Background
Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy. It is the fourth leading cause of cancer death with a 7% five-year survival rate in the United States [
1], and is predicted to be the second cause of cancer-related death by 2030 [
2]. The mean age of PDAC patients at presentation is 71 years [
3]; however, 5–10% of these patients are diagnosed with this malignancy at a young age, when they are less than 50 years old [
4‐
7]. This important subgroup of PDAC patients, often referred to as early onset pancreatic cancer (EOPC), has been poorly studied, and the cause of such an early presentation of the disease remains unknown [
6,
8‐
14].
PDAC is considered to be more frequent in individuals with familial history [
15‐
18] and hereditary genetic syndromes, such as Hereditary Pancreatitis (HP) [
19‐
21], Lynch syndrome [
22] and Peutz-Jeghers syndrome [
23,
24]. Modifiable risk factors include tobacco exposure, alcohol use, chronic pancreatitis, diabetes mellitus, diet, obesity, previous radiotherapy, as well as certain types of abdominal surgery and infections [
25‐
33]. Also, an inverse association between PDAC and atopic diseases has been identified [
34].
In this report, we provide the data of a comprehensive and systematic study on demographics and known PDAC risk factors, as well as detailed clinicopathological, treatment and outcome figures for EOPC patients. The study comprised retrospective examination of notes on PDAC patients collected over the 11-year period between September 2004 and September 2015, from one of the major Hepato-Pancreato-Biliary (HPB) referral hospital centres in London, UK. We compared these data to the data collected for the older PDAC patients from the same centre in order to identify differences and potentially suggest clues to the biology of the disease.
Discussion
In this study, we performed a detailed retrospective analysis of EOPC patients with histologically confirmed PDAC in the setting of one of the largest HPB centres in the United Kingdom. While previous EOPC reports also included patients with pathological “variants” (e.g. mucinous cystic neoplasms) which are not included in the current WHO classification of pancreatic ductal adenocarcinoma, our report is based on the most recent PDAC classification and staging. We have used 50 years as the cut-off age for EOPC patients, which, although arbitrary, has been used previously [
4‐
7]. A detailed summary of comparisons between different EOPC studies is shown in Table
5. The main differences between the two PDAC groups were seen in demographic data. EOPC patients in our population were more frequently males, in agreement with previous studies [
5‐
7,
12,
13,
36,
37]. In addition, our EOPC patients were less frequently of white British background and more commonly Asian or from ‘any other white background’. The latter comprised mainly Central and Eastern Europeans. Similar findings were reported by Raimondi et al. who demonstrated in a worldwide study a higher number of male than female patients and a peak in Central and Eastern European countries followed very closely by Asian countries [
28]. The association of gender and race/ethnic group with incidence of pancreatic cancer has also been documented in a US report conducted by the National Cancer Institute, where the authors showed the higher incidence and mortality rate in men than in women in each racial/ethnic group, between the age of 30 and 54 [
38]. Miller et al., showed up to 50% higher incidence and mortality rate in the black compared to the white population, for the same age group (30–54 years) [
38].
Table 5
Comprehensive comparison of 14 studies on EOPC, including our study (first column)
|
Ntala C 2018, RLH, UK
| Piciucchi M 2016, Italy [ 7] | Tingstedt B 2011, Sweden [ 5] | Luttges J 2003, Germany [ 8] | Bergmann F 2006, Germany [ 9] | | |
Length of the study in years | 11y (2004–2015) | 7y (2006–2013) | 15y (1993–2008) | 26y (1973–1999) | 2006 | 13y (1995–2008) | 34y (1975–2009) |
DEMOGRAPHIC |
No. EOPC (%) | 35 (9.5%) | 25 (8.5%) | 33 (5.7%) | 10 (2.3%) | 7 cases | 136 (4.4%) | 75 (7.9%) |
Age included in study (range) | ≤50y (33–50) | ≤50y | ≤50y (30–50) | ≤39 (10-39y) | ≤40y (35–40) | ≤45y (20–45) | ≤45y (31–45) |
Male | 71% (p = 0.043) | 68.0% | 61.0% (p = 0.02) | 100.0% | 0 | 54.0% | 56.0% |
White | 37% (p = 0.002) | | | | | | 89.0% |
Black | 9.0% | | | | | | 4.0% |
Other | 31.0% | | | | | | 7.0% |
RISK FACTORS |
Smokers | 31.0% | 56%* (p = 0.001) | 73.0% | | 71.4% | 37.0% | 37.0% |
Use of alcohol | 26.0% | 36.0% | 21.0% | | | | |
Obesity (BMI > 30) | 6.0% | mean BMI = 27 | 9.0% | | | | |
History of CP | 14.0% | 0.0% | 12.0% | | 14.3% | 13.0% | |
History of diabetes | 23.0% | 4.0% (p = 0.00001) | 3.0% | | | | |
Family history of cancer (1st degree relative) | 11.4% | 48.0% | | | 71.4% | 5.1% | |
Family history of pancreatic cancer (1st degree relative) | 0.0% | 8.0% | 3.0% | | 0 | 2.2% | |
SYMPTOMS AT PRESENTATION |
New onset diabetes | 6.0% | 4.0% | 21.0% | | | | |
Weight loss | 54.3% | 52.0% | 55.0% | | | | 33.0% |
Jaundice | 62.8% | 16.0% (p = 0.006) | 61.0% | | | | 45.0% |
Abdominal pain | 45.7% | 68.0% (p = 0.06) | 91.0% (p = 0.001^) | | | | 32.0% (p = 0.06) |
PATHOLOGY |
Location-Head | 77.0% | 64.0% (p = 0.03) | 79.0% | | 71.40% | | |
Location-Body | (B + T) 23% | | 12.0% | | | | |
Location-Tail | | | 9.0% | | 28.60% | | |
G1 - Well differentiated | 5.7% | | 20.0% | 10.0% | 57.2% | | |
G2 - Moderately differentiated | 45.7% | | 45.0% | 45% | 42.8% | | |
G3 - Poorly differentiated | 34.3% | 61.0% | 25.0% | 14% | | | |
Perineural invasion | 34.3% | | | | | | 64.0% |
Localised/Resectable | 22.9% (p = 0.015) | 16.0% | 18.0% | | | 25.7% | 32.0% |
Locally advanced | 54.0% | 36.0% | 27.0% (p = 0.005) | | | 20.1% | 68.0% |
Metastatic | 22.9% | 48.0% | 52.0% (p = 0.001) | | 14.3% | 50.0% | |
TREATMENT |
Resected cases | 22.9% (p = 0.015) | 16.0% | 27.0% (p = 0.01) | | 71.4% | 25.7% | (R0) 69.0% |
Palliative chemo/radiotherapy | 60.0% (p = 0.008) | 48.0% (p = 0.003) | 45.0%/36.0% (p = ns/0.002) | | 28.6% | | |
Supportive treatment | 17.1% | | | | | | |
SURVIVAL (months) |
Median OS | 12 | 11 | 5.7 | | | 12.3 | 19 |
Median OS (resectable cases) | 25 | | | | | 41.8 | |
Stage associated survival (%; (OS, months)) |
Stage I + II | 22.8% (25) | | | | | 25.7% (41.8) (p = 0.0001) | I + IIA:32% (27) |
Stage III | 54.3% (11) | 36.0% (11) | | | | 20% (15.3) | IIB + III;68% (16) |
Stage IV | 17.1% (6) | 48.0% (7) | | | | 50% (7.2) | |
Survival rate |
1 year survival rate |
5 years survival rate | | | | | | 3.3% | 24.00% |
10 years survival rate | | | | | | | 17.00% |
5 years survival rate I-IIA | | | | | | | 42.00% |
5 years survival rate IIB-III | | | | | | | 16.00% |
| Beeghly-Fadiel A 2016, USA [ 6] | McWilliams RR 2017, USA [ 14] | Ohmoto A 2017, Japan [ 37] | Jiang Q-L 2017, China [ 13] | | Soliman AS 2002, Egypt [ 41] | Raissouni S 2012, Morocco [ 36] |
Length of the study in years | 25y (1988–2013) | 11y (2000–2011) | 11y (2002–2013) | 16y (1999–2014) | 19y (1990–2009) | 5y (1995–2000) | 5y (2005–2010) |
DEMOGRAPHIC |
No. EOPC (%) | 118 (8.4%) | 226 (11.5%) | 17 (1.87%) | 156 (8.7%) | 25 (10.2%) | 165 (22.6%) | 32 (17%) |
Age included in study (range) | ≤49y | ≤44y | ≤40y (21–40) | ≤45y (17–45) | ≤49y | ≤50y | ≤45y (28–45) |
Male | 60.2% | 54.0% | 64.7% | 75% (p = 0.006) | | | 65.0% |
White | 86.3% | | | | | | |
Black | 11.10% | | | | | | |
Other | 2.60% | | | | | | |
RISK FACTORS |
Smokers | | 35% and 6%§ | 58.8% | 34.6% (p = 0.024) | 44.0% | | 12.5% |
Use of alcohol | | 11%† | | 35.3% | 32.0% | | |
Obesity (BMI > 30) | | 19% | | (BMI ≥ 28) 16.7% | | | |
History of CP | | 1.0% | | | 16.0% | | |
History of diabetes | | 3.0% | | 11.5% | 4.0% | | 6.0% |
Family history of cancer (1st degree relative) | | | 29.4% | 17.3% | | | |
Family history of pancreatic cancer (1st degree relative) | 17.5% | 8.0% | 5.8% | 3.8% | 8.0% | | |
SYMPTOMS AT PRESENTATION |
New onset diabetes | | | | 11.5% | 4.0% | | |
Weight loss | | | | 46.2% | 48.0% | | 43.0% |
Jaundice | | | | 18.9% | 52.0% | | 68.0% |
Abdominal pain | | | | 62.1% | 72.0% | | 87.5% |
PATHOLOGY |
Location-Head | 67.0% | | 52.90% | 69.90% | | | 75.0% |
Location-Body | 12.3% | | (B + T) 47.1% | (B + T) 30% | | | 12.5% |
Location-Tail | 12.3% | | | | | | 12.5% |
G1 - Well differentiated | | | | 3.8%% | | | |
G2 - Moderately differentiated | | | | 14.7%% | | | |
G3 - Poorly differentiated | | | | 26.3%% | | | |
Perineural invasion | | | | | | | |
Localised/Resectable | 40.0% | | | 28.8% | 40.0% | | 18.7% |
Locally advanced | 16.0% | | | 34.0% | | | 21.8% |
Metastatic | 44.0% | | | 37.2% | 52.0% | | 59.3% |
TREATMENT |
Resected cases | 23.3% | | 23.20% | 20.5% | 40.0% | 33.1% | 18.7% |
Palliative chemo/radiotherapy | 38.9% | | 70% | 47.4% | | 30.7% | 26.2% |
Supportive treatment | 37.9% | | | | | 14.6% | 37.5% |
SURVIVAL (months) |
Median OS | 9.3 (p = 0.045) | | 6.7 | 8 | 5.6 | | 6.6 |
Median OS in resectable | | | 19.6 | 19 | 10.3 | | 32 |
Stage associated survival (%; (OS, months)) |
Stage I + II | 6% + 34% | | 23.2% (19.6) | 9% (19) | | | 18.8% (32) |
Stage III | 16.0% | | 23.5% (18.2) | 53.8% (9) | | | 21.8% (7.9) |
Stage IV | 44.0% | | 52.9% (5) | 37.2% (5) | | | 59% (6.4) |
Survival rate |
1 year survival rate | | | 37.5% | | 28% (40% in resected cases) | | |
5 years survival rate | | | | | 4% (10% in resected cases) | | |
10 years survival rate |
5 years survival rate I-IIA |
5 years survival rate IIB-III |
One of the putative explanations for the higher incidence of EOPC in males is smoking, a known independent risk factor for pancreatic cancer in all age groups [
3,
7,
28,
30,
39,
40]. Indirect association of EOPC and smoking in males was first highlighted by Raimondi et al. who correlated the higher EOPC male/female ratio positively with an early onset of lung cancer (< 50 years of age) [
28]. Direct association was provided by Piciucchi et al. [
7], who, based on patient interviews, demonstrated a significantly increased risk of EOPC among the ‘current smokers’ group and a positive correlation with the ‘young age at smoking initiation’ [
7]. In our cohort, however, only 31% of the total EOPC population had a smoking history which was comparable to the older PDAC cases (29%).
Interestingly, the highest incidence of EOPC patients was reported in two independent studies conducted in North Africa, in Morocco [
36] and Egypt [
41]: 17% of PDAC patients were younger than 45 years in Morocco [
36], and almost 25% in the East Nile Delta were under the age of 50 [
41]. In both countries the male to female ratio was around 2:1, in accordance with other reports. Regarding smoking, in the Moroccan population only 12.5% of all EOPC patients were smokers [
36]. In contrast, in Egypt smoking is highly prevalent (40% of the general population are smokers). While the authors do not report the smoking history of the EOPC patients, they speculate that occupational and environmental exposure to heavy metals like cadmium, nickel and chromium, as well as other polluting chemicals, could contribute to the high incidence of EOPC in this heavily industrialised region [
41]. Unfortunately, we do not have any information on environmental exposure of our study population, and the effect of pollution on our London-based patients would be interesting to explore.
Our study did not identify any differences between EOPC and older PDAC patients in any of the previously identified risk factors for PDAC, i.e. alcohol intake, obesity, history of chronic pancreatitis, history of diabetes, previous abdominal surgery and previous radiotherapy. The rate of recent onset diabetes was somewhat lower in EOPC (6% EOPC vs 12% PDAC, p = 0.299) although this was not statistically significant.
None of the patients in our EOPC cohort met the criteria for a familial pancreatic cancer syndrome [
42]. Four of the EOPC patients in our cohort had a family history of any cancer but none had a first-degree relative with pancreatic cancer, and only one patient had a hereditary genetic syndrome (Lynch Syndrome) associated with increased risk of pancreatic cancer [
22]. A similarly low incidence of familial cases, with no significant difference between young and old PDAC groups, has been reported in other studies. In the cohort described by Duffy et al. [
10], only 2.2% of EOPC patients had a family history of pancreatic cancer and no EOPC patients were affected by any of the hereditary syndromes. Tingstedt et al. [
5] reported 3% of EOPC with a first-degree relative with pancreatic cancer. However, somewhat higher incidences were found by Piciucchi et al. [
7] in both young and older patients, where 8% and 6.3% of cases respectively had a family history of pancreatic cancer. A recent study by Ohmoto et al. [
37] suggests a lack of association between hereditary genetic factors and EOPC. The authors assessed the mutation status of 49 genes involved in hereditary syndromes in the germline of EOPC patients younger than 40 years, but did not find any variants [
37]. In contrast, James et al. [
17] reported an overall incidence of familial pancreatic cancer of 3%, with the percentage of patients ≤50 years of age being significantly higher than among the sporadic cancer patients (36% and 18.3%, respectively,
p = 0.017). Overall, the underlying factors influencing the young onset of pancreatic cancers remain to be determined.
In our study, the presenting symptoms (obstructive jaundice, abdominal pain, and change in bowel habit, nausea /vomiting, anorexia or weight loss) were largely shared between the two cohorts, and both young and old PDAC patients most commonly presented with obstructive jaundice, probably due to a high incidence of lesions located in the pancreatic head. Interestingly, in a study by Piciucchi et al. [
7], jaundice at presentation occurred in only 16% of the EOPC patients, a significantly lower rate than in older PDAC patients (44%,
p = 0.06) [
7]. This was probably due to a lower rate of tumours located in the head of the pancreas (64% vs 83%,
p = 0.03). Jiang et al. [
13] also reported a low frequency of jaundice in EOPC patients, although this could not be explained by tumour location.
The two groups also showed similar pathological characteristics. Poorly differentiated tumours tended to be more common in older PDAC patients (34% vs 51%) and moderately differentiated in EOPC (46% vs 38%), but this was not statistically significant. Furthermore, no difference was observed in the rates of perineural and vascular invasion. Other studies have also showed that the pathological features in EOPC patients are similar to those seen in older PDAC patients, [
8,
9] although the presence of more histological variants, especially mucinous carcinomas, has been observed in EOPC cases [
8]. Interestingly, a lower rate of KRAS mutations in EOPC patients was found in two studies, [
9,
43], although both were performed on a small number of cases (five and seven, respectively).
In our data, EOPC patients presented at a more advanced stage compared to older PDAC group (77% vs 56%,
p = 0.015) but they were more frequently fit for adjuvant or palliative treatment (60% vs 46%,
p = 0.008). While the overall survival of EOPC was similar to older PDAC patients with no statistically significant difference, EOPC patients who underwent surgical resection had a longer median overall survival of 25 months compared to 13 months for the same PDAC subpopulation. A similar finding has been observed in previous studies, with the highest survival of 41.8 months for resected cases reported by Duffy et al. [
10] which has been attributed to young people having fewer comorbidities and being more suitable candidates for surgery and adjuvant chemotherapy [
10,
12,
13,
36,
37]. Furthermore, He et al. also showed that EOPC patients had fewer post-operative complications [
12] and McWilliams et al., [
14] attributed the better survival rate among young people to a multitude of factors, including race, sex, year of diagnosis, stage of disease, tumour location and treatment [
14].
Our study adds to a growing body of literature on the demographic and clinicopathological characteristics of EOPC patients, using contemporary classification and staging manuals. There are some limitations to our study: firstly, the disproportionate sample size of the two comparison groups, EOPC and older PDAC, although reflecting the general incidence of the disease and unavoidable, may have contributed to statistical errors in our analysis. In addition, the retrospective nature of the study has its own pitfalls, which include possible omission of patients that did not have a tissue diagnosis, and review of medical records with sometimes incomplete data. Finally, the study was conducted in a single tertiary expert centre with referred cases and may over-represent the patients that were suitable to undergo tissue biopsy prior to receiving more aggressive treatment. Enlarging the data set through a multi-centre collaborative approach might produce more robust results.