Introduction

Cancer of unknown primary site (CUP) is the 14^th most commonly diagnosed cancer and the 6^th most common cause of cancer death in Australia.[1] It is characterized by metastatic disease with an unidentified primary site, and extremely poor survival;[2–5] in Australia, the 5-year survival rate is 13%.[6] Population-based CUP incidence rates have declined over time,[2,6,7] a trend that can most likely be attributed to advances in diagnostic investigations. While a diagnosis of CUP ideally should be limited to people with a histological confirmation of metastatic cancer, in whom thorough testing has failed to identify the site of the primary tumor, people registered with a diagnosis of CUP in population-based cancer registries are heterogeneous, with many people receiving a diagnosis based on clinical examination only.[4,5,8–11] Thus, it is difficult to compare population-based studies of registry-notified CUP to cases series of “true CUP” cases, who have received exhaustive investigations.

Studies of how people diagnosed with CUP interact with the health system prior to their definitive diagnosis, and what investigations they receive, are limited.[8,12] Although there are no Australian CUP clinical practice guidelines, the US National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) CUP-specific guidelines support the judicious use of diagnostic investigations, in keeping with a patient’s prognosis and treatment options.[13,14] Yet, the diagnostic pathway of patients with a cancer-registry notified CUP diagnosis is highly variable,[8,15,16] which may reflect heterogeneity in clinical presentation and patient characteristics.

Previous studies suggest that the diagnostic pathway for people with CUP differs compared to people diagnosed with other cancers, including late-stage cancers of known primary site.[8] CUP appears more likely to be diagnosed following an emergency department visit compared with all other cancers, and diagnosis may involve less specialist input and fewer invasive diagnostic procedures, including histopathological diagnosis of cancer.[8,15] In this prospective Australian cohort study, we sought to compare the pathway to diagnosis for people diagnosed with a cancer-registry CUP diagnosis, compared with people diagnosed with metastatic cancer of known primary site.

Materials and methods

Results

We identified 327 incident cases of CUP and 977 matched incident solid metastatic cancer controls, diagnosed between 2006 and 2012. The median age at diagnosis of CUP was 76 years (interquartile range, IQR: 66–82 years) and 68 years (IQR: 60–76 years) for solid metastatic cancer controls. The median time from completion of the baseline questionnaire to cancer diagnosis was 33 months (IQR: 21–46 months). Of the people with a registry-notified CUP diagnosis, 165 (50.5%) had a histopathogical diagnosis, 49 (15.0%) a cytological diagnosis (including fine needle aspiration, smears, washing and sputum), 88 (26.9%) a clinical diagnosis (including clinical, imaging and biochemical procedures) and 25 (7.6%) were identified by death certificate only. Of the CUP cases (n = 165) registered with a NSW Cancer Registry histopathological diagnosis, 20 (12.1%) tumors were carcinoma (subtype not specified), 81 (49.1%) were carcinoma (subtype specified), 50 (30.3%) were adenocarcinoma, and 14 (8.5%) were other morphological types. Of the 870 people with metastatic cancer of known primary with a histopathological diagnosis, 407 (46.8%) tumors were carcinoma, 395 (45.4%) were adenocarcinoma, and 68 (7.8%) were other. The most common primary sites for the solid metastatic cancer controls were breast (C50; n = 168), bronchus and lung (C34; n = 163), colon (C18; n = 152), prostate (C61; n = 123) and rectum (C20; n = 57).

In the month of diagnosis and the three months prior, people with a cancer-registry notified CUP diagnosis were more likely to have an ED visit (odds ratio, OR = 1.84, 95% confidence interval, CI 1.41–2.40) and less likely to have a specialist consultation (OR = 0.66, 95%CI 0.48–0.92), compared to solid metastatic cancer controls (Table 1) in models adjusted for age and sex only. During this period there was no difference between the two metastatic cancer groups in terms of hospitalisation or consultations with a GP, allied health practitioner, nurse, or specialist indicating complex care. People diagnosed with CUP were more than 3-fold more likely to be in aged care (OR = 3.42, 95%CI 1.78–6.56). We found people diagnosed with CUP were less likely than controls to have an endoscopy, a surgical (non-cutaneous) resection, and histopathology (Table 2). Conversely, they were more likely to have serum tumor marker tests and cytology. Overall, 21 (6.4%) people diagnosed with CUP did not have any cancer-related investigations, as defined by imaging procedures, endoscopy, medical procedures (e.g. resection), or pathology tests. Among controls, 60 (6.1%) did not have any cancer-related investigations.

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Table 1. Association between recent health service use and diagnosis of CUP compared to metastatic cancer of known primary.

https://doi.org/10.1371/journal.pone.0230373.t001

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Table 2. Association between recent cancer-related diagnostic tests and procedures and diagnosis of CUP compared to metastatic cancer of known primary.

https://doi.org/10.1371/journal.pone.0230373.t002

In our fully adjusted model, the only confounding factors were age and educational attainment, with those diagnosed with CUP more likely to be older and to have no school certificate (less than 4 years of secondary education) (Table 3).[18] After adjustment for these factors, and the mutual adjustment for health service use, diagnostic tests and procedures, the only variables that remained associated with an increased probability of a CUP diagnosis were being in an aged care facility (OR = 2.78, 95%CI 1.37–5.63), ≥1 ED visit (OR = 1.65, 95%CI 1.23–2.21), and the following pathology tests: serum tumor marker tests (OR = 1.51, 95%CI 1.12–2.04), and cytology without immunohistochemistry (OR = 2.01, 95%CI 1.47–2.76). People diagnosed with CUP were less than half as likely to have had a histopathology test without immunohistochemistry (OR = 0.43, 95%CI 0.31–0.59).

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Table 3. Association between recent health service use, cancer-related diagnostic tests and procedures, and diagnosis of CUP compared to metastatic cancer of known primary.

https://doi.org/10.1371/journal.pone.0230373.t003

Discussion

In a contemporary cohort of Australian adults, we observed differences in the pathways to diagnosis for people with a cancer-registry notified CUP diagnosis compared with people notified with metastatic cancer of known origin. People with CUP were more likely to be in aged care, and their pathway to diagnosis was more likely to involve an emergency presentation and the use of less invasive diagnostic tests. Many ED visits in people with cancer are avoidable;[22] however, the use of less invasive diagnostic tests, for example imaging and fine needle aspiration, may be appropriate for people who are frail (including many aged care residents [23]), or those with a poor prognosis, and this diagnostic pathway is supported by clinical guidelines for CUP [14,21].

This is one of the first studies to identify an increased risk of a CUP diagnosis in aged care residents.[8] Very few cohort studies have examined the association between aged care residency and cancer diagnosis as this information is not typically available at the population-level. A US cancer-registry study of women insured by Medicaid observed a 2.5-fold excess risk of late breast cancer diagnosis in women who were nursing home residents or were in a long-term care facility.[24] A more recent US study[25] found that very few Medicaid-insured nursing home patients received cancer services, and they exhibited a high prevalence of late or unstaged common cancers. While these studies may not be generalizable to the Australian context, it is known that on average, aged care residents are likely to be frail with potentially complex multimorbidity and health care needs. In addition, they may not have close family members to advocate on their behalf regarding changes in their health status. Frail patients may not tolerate cancer treatment due to the increased risk of toxicity and mortality [26], decreasing the need for comprehensive testing to identify the tissue of origin. Late diagnosis may not necessarily be a marker of inadequate care in this setting, as it is possible that functional impairment, care dependency, prognosis, and patient preferences were taken into account when considering the most appropriate diagnostic management of people with metastatic cancer of unknown origin, in keeping with clinical guidelines[13,21].

Confirming previous studies, we found that people with a cancer-registry CUP diagnosis were nearly twice as likely to have had an ED visit in the time period immediately preceding diagnosis, compared to people diagnosed with metastatic cancer of known primary. In our study, 53% of people diagnosed with CUP had a recent ED visit, which is similar to previous Australian studies (50–57%)[8,27] and a UK study of a national cancer registry (57%).[28] Cancer diagnosis via ED presentation is considered a marker for late or delayed diagnosis, and is generally associated with older age, greater deprivation, less access to health services, and poorer prognosis.[29–31] However, the reasons for presentation via ED are complex and many patients also have significant interaction with the health care system prior to their ED presentation, which may represent lost opportunities for diagnosis in individuals with good quality of life and life expectancy who are most likely to benefit from treatment.[31]

While the reasons for ED presentation in people diagnosed with CUP are not known to us, the non-specific and variable nature of CUP symptoms may lead to delayed diagnosis, even in patients who regularly interact with the health care system. As such, we saw no difference between CUP and metastatic cancer of known origin in terms of household income, rural residential location, hospitalisations, GP visits, or allied health visits in this cohort. Although this replicates our previous findings in a veterans cohort,[8] we acknowledge that both studies had limited statistical power, and suggest these associations deserve further scrutiny in large, well-annotated cohorts. It is important to understand the reasons for ED presentation prior to diagnosis, and whether there were missed opportunities for earlier diagnosis, specifically through earlier presentation to a GP, and identification of symptoms suggestive of cancer, leading to suitable investigations.

Only a small proportion of cases and controls had no cancer-related investigations (6%); however, the types of investigations between the two groups differed. People diagnosed with CUP had a greater use of less invasive tests such as serum tumor markers and cytology, and less use of histopathology, compared to controls. While the former are less invasive, the routine use of non-specific serum tumor markers is not recommended for patients with suspected cancer because they can be overexpressed in some people without cancer.[13,32] While histopathology is considered part of the diagnostic approach to identify the primary tumor in CUP patients,[32] only 50% of registered CUP cases in our study were histopathologically verified. This is lower than observed in other population-based studies of CUP[2,7,11,15,33] but higher than our previous study in Australian veterans (36%).[8,15] CUP is a heterogeneous diagnosis, and encompasses individuals who may have undergone exhaustive investigation but a primary site cannot be identified (i.e. people with “true CUP”), and also individuals with a clinical diagnosis only, for whom invasive tests are neither warranted nor desired.[13] In a 2019 US study, only 35% of elderly people with CUP received guideline recommended diagnostic evaluation.[33] Patients with a clinical diagnosis only tend to be older, and have poorer outcomes.[7,8] Unfortunately, we are unable to determine whether the diagnostic approach was clinically appropriate; however, it is recommended that investigations considered to have no impact on prognosis should be avoided.

The strength of this study is the comprehensiveness and quality of the data for a large, prospective cohort; incident cancers and deaths were ascertained by high-quality population-based registries, and we had near complete capture of all subsidized health service interactions for our population, including community-based consultations and tertiary care, diagnostic tests and procedures, as well as information on aged care. This allowed us to construct a comprehensive picture of people’s health service use prior to cancer diagnosis. While our sample size is one of the largest population-based studies of people with CUP[8,9], it is modest. As a result, we may have had insufficient power to detect an association with some health services, and where we did, the confidence intervals are wide. While 45 and Up Study participants are healthier on average than the general population, relative estimates calculated from within-cohort comparisons are valid.[34,35] Two data issues are also unlikely to have affected our within-cohort comparisons; firstly, the ED data mainly captured visits to metropolitan and large regional public hospitals (72% and 88% of ED presentations in NSW, respectively).[36,37] Secondly, some pathology services will be under-ascertained as MBS claims data only capture the three most expensive pathology items in an episode of care performed by a GP.[38]

People diagnosed with CUP represent people for whom the primary site could not be identified despite exhaustive testing, as well as those who received minimal diagnostic evaluation; unfortunately we could not distinguish these two groups based on the cancer registry data alone. Ideally, such distinct groups would receive distinguishable diagnoses, but this is not the case. Given the improvement in diagnostics over time, it is likely that the prevalence of “true CUP” will decrease, with most people diagnosed with CUP representing those who did not receive all clinically-indicated tests, and it is important that these people are not ignored in cancer research. Finally, we have made the assumption that the identified procedures and tests were diagnostic for cancer, but some procedures, particularly non-specific tests such as endoscopy and ultrasound, may have been performed for other reasons. Importantly, we could not directly measure frailty in our study. Frailty plays a role in health decisions and outcome, yet is a concept that is difficult to capture in administrative claims data; while many studies have tried they each have their limitations.[39,40] Our findings support the need for further research to elucidate the relationship between frailty, health service utilisation, and CUP diagnosis.

Conclusions

We have shown that people with a cancer-registry notified CUP diagnosis had a different pathway to diagnosis than patients with metastatic cancer of known primary. People diagnosed with CUP were more likely to be aged care residents, to have had an ED presentation immediately prior to diagnosis, and to have received fewer invasive tests. Interestingly, despite CUP patients having poorer self-reported overall health,[18] the two groups exhibited no difference in the likelihood of having at least one hospitalisation or consultation during the month of diagnosis and three months prior. Further research is required to examine whether these results indicate missed opportunities in CUP patients for earlier detection and diagnostic testing to reveal the tissue of origin, or conversely represent clinically appropriate differences in management based on patients’ underlying health and life expectancy.

Acknowledgments

We thank the 45 and Up Study, the Department of Human Services (DHS), the NSW Ministry of Health and the NSW Cancer Registry for providing the data used for this study. This research was completed using data collected through the 45 and Up Study (www.saxinstitute.org.au). The 45 and Up Study is managed by the Sax Institute in collaboration with major partner Cancer Council NSW; and partners: the National Heart Foundation of Australia (NSW Division); NSW Ministry of Health; NSW Government Family & Community Services—Ageing, Carers and the Disability Council NSW; and the Australian Red Cross Blood Service. We thank the many thousands of people participating in the 45 and Up Study.