Delayed Diagnosis Of Primary Malignant Bone Tumors: Patient Or Healthcare System Delays

Introduction

Primary malignant bone tumours (PMBTs) are relatively rare, accounting for 3%–5% of all childhood cancers and less than 1% of all cancers in adults.¹ The incidence of these tumours is reported to be 0.11%–0.31% per 100,000 persons in Nigeria.² Though these malignancies are rare, they frequently cause disproportionately high morbidity and mortality rates, which make them the third leading cause of mortality in the United Kingdom.¹

Though PMBTs are relatively rare globally, the burden of these tumors is shown to be high and is increasing. Analysis of five years of data from multiple cancer centers in India showed that years of life lost (YLLs) and disability adjusted life years (DALYs) to bone tumors stood at 12.0 and 12.9 years, respectively, per 100,000 persons, signifying a YLLs to DALYs rate of 92.6%. Thus, about 92.6% of persons who develop a bone tumor may lose their lives prematurely, which is comparable to lung cancer.³

The common PMBTs include osteosarcoma, chondrosarcoma, Ewing sarcoma, and multiple myeloma. Among these tumours, Osteosarcoma is recognized as the most common PMBT with a bimodal incidence peak during adolescence and older adulthood.⁴ Osteosarcoma in the elderly population is often secondary to a chronic underlying pathology such as Paget’s disease of bone and chronic osteomyelitis. Ewing sarcoma and chondrosarcoma rank as the second and third most common PMBTs, respectively.⁴

The clinical course of these tumours is often insidious with the most frequent presenting complaint being a dull pain, which is worse at night and progressively worsening. The insidious and nonspecific nature of the presentation of these tumours coupled with lower public awareness are cited anecdotally as reasons for the delay in presenting to health institutions. The delay in diagnosis and treatment of these tumours is often challenged by short falls in expertise and diagnostic equipment, especially in developing countries.^5,6

Malignant tumours should be diagnosed at an early stage of the disease when curative treatment can be given. There exist varying definitions of a delay in the diagnosis of PMBTs. In 2016, an expert group of oncologists in the Netherlands, known as stichting oncologische samenwerking (SONCOS), defined a delay as the time frame between the onset of the first symptoms of the disease and when a confirmatory diagnosis is obtained; they further categorized this time frame into either short (≤4 months) and prolonged (>4 months).⁶

Another single-center study in Uganda categorized delays into short (≤3 months) and prolonged (>3 months). The study in Uganda found that most patients presented to a health facility for the first time after three months of onset of the first symptoms of the disease. Prolonged delays in diagnosis were associated with factors such as young age, female sex, low level of education, poor knowledge of tumours, belief systems, and negative perceptions of bone tumours.⁵

A paucity of studies exists regarding the timing to diagnoses of primary bone tumours in Ghana and, by extent, the African continent. The quantification of this duration and the identification of implicated factors have the potential to aid policy formulation and public education to reduce the time to diagnose these tumours.

Thus, this study aims to assess the time of presentation and diagnosis of PMBTs and the factors associated with the time to diagnosis of the disease condition in our resource-limited subregion.

Methods

Study design

This is a cross-sectional study involving retrospective analysis of prospectively collected data retrieved from the bone tumor registry of the Orthopedic department of Tamale Teaching Hospital (TTH). Data including demographics, clinical features, duration of presentation, duration of obtaining confirmatory diagnosis, histologic diagnosis, Enneking stage, treatment modalities, and follow-up laboratory results were collected into the tumor registry of the hospital after anonymizing patients. Informed consent was obtained from each patient or guardian at the time of entry into the registry.

The data were collected prospectively from January 2021 to December 2023. Data were collected from participants who visited the hospital through the surgical clinic or the accident and emergency department of the hospital. Data were retrieved from the registry onto Microsoft Excel sheets and filtered; errors were appropriately corrected before uploading onto the Statistical Package for Social Sciences (SPSS) version 23.

Study variables

The study evaluates the demographic features of patients diagnosed with PMBTs, the duration from the onset of the first symptom of the disease and presentation to a health facility for the first time, the duration of first health facility presentation to obtaining a confirmatory diagnosis, and the factors associated with the duration of onset of symptoms to obtaining confirmatory diagnosis. The duration between the appearance of first symptom of the disease and confirmatory histopathologic diagnosis was categorized into short delays (≤3 months) and prolonged delays (>3 months).

Study population

Adult and pediatric patients were diagnosed and treated for PMBTs such as osteosarcoma, Ewing sarcoma, and chondrosarcoma at the study site. These patients were either referred from other facilities to the tertiary center through the orthopedic specialist clinics or presented directly to the accident and emergency department due to acute complications of the disease.

Study site

TTH is a tertiary health facility serving the five regions of the Northern Ghana, which include Northern, Savannah, North East, Upper East, and Upper West regions. A substantial number of patients are seen from the Bono and Oti regions. The study site serves as the training institution for training medical students at the University of Development Studies’ School of Medicine. It also serves as the postgraduate training center for residents of Ghana College of Physician and Surgeons and the West African College of Surgeons. The points of entry for patients into the trauma and orthopedic departments of the hospital are the specialist clinics and the accident and emergency department of the hospital.

Selection Criteria

Inclusion criteria

Pediatric and adult patients whose data on the tumor registry are complete and who had obtained a histologic diagnosis of PMBTs such as osteosarcoma, Ewing sarcoma, chondrosarcoma, and multiple myeloma. Data from these patients were taken with their informed consent or consent from their guardians in the case of children.

Exclusion criteria

Patients with missing data, no confirmatory histologic diagnosis, or missing histologic diagnosis were excluded. Patients who were diagnosed with benign bone tumors or soft tissue sarcomas were also excluded from the study.

Sampling method

All patients who were diagnosed with a PMBT by histopathology and had complete data recorded in the tumor registry between January 2021 and December 2023 were included in the study.

Data analysis

Data were extracted from the tumor registry spanning the study period, entered into Microsoft Excel, and checked for accuracy and completeness. It was subsequently imported into SPSS version 23. The distribution of the data was confirmed using the Shapiro-Wilk test. Analysis was done using descriptive statistics and presented in tables and charts. Chi-square testing was employed to determine the association of categorical variables. Stratification was used to do subgroup analysis of patients who presented within three months of the onset of symptoms.

Ethics

Permission to publish was sought from the research department of TTH. The study was conducted by maintaining the standards of confidentiality, respect, and beneficence.

Results

Records of 106 musculoskeletal tumour cases were in the tumour data registry. Of these cases, 62 were soft tissue sarcomas and benign bone tumours, which were excluded. The remaining 44 cases were PMBTs; however, 14 cases had incomplete records and thus were excluded. The study included 30 cases of patients with PMBTs.

The mean age of the participants was 23 ± 14 years, with the youngest being 8 and the oldest being 61. About half (53.3%) of the patients in this study were adolescents and a third (33.3%) were young adults between 20 and 40 years of age. Most participants (60%) were female, half (50%) had a primary school education, and the majority (66.7%) were single (Table 1).

The decision to present to a health facility after the appearance of the first disease symptoms was delayed, and there were delays seen between the time of presentation and obtaining a confirmatory histopathologic diagnosis. The average period from experiencing the first symptom of the disease to presenting at a health facility for the first time was 6.3 ± 5.3 months with the shortest duration of presentation being <1 month. About half (53.3%) of the patients presented to a health facility for the first time after 3 months of onset of the first symptom of the disease (Table 2).

A subgroup analysis of those who presented within the short delay period (≤3 months) for the first time to a health facility revealed a mean duration from that presentation to obtaining a confirmatory diagnosis of 2 ± 0.8 months.

It took a mean duration of 7.3 ± 9.5 months for patients to obtain a confirmatory diagnosis after first contact with a facility. Thus, patients who presented to the study center directly obtained a confirmatory diagnosis within a month of presentation.

The mean time from the first symptom to obtaining a confirmatory diagnosis was 13.6 ± 10.8 months, with the majority (90%) occurring more than 3 months after the appearance of the first symptom. Thus, it took a minimum of 2.8 months to obtain a diagnosis from the onset of symptoms (Table 2).

Level of patient education (P = 0.027) had significant statistical association with the duration of time to obtaining confirmatory diagnosis with the majority of patients who had prolonged delay (>3 months) having primary education or no education.

Occupation status of patients or their caregivers was also found to be a factor in the duration of time to obtaining confirmatory diagnosis (P < 0.001). Most of the patients who had no employment obtained confirmatory diagnosis after 3 months of the onset of symptoms.

The age of the patient at diagnosis (P = 0.016) was found to have a significant statistical association with a prolonged delay in obtaining a histologic diagnosis.

Just over half (53.3%) of the patients were diagnosed at Enneking stage III, indicating that they had detectable metastasis at diagnosis (Table 3).

An advanced stage of the disease (P < 0.001) was associated with late diagnosis. Thus, patients who were diagnosed >3 months after onset of first symptom were likely to have a more advanced form of the disease.

Metastasis at diagnosis to distant parts was found to be associated with patients who were diagnosed late (P = 0.022). The most common site of distant metastasis was the lungs, which constitute 93.8% of cases that had distant metastases at diagnosis.

The mean age of patients in this study was 23 ± 14 years, supporting several studies indicating a predilection for PMBTs to appear in young growing children and adolescents.^1,7,8 These tumours were found to be 1.5 times more common in females than in males, contrary to the findings of Kumar and Gupta (2016), which reported them to be 1.5 times more common in males and a 1:1 male-to-female prevalence ratio found by Green et al. (2021) in the United Kingdom.^1,9 The findings in our study could be attributed to the notion that females tend to seek healthcare earlier or are more concerned about their health than males, which also applies to parents’ health-seeking behavior for their children as well in our study area.

PMBTs often lead to significant morbidity and mortality, despite accounting for less than 1% of all cancers.¹ Morbidity and mortality in this group are further exacerbated by delayed diagnosis and delayed initiation of appropriate treatment. An overwhelming majority (90%) of patients in this study received a confirmatory diagnosis more than 3 months after the onset of the first symptom with a mean duration of 13.6 ± 10.8 months. This duration is double that of the duration found in the studies by Lingerih et al. and Kotrych et al., which reported median durations of 5 and 7 months, respectively; however, most participants in these studies had a confirmatory diagnosis after 3 months of symptom onset.^10,11 While patients contribute to this delay, this study shows that referral systems may also play a role. Our referral system likely needs to be strengthened to better assist patients with suspected malignancies in reaching the diagnostic facility on time. Additionally, further training is necessary for health workers in lower-level health facilities to recognize early signs and symptoms of bone tumors.

Further analysis indicated that the mean duration from the appearance of the first clinical symptom to the initial presentation at a health facility was 6.3 ± 5.3 months, with slightly more than half (53.3%) presenting after 3 months. Subgroup analysis of those who presented early (≤3 months) to a health facility showed a mean duration from that presentation to receiving a confirmatory diagnosis of 2 ± 0.8 months. This aligns with a 3.2-month median delay reported in a study of soft tissue and bone sarcomas at a single center in the United Kingdom¹² and the 156.2 ± 210.9 days recorded in a similar study in the Netherlands.⁶ A delay of over 30 days in the referral of primary bone tumours was identified as an independent factor linked to metastasis and poor outcomes in Japan¹³

The duration from the onset of the first symptom to receiving a confirmatory diagnosis was compared based on patient and clinical factors. The age of participants, level of education, presence of a swelling, and advanced stages of the disease were significantly associated with a delay in diagnosis beyond 3 months. Just over half (53.3%) of the patients diagnosed more than 3 months after the onset of symptoms were below 20 years of age and unemployed (66.7%), which may impact their ability to make independent decisions to seek orthodox medical care in a timely manner. This supports Schnurr et al.'s conclusion that patients under 30 years of age are predisposed to diagnostic delays.¹⁴

Prolonged delays (>3 months) observed in our study were associated with low levels of education (P = 0.027). However, slightly more than half of the patients were under 20 years old, and their education level as a related factor for prolonged delays should be interpreted cautiously, as they may lack the capacity to make informed decisions. Additionally, lower education levels were linked to late presentations among bone sarcoma patients in a single center in Uganda.⁵ Therefore, enhancing education may improve health literacy and reduce delays in patients seeking medical care.

Due to the high costs of cancer treatment, significant catastrophic expenditures have been observed among patients.¹⁵ Thus, patients must be gainfully employed and earn a substantial income to afford various services; as demonstrated in our study, employment status is significantly linked to delayed presentation.

In our study, most patients (86.6%) diagnosed after 3 months had Enneking stage IIB and III disease. The advanced stage of the disease at diagnosis is linked to poor outcomes.¹³

Conclusion

About 90% of patients received a confirmatory diagnosis after 3 months of symptom onset, with a mean delay of 6 months before presenting to a health facility for the first time and a 7-month mean delay from that initial presentation to a confirmatory diagnosis. A delay of more than 3 months from the onset of symptoms to diagnosis (in 90% of patients) was influenced by factors such as education level, age, disease stage, and the presence of pain and swelling.

Recommendation

We recommend public education on primary malignant bone sarcomas and the importance of patients seeking early treatment at the hospital.

Regular in-service training for primary health care personnel should enhance the practitioner’s index of suspicion, facilitate prompt diagnosis, and ensure timely referral. We recommend that once a clinical diagnosis of a primary bone tumor is made or suspected, the patient should be promptly referred and seen at the secondary or tertiary facility within a week.

Limitations

This study was conducted in a single center which may not represent the entirety of the duration it takes for a patient to obtain a confirmatory diagnosis of PBMTs in Africa. However, this may serve as the basis for a large-scale multicenter study.

Acknowledgments

We sincerely thank all the staff of the Trauma and Orthopedic Department at Tamale Teaching Hospital for their ongoing support.

Ethical Approval

Permission was obtained from the department of research and development of the Tamale Teaching Hospital to retrieve and analyze data retrospectively from the hospitals bone tumour data registry. Permission was granted with reference number TTH/R&D/SR/24/321.

Informed Consent

Deidentified data was retrieved from the bone tumour registry of the hospital. Informed consent was obtained from each patient at the time of presentation and surgical intervention before data entered the tumour registry. Thus, an informed consent waiver was obtained before retrieval of data retrospectively. The study adhered to the principles of Helsinki declaration.

Data Availability

Deidentified data is available on request

Conflict of Interest

None

Funding

None