirmation and supported retrospectively by the resolution of the illness after antibiotic therapy.15,16 Our patient responded well to antibiotics and anti-inflammatory agents, but had a first recurrence of symptoms 5 months after the completion of antibiotics. He developed a total of 5 episodes of relapse of pain, fever, and elevation of the C-reactive protein in a period of 34 months since initial presentation. Each episode was treated with antibiotics and anti-inflammatory analgesics, with good response and the return of C-reactive proteins to baseline levels. Response to anti-microbial therapy had been considered as retrospective confirmation of an infective condition.

We offer possible explanations for the low-grade nature of this Ewing's sarcoma and its response to antibiotics. Elevated levels of arachidonic acid metabolites and prostaglandins have been proven in malignancies.17-20 It has been demonstrated that expression by cyclooxygenase (COX-2) contributes to tumorigenesis by: (1) inhibiting apoptosis, (2) increasing angiogenesis, (3) increasing invasiveness, and (4) modulating inflammation or immuno-suppression.20-22 The use of non-steroidal anti-inflammatory agents and COX-2 inhibitors have been shown to inhibit the growth of tumours in animal studies.19,20,22 Conversely, the stimulation of COX-2 and prostaglandin PGE receptors have proved to promote tumorigenesis.23 Tsutsumi et al.24 observed that some tumours respond to antibiotics and anti-inflammatory drugs. The clinical response experienced may have been due to the administration of anti-inflammatory agents that modulated the clinical symptoms and growth rate of the tumour.

CONCLUSION

Ewing's sarcoma is a high-grade aggressive neoplasm with a poor prognosis if not treated. This patient presented with a misdiagnosis of osteomyelitis, which repeatedly responded clinically and biochemically to antimicrobial and anti-inflammatory therapies. The case is typical only in that Ewing's sarcoma occurred in a patient in his mid-20s. Unusually, the disease remained localised and limited despite the patient's fever-a symptom of disseminated disease-and a delayed diagnosis of 3 years. We postulate the possibility of cyclooxygenase inhibition in tumour suppression in the patient. Furthermore, this case underscores the difficulties encountered in the diagnosis of Ewing's sarcoma, where round cell tumours are uncovered through histopathologic analysis. Newer and additional immunohistochemical analyses should be done routinely on cases where the diagnosis is in doubt, preferably by a musculoskeletal pathologist.

REFERENCES

1. Unni KK. Ewing's sarcoma. In: Unni KK, editor. Dahlin's bone tumours: General aspects and data on 11,807 cases. 5th ed. Philadelphia: Lippincott Raven; 1996:249-61.

2. Huvos AG. Bone tumors: Diagnosis, treatment and prognosis. 2nd ed. Philadelphia: WB Saunders; 1 991:523-52.

3. Harris M. Pediatric Ewing's sarcomas, osteosarcomas, and primitive neuroectodermal tumours. In: Lewis M, editor. Musculoskeletal oncology multidisciplinary approach. Philadelphia: WB Saunders; 1992:105-13.

4. Campanacci M. Ewing's sarcoma, primitive neuroectodermal tumours (PNET). Bone and soft tissue tumours. Berlin: Springer-Verlag; 1999:105-13.

5. Fizazi K, Dohollou N, Spielmann M, Le Cesne A, Pouillart P, Tursz T, et al. Adults with Ewing's sarcoma: a retrospective study of 146 cases. Eur J Cancer 1995;31A:250S.

6. Dorfman HD, Czerniak B. Ewing's sarcoma and related entities. In: Dorfman HD, Czerniak B, editors. Bone tumors. Philadelphia: Mosby; 1998:607-63.

7. Coindre JM. Ewing's sarcoma. In: Forest M, Tomeno B, Vanel D, editors. Orthopedic surgical pathology. Philadelphia: Churchill Eivingstone; 1998:441-65.

8. Claus-Peter A, Kazimierz K, editors. Primary bone tumour and tumorous conditions in children. Berlin: Springer-Verlag; 1993:82-5.

9. Jurgens H, Donaldson SS, Gobel U. Ewing's sarcoma. In: Barret P, Lemerle J, editors. Cancer in children. 3rd ed. Berlin: Springer-Verlag; 1992.

10. Cangir A, Vietti TJ, Gehan EA, Burgert EO Jr, Thomas P, Tefft M, et al. Ewing's sarcoma metastatic at diagnosis. Results and comparisons of two intergroup Ewing's sarcoma studies. Cancer 1990;66:887-93.

11. Durbin M, Randall RL, James M, Sudilovsky D, Zoger S. Ewing's sarcoma masquerading as osteomyelitis. Clin Orthop 1998;(357):176-85.

12. Lyall HA, Constant CR, Wraight EP. Case report: Ewing's sarcoma in distal tibial metaphysis mimicking osteomyelitis. Clin Radiol 1993;48:140-2.

13. Dworzak MN, Fritsch G, Buchinger P, Fleischer C, Printz D, Zellner A, et al. Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood. Blood 1994;83:415-25.

14. Barr N, Wu N, Taylor C. Immunohistochemical and diagnostic pathology. In: Bancroft JD, Gamble M, editors. Theory and practice of histologic techniques. 5th ed. London: Churchill Livingstone; 2002:537-52.

15. Burgert EO Jr, Nesbit ME, Garnsey LA, Gehan EA, Herrmann J, Vietti TJ, et al. Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: intergroup study IESS-II. J Clin Oncol 1990;8:1514-24.

16. Dagan R. Management of acute hematogenous osteomyelitis and septic arthritis in the pediatric patient. Pediatr Infect Dis J 1993;12:88-92.

17. Neoptolemos JP, Husband D, lmray C, Rowley S, Lawson N. Arachidonic acid and docosahexaenoic acid are increased in human colorectal cancer. Gut 1991;32:278-81.

18. Bennett A, Tacca MD, Stamford IF, Zebro T. Prostaglandins from tumours of human large bowel. Br J Cancer 1977;35:881-4.

19. Maxwell WJ, Kelleher D, Keating JJ, Hogan FP, Bloomfield FJ, MacDonald GS, et al. Enhanced secretion of prostaglandin E2 by tissue-fixed macrophages in colonie carcinoma. Digestion 1990;47:160-6.

20. Dempke W, Rie C, Grothey A, Schmoll HJ. Cyclooxygenase-2: a novel target for cancer chemotherapy? J Cancer Res Clin Oncol 2001;127:411-7.

21. O'Byrne KJ, Dalgleish AG. Chronic immune activation and inflammation as the cause of malignancy. Br J Cancer 2001;85:473-83.

22. Oshima M, Taketo MM. COX selectivity and animal models for colon cancer. Curr Pharm Des 2002;8:1 021-34.

23. AsanoT, Shoda J, Ueda T, Kawamoto T, Todoroki T, Shimonishi M, et al. Expressions of cyclooxygenase-2 and prostaglandin E-receptors in carcinoma of the gallbladder: crucial role of arachidonate metabolism in tumor growth and progression. Clin Cancer Res 2002;8:1157-67.

24. Tsutsumi M, Kitada H, Shiraiwa K, Takahama M, Tsujiuchi T, Sakitani H, et al. Inhibitory effects of combined administration of antibiotics and anti-inflammatory drugs on lung tumor development initiated by N-nitrosobis(2-hydroxypropyl)amine in rats. Carcinogenesis 2000;21:251-6.

BPB Tow, MH Tan

Department of Orthopaedic Surgery, Singapore General Hospital, Singapore

Address correspondence and reprint requests to: Dr Tan Mann Hong, Senior Consultant, Department of Orthopaedic Surgery, Singapore General Hospital, Outram Road 169608, Singapore. E-mail: goctmh@sgh.com.sg

Copyright Western Pacific Orthopaedic Association Apr 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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