Cancers of unknown primary diagnosed during hospitalization: a population-based study

Cancers of unknown primary (CUP) are metastatic malignancies for which a primary site has not been identified [1]. They are therefore a disparate group of cancers that present at an advanced stage. The incidence of CUP has risen and then fallen over the past 50 years, [2‐5] possibly driven initially by greater diagnostic sensitivity detecting more metastatic disease and then latterly by better identification of the primary site reducing the number of unknown primaries. Worldwide, CUP are the 6^th to 8^th most common cancers, accounting for 2.3–5% of all cancer diagnoses but the 3^rd to 4^th most common cause of death from cancer [6, 7]. They comprised 3.2% of all invasive cancers in Scotland between 2001 and 2010 [7]. They were responsible for 7% of United Kingdom (UK) cancer deaths in 2009 [8]. Survival is poor, with a median of 5.6 weeks [7]. Survival is more favourable among patients whose disease mimics clinicopathological features of known metastatic cancers and responds to appropriate treatment (median survival 24 months) but the majority of patients (80–85%) respond poorly to treatment [6].

In the United Kingdom, The National Institute for Health and Care Excellence (NICE) issued a guideline on CUP in 2010 [1]. Its recommendations included that every hospital with a cancer centre should have a dedicated CUP team and that investigations and management be the responsibility of that team. The guideline is currently on NICE’s static list, indicating that no new evidence has become available. The European Society for Medical Oncology (ESMO) issued clinical practice guidelines the following year, emphasising the need to identify those patients with more favourable prognoses so that they might benefit if directed to appropriate multidisciplinary care [9]. The National Cancer Intelligence Network reported on routes to diagnosis of CUP between 2006 and 2010 [10]. They reported that diagnoses were 20% higher among females, nearly 40% were over 80 years old and 57% were diagnosed after an emergency hospital admission. However, there is a paucity of evidence on patterns of hospital care for patients with CUP and therefore on the capacity to better identify patients so that they might be directed to specialist teams.

In order to inform the care of patients diagnosed with CUP during hospital admission, we carried out a descriptive study of all patients diagnosed over the most recent 14-year period for which data were available, using cancer registry data individually linked to hospital and death records.

7,599 diagnoses of CUP were made in the West of Scotland between 1998 and 2011. Table 1 summarises the demographics, ICD-10 site and morphology classifications of these diagnoses. Median age at incidence was 73 years in males and 77 years in females. Patients aged over 70 years accounted for 67.4% of incident cases. The crude rate of diagnoses averaged 18.14 per 100,000 persons between 2008 & 2010.

A socioeconomic gradient was present, with 36.7% of cases from the most deprived SIMD quintile versus 11.4% of cases from the least deprived quintile. The most common ICD-10 site codes were C78 (secondary malignant neoplasm of respiratory and digestive organs) at 44.6% and C80 (malignant neoplasm, without specification of site) at 33.3%.

Not otherwise specified (NOS) morphology accounted for 67% of all incidences, adenocarcinomas for 24.8%, SCC for 4.3% and all others 3.8%. Morphology varied by age. Increasing age was associated with increased NOS morphology, comprising 82.2% in patients aged 80 years and older (Χ ² = 706, df = 9, p <0.001). SCC, adenocarcinoma and other morphologies had greatest proportions in under-60 year-olds, their proportions decreasing with ascending age.

In a large population-based series of patients with Cancers of Unknown Primary, we found that the majority were diagnosed during a hospital admission, half of whom died during that admission. Survival after admission was short, being a median of 33 days and poorer in emergency compared to elective admissions. Median age was 75 years.

Survival in our study was less than the median 2–3 months reported by others [2‐5, 10]. This may reflect that patients in our study were diagnosed during a hospital admission and may therefore have more advanced CUP or other morbidities requiring admission. We also found that a considerably smaller proportion of patients survived 5 years compared with others’ observations [2‐5]. Long-term survivors are considered as belonging to a favourable prognostic subset, who respond to treatment for a primary cancer that CUP appears to mimic [6]. Research into treatment regimens is increasing for patients in both unfavourable and favourable prognostic subsets; the ability to identify those most likely to benefit from these treatments is important. Despite this, those in the unfavourable prognostic subset have limited treatment options, realistic aims being modest prolongation of life and symptom relief [9].

Younger patients who were admitted electively have the best survival from CUP. This is consistent with demographic prognostic indicators noted previously. This raises questions of whether physiological or pathological processes can explain the development of CUP; newer genetic profiling and imaging techniques are being used to try to clarify the underlying physiological and pathological processes in CUP development. Inequity regarding treatment by sex, age and deprivation is unlikely as currently there are no proven treatments for patients belonging to the unfavourable prognostic subset.

The increased risk of death in patients admitted to geriatric medicine in multivariate analysis despite adjustment for factors including age, sex, admission type and CUP site and morphology codes is interesting and the underlying reasons have not been determined. These patients may be more frail or have multiple comorbidities. It is unlikely that their increased risk of death is due to treatment because, as previously discussed, currently treatment options are limited and unlikely to significantly improve survival. We found that survival appeared better for ICD-10 C77 and “other” morphologies. It is probable that some lymph node metastases (C77) will represent regional rather than distant spread which may explain their better survival on average. Further research may be possible to better understand whether particular morphological “other” groups are associated with better survival but numbers may be small. We found that the morphology was coded as cancer “not otherwise specified” (NOS) in 67% of all CUP incidences. We anticipate that this was most commonly because biopsy and microscopic assessment (i.e. pathological confirmation) have not been undertaken, often because this would not influence patient management and/or because of the patient’s poor performance status. In Brewster’s previous study of CUP in the Scottish population between 2001 and 2010, 58% of CUP cases were recorded as not microscopically verified [7]. We anticipate that a proportion of incidences coded as cancer NOS will have shown a poorly differentiated tumour, preventing more detailed cancer typing and sub-typing.

Given the poor outcomes of patients admitted to hospital with CUP, is there scope for better primary and secondary prevention? Current understanding of the underlying biology and pathogenesis of CUP is incomplete [13]; therefore, the possibility of detecting CUP earlier is uncertain. Unlike other cancers, for example ovarian, rather than following a type 1 progression (from a pre-malignant to malignant lesion) it may be malignant from the start – that is, type 2 progression [6, 14]. Furthermore, the heterogeneity of CUP - its occurrence at any site as a variety of histological morphologies - does not lend it to a simple and acceptable method for early detection. Heterogeneity also results in a wide range of signs and symptoms, making it a poor candidate for a public health education campaign aiming to increase awareness of potential signs and symptoms of cancer and encourage primary care consultation. An issue with this health awareness approach in patients with CUP is that late presentation is often due to the lack of symptoms until advanced stages of the disease rather than failure to present to health services amongst symptomatic patients. There is evidence of CUP clustering in families where a sibling has experienced CUP, colorectal, hepatic, breast, ovarian, lung and renal cancers; suggesting a genetic basis to development of CUP, an area for future research, which may aid earlier detection and prevention of CUP [15].

Our study has strengths and weaknesses. Its strengths include the use of high quality cancer registry data and linkage to comprehensive hospital admission and death records, making it unlikely that significant numbers of patients have been excluded from our sample. The largest weakness – which is common to the study of CUP – is that it is based on a diagnosis of exclusion rather than confirmation and thus a product of the investigations that are deemed appropriate for any individual. Further research may be possible into investigations made prior to diagnosis using Scottish Morbidity Records (hospitalisation records), which include up to four paired Office of Population Censuses and Surveys version 4 operations and procedures codes. It would also be potentially possible to study prior and concurrent co-morbidities which may influence what investigations and/or treatments might be tolerated by patients, as well as outcome.

Cancers of Unknown Primary have poor outcomes and the opportunities to better identify and manage such patients may be limited because of patients’ short survival after hospital admission. Supportive and palliative care may therefore be key contributions that specialist CUP teams can offer patients. For those patients who present with more favourable disease, however, early effective treatment is a priority. Further research on investigations prior to diagnosis may help to inform more efficient diagnostic pathways that could benefit patients in either prognostic group.