Possibilities with differential diagnosis of hematogenous osteomyelitis and malignant bone tumour

Introduction Hematogenous osteomyelitis and malignant bone tumours are not rare and present a clinical and radiological variety of bone changes. Morphological patterns can be studied at large institutions having relevant medical facilities for the diagnosis of bone lesions. Despite the advanced technologies of recent decades used to verify the pathological conditions differential diagnosis of infectious diseases and malignant bone tumors is still a problem for medical science and practice. Material and methods The study included 96 patients with hematogenous osteomyelitis and 31 patients with malignant bone tumour characterised by atypical clinical manifestations that required differential diagnosis. A. Wald’s consecutive analysis was used to compare the findings of clinical, laboratory and instrumental examinations. Results Mathematical model for differential diagnosis of hematogenous osteomyelitis and malignant bone tumour was developed with database of 127 patients. 13 differential diagnostic criteria were identified and quantified including patients’ gender, age, comorbidities, localisation of the pathological process, results of laboratory tests, etc. An algorithm for differential diagnosis of hematogenous osteomyelitis and malignant bone tumour was devised. Immune parameters in blood of 63 patients were evaluated with prognostic purposes. Conclusion Practical evaluation of differential diagnosis of hematogenous osteomyelitis and malignant bone tumour showed accuracy of primary diagnosis of 89.2 % at outpatient phase and 91.6 % in the retrospective group that resulted in a reduced workup procedure and referral to a tertiary hospital.


INTRODUCTION
Hematogenous osteomyelitis (HO) has long been known to be a surgical problem.The incidence has remained relatively stable and HO accounts for 14.8 to 28.8 % of all cases of osteomyelitis [1,2,3].Diagnosis of HO is not difficult with evident clinical presentation.Unfortunately, sometimes HO causes no signs or symptoms with atypical laboratory tests and results of radiography being equivocal and too nonspecific to allow a diagnosis to be reached [4,5,6].Identification of the causative microorganisms is essential for treatment [7].This can be problematic with outpatient medical care and at the hospitals located far from regional administrative centres [8].
Differential diagnosis between bone infection including HO and bone tumours that are not rare is important to distinguish osteomyelitis from malignant lesions that can occur at early childhood and elderly people when the clinical context does not discriminate between these [9,10,11].This confusion can lead to delays in treatment, inadequate management and poor outcomes [12].
There is a steady increase in publications on differential diagnosis between osteomyelitis and bone tumours seen in recent years [11,13,14,15,16].They are mostly descriptive and the data of the practical application are controversial.There is no consensus regarding types and importance of differential diagnosis criteria.Study of aspects related to differential diagnosis between hematogenous osteomyelitis and malignant bone tumours can be relevant for scientific medical investigations.
The purpose of this study was to identify diagnostic criteria for hematogenous osteomyelitis and malignant bone tumours, produce the quantitative assessment and devise mathematical representation of differential diagnosis.

MATERIAL AND METHODS
The study was approved by the institutional review board of North The two subgroups of retrospective study were compared using A.Wald's (1945) sequential analysis modified by E.V. Gubler and A.A.Genkin (1973) [17,18] to determine criteria of differential diagnosis and the quantitative equivalent.The model of differential diagnosis between HO and MBT was created using rating values at risk of a pathological condition caused by infection or malignancy detected retrospectively.
Decision making relied on the total index of differential diagnosis compared with threshold values calculated using formulas: threshold А = 10 × ln((1-α)/β), threshold B = 10 × ln(α/(1-β)), where α and β are type I and type II errors [12] 127 participants, 96 HO and 31 MBT patients, were recruited for the study.Those were the cases that required more diagnostic procedures to make a final diagnosis.Comparative analysis of clinical, laboratory, radiographic and immune findings was conducted in patients of the two groups identifying criteria of differential diagnosis and the quantitative equivalent.
Effectiveness of the technique developed was evaluated in 148 patients in 2017.Among them there were 87 inpatients and 61 outpatients seen at outpatient hospitals of Saint Petersburg and Leningradskaya oblast, municipal outpatient hospitals № 38 and № 120, Lomonosovskaya regional hospital, 38 occupational health facilities FMBA of Russia.
Hematological parameters were determined using automated flow cytometry with "CytoDiff ® " reagents to detect laboratory markers of differential diagnosis between HO and MBT with Cytomics FC500 flow cytometer (Beckman Coulter, USA).The test involves the capability of specific monoclonal antibodies to bind with antigen determinants and identifies white blood cells differentiating 14 hematological parameters including total leukocyte count, lymphocytes, B-lymphocytes, T-lymphocytes/NK (activated and non-activated T-NK-cells), inflammatory and non-inflammatory monocytes, mature segmented neutrophils, immature granulocytes, eosinophils and basophils.The result is recorded as the percentage of positive staining cells.The use of total leukocyte count measured with automated hematology analyser allows for obtaining absolute content of cell populations in assay.
The Ilizarov Journal of Clinical and Experimental Orthopaedics Tom 24, No 2, 2018

RESULTS
The review of 76 parameters describing patient's condition, his/her objective, laboratory and instrumental findings was produced to include general and local status of the patient, gender, age, comorbidities, body mass index, etc. Particular laboratory and instrumental tests were analysed.Parameters used for differential diagnosis between HO and MBT comprised 14 criteria.The data on distribution of HO and MBT patients with regard to localisation of pathological process as one of differential diagnosis criteria are presented in Table 1.
As seen from Table 1 HO group showed 78 % involvement of long bones while pathologic process was localised in cancellous bone in 55 % of MBT patients.Statistical analysis exhibited 3 degrees of freedom and χ 2 measured 12.126.Critical χ 2 was 11.345 with significance level at p < 0.01.Correlation between factorial and resultant characteristics was statistically significant with significance level at p < 0.01.The type of involved bone was recognised for mathematical model of differential diagnosis.Other criteria were selected in a similar manner.
Correlation index and prognosis coefficient were calculated with full list of relevant factors identified for differential diagnosis.Correlation index was defined as a ratio between the incidence of an attribute in HO group and the incidence of the attribute in MBT.Prognosis coefficient was defined as the natural logarithm (ln) of correlation index multiplied by 10 for easier calculations.The resultant prognosis coefficient was «+3.5» in involved long bones, «-7.9» in involved cancellous bone, «-7.4» in spine and «-4.2» in other bones.Long bone involvement allowed us to suspect the greater probability of HO.Then all prognosis coefficients calculated were summarised and the resultant presented a cumulative prognosis index (PI).PI was calculated at different stages of examination and treatment with confidence interval ranging from «-14» to «+14» conventional units (CU).If the cumulative PI was «+14» CU and over the probability of HO was more than 80 %.The cumulative PI of less than «-14» CU showed the similar probability of MBT.Diagnosis was ambiguous for the reliability target with cumulative PI ranging from «-14» to «+14» CU.Full list of prognostic criteria and indexes calculated for differential diagnosis is presented in Table 2.  [19,20,21].The tests were performed for 63 patients of the prospective group including 34 HO and 29 MBT patients (Table 3).

Сontinuation of table 2
Structure of criteria used for differential diagnosis between HO and MBT Table 3 Counting mean numbers of specific leukocyte subpopulations in patients with HO and MBT

Leukocyte populations
Ме (С25-С75) × 10 No statistically significant differences were found in total leukocyte count of HO and MBT cases.Statistically significant (p < 0.05) increase in absolute number of total leukocyte count was detected in HO group due to increase in B-lymphocyte, Т/ NK-lymphocyte as well as basophil and eosinophil count as compared to MBT patients.The changes are descriptive of specific immune response to infectious agent.There was statistically significant (p < 0.05) decrease in identical population count in whole blood of MBT patients due to the ability of cancer cells produce immunosuppression substances (transforming growth factor-β (TGF-β), interleukin-10), inhibitors of cytotoxicity, complement-inhibitory proteins, etc. Identical total leukocyte count in different types of bone pathology does not allow for adequate evaluation of immune system whereas changes in leukocyte subpopulation count have a distinct clinical significance for differential diagnosis between HO and MBT.Questions of differential diagnosis between HO and MBT have been discussed in Russian and foreign literature since the 40-es of the last centuries [22,23].Although tremendous progress has been made in diagnosis of bone pathology using radiography, computed tomography and magnetic resonance imaging, immunological tests, morphological study the problem is still urgent in clinical medicine since it involves both organizational and technological aspects.On the one hand, not all primary care hospitals are staffed with specialist who can perform adequate bone harvesting procedure, and osteomorphologists are available at major health care facilities.On the other hand, the patients often receive treatment at a non-core health care facility since HO and MBT must be treated at infection surgery and oncology departments, correspondingly, from legal point of view.And it takes longer to get accurate diagnosis.
The treatment tactics are conceptually different for HO and MBT and delayed verification of the diagnosis can result in lethal outcome in both cases.
The model offered for differential diagnosis with simple and accessible criteria facilitates provisional diagnosis to be made at preadmission phase, referrals of patients to a core health care facility and pathogenically substantiated treatment to be undertaken early for the best possible outcome.CONCLUSION Therefore, the usage of differential diagnosis between hematogenous osteomyelitis and malignant bone tumour in clinical settings showed accuracy of provisional diagnosis in 89.2 % to 91.6 % of the cases.Physicians were able to formulate conceptual framework of management within short period of time.Clinical testing of differential diagnosis between HO and MBT in patients of prospective group confirms adequate choice of criterion.
Criterion with maximum range of positive and negative prognosis coefficients were most important for tentative diagnosis of hematogenous osteomyelitis including male gender, age over 30 years, an injury and sinuses reported in medical history.
Frequency of HO and MBT has not been reported to decrease.In recent years atypical clinical manifestations of the conditions have been verified.Early diagnosis including outpatient tests is essential for reduced workup and timely specialised medical assistance.Our findings showed that modern organisational approaches in patients with atypical clinical manifestations of bone infections and tumours allowed for improved outcomes due to early diagnosis and timely specialised medical assistance.
-West Mechnikov State Medical University and conducted in accordance with Declaration of Helsinki "Ethical principles for medical research involving human subjects" as amended in 2000 and "Guidelines for medical practice in the Russian Federation" regulated by Decree № 266 dtd 19.06.2003Minzdrava RF.
From them, 159 patients were diagnosed with HO, and 34 with MBT.Evident clinical presentation, radiological manifestations and laboratory tests being typical for HO were detected in 63 (39.6 %) out of 159 patients with no need of differential diagnosis.The 63 observations were excluded from the study.MBT was definitely diagnosed in 23 (42.6 %) cases out of 54 malignant patients.Metastatic bone tumours were detected in all the observations with histologically confirmed primary cancer of different localisation.The study included 31 MBT patients who required differential diagnosis of other pathological conditions.

Table 1
Distribution of HO and MBT patients with regard to localisation of pathological process