Non-ocular primary malignancies in patients with ...

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BJO Online First, published on July 15, 2015 as 10.1136/bjophthalmol-2015-306914 Clinical science

Non-ocular primary malignancies in patients with uveal melanoma: the Liverpool experience Florian M Heussen,1 Sarah E Coupland,2 Helen Kalirai,2 Bertil E Damato,3 Heinrich Heimann1 1 St Paul’s Eye Unit, Liverpool Ocular Oncology Centre, Royal Liverpool University Hospital, Liverpool, UK 2 Liverpool Ocular Oncology Research Group, Department of Cellular and Molecular Pathology, University of Liverpool, Liverpool, UK 3 Ocular Oncology Service, Departments of Ophthalmology and Radiation Oncology, University of California, San Francisco, California, USA

Correspondence to Dr Florian M Heussen, Liverpool Ocular Oncology Centre, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK; fl[email protected] Presented at the 46th OOG Meeting at ‘EVER’ in Nice, 2014. Received 23 March 2015 Revised 6 June 2015 Accepted 29 June 2015

ABSTRACT Aim To identify the prevalence of self-reported nonocular primary malignancies in patients at the time of diagnosis with uveal melanoma (UM) and to describe the cohort’s characteristics. Methods A data query for cases of UM seen at the Liverpool Ocular Oncology Centre between January 1993 and May 2014 was performed. Only patients who had UM with other non-ocular primary malignancies were included. Demographic and clinical data were analysed. Results A total of 5042 (2563 males, 50.8%) patients with UM were found in the database; of whom, 216 (4.3%) had at least one other primary non-ocular malignancy. Of these 216 patients, 119 were males (55.1%). Forty five males (37.8%) had been diagnosed with prostate cancer, 30 (25.2%) with unspecified skin cancers, 15 (12.6%) with colon and bowel carcinoma, eight (6.7%) with systemic lymphoma and the remaining patients with less common tumours. Of the 97 females, 45 (46.4%) had been diagnosed with breast carcinoma, 19 (19.6%) had unspecified skin cancers, seven (7.2%) renal cell carcinoma, six (6.2%) colon and bowel carcinoma, and the remaining patients had other less common tumour types. In this cohort, the frequency of the most common additional malignancy in male and female patients with UM was comparable with their prevalence in the general UK population. Conclusions Additional primary malignancies can occur in association with UM; therefore, medical history taking in patients with UM should always include this aspect. Apart from providing demographic and clinical data in such cases, future collaborative studies, which would include germline mutational testing, may reveal relevant common patterns.

INTRODUCTION

To cite: Heussen FM, Coupland SE, Kalirai H, et al. Br J Ophthalmol Published Online First: [please include Day Month Year] doi:10.1136/ bjophthalmol-2015-306914

Although uveal melanoma (UM) is the most common primary intraocular tumour in adults in the UK, it is a relatively rare condition with an incidence of approximately seven new cases per one million per year,1 and is greatly outnumbered by other malignancies in the general population. In the UK, the most common cancers are prostate carcinoma in men and breast carcinoma in women, followed by lung and bowel carcinoma.2–5 The improved survival of patients with many cancers over the last decades has meant that it is not uncommon for patients to present with a history of multiple primary malignancies.6–8 The management of these individuals can prove particularly challenging, and demands an individualised approach to care.9 While most cancers arise sporadically, there are also known associations between germline

mutations and an increased lifetime risk for cancer development. For example, a mutation in the BRCA1 associated protein 1 (BAP1) gene is linked to the development of UM, mesothelioma, cutaneous melanoma and renal cell carcinoma in some patients.10 11 Knowledge of these germline mutations and their associations can influence patient management, ranging from screening for early cancer detection to alteration of treatment plans and aftercare. It may also prove to be essential in addressing patient-centred concerns, for example, an increased risk for cancer development in their children or other first-degree relatives. At present, broad spectrum screening for known germline mutations is not economically feasible.12 A retrospective database audit of the Liverpool Ocular Oncology Centre (LOOC) was conducted to identify patients with UM who had an additional non-ocular malignancy in order to: (a) determine the range and frequency of these second tumour types and (b) to establish if any particular patterns in this patient cohort were apparent, and potentially providing information for patient selection for more detailed genetic analyses, including various germline mutations, in future studies.

MATERIALS AND METHODS A database query of all patients with UM who were examined and treated at the LOOC at the Royal Liverpool and Broadgreen University Hospital Trust between 7 January 1993 and 19 May 2014 was performed. LOOC receives referrals from across the UK, and is not geographically limited to the cases seen. This may be due to the fact that differing services are offered at the four centres in the UK, and that Liverpool, in particular, has access to the proton beam facility, conducts local tumour resection and offers prognostication for consented patients with UM. The LOOC database is based on the medical information recorded in the notes during the first consultation with the patient at the LOOC. As such, information about other systemic conditions is self-reported by the patient. Patients within the database were identified by the Hospital numbers. Clinical and demographic data were collected, including gender, diagnosis, date of first visit to LOOC, treatment, follow-up and other systemic conditions. Information also included date and cause of death, where applicable. Patients with multiple primary non-ocular malignancies were then identified, and additional information, including age, pathology report details as well as UM genetic data, was also collected as available. During this time period, the UM were analysed for

Heussen FM, et al. Br J Ophthalmol 2015;0:1–4. doi:10.1136/bjophthalmol-2015-306914

Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.

1


Clinical science chromosome 3 status analysed using either fluorescence in situ hybridisation (FISH)13 or, more recently, using multiplex ligation-dependent probe amplification (MLPA) or microsatellite analysis (MSA), as previously described.14 The additional non-ocular malignancies were recorded by type, frequency and gender association. Classification of the additional malignancies depended on the medical history taken at the time of presentation to the LOOC. The frequency of occurrence was computed according to the number of patients affected by a certain malignancy divided by the total number of cases in the dataset. This was then compared with prevalence data for the general population from public data sources.15 The current study adhered to the tenets of the Declaration of Helsinki. Written informed consent was routinely obtained from every patient at the LOOC to permit the collection and use of demographic data for research.

RESULTS A total of 5042 patients with UM treated at LOOC between January 1993 and May 2014 were identified; 2479 were female (49.2%) and 2563 were male (50.8%). Of the 5042 cases, 216 (4.3%) had one or more additional non-ocular primary malignancies at the time of presentation to LOOC. The mean age of this subgroup was 67 years, ranging from 26 years to 98 years. Ninety seven of the 216 patients were female (4.9%). Of the 216 cases with UM, 10 had an iris melanoma, and 206 were diagnosed with a choroidal or ciliary body melanoma. In the group of choroidal or ciliary body melanomas, the mean largest basal diameter of the tumour mass was 12.7 mm (SD 3.8) with a mean height of 4.9 mm (SD 3.4). The most common tumour, node, metastases (TNM) categories for tumour size according to the American Joint Committee on Cancer Staging manual16 17 were T1a 74 cases (35.9%), T2a 41 cases (19.9%), T3a 34 cases (16.5%) and T4a 19 cases (9.2%) (table 1). For the 10 iris tumours, median largest basal diameter of the tumour was 4.9 mm (range 2.1–7.0), and median tumour height was 1.4 mm (range 0.7–4.2). Six of the 10 cases were categorised as T1a, two as T1b and one each as T2a and T4a (table 2). The most common additional non-ocular primary malignancies were prostate carcinoma in men (45/119, 37.8%) and breast carcinoma in women (45/973, 46.4%). The second most common group of malignancies were primary skin cancers (30 men and 19 women, 49/216, 22.7%). Of note, the diagnosis of ‘primary skin tumour’ could not be further specified due to the retrospective nature of the study, and due to limited access to external pathology reports. Less common additional non-ocular malignancies are listed in table 3. Of interest, 15 patients with UM and two or more additional non-ocular primary malignancies were identified (15/216, 6.9%); primary prostate carcinoma was most commonly associated with another type of cancer in 5 out of 10 males, and primary breast carcinoma was most commonly associated with another malignancy in three out of five females. Primary skin cancers together with another malignancy were identified in 5 out of 10 cases (all males). Of the 216 patients with UM, 70 had their UM examined either cytogenetically (ie, FISH) or by molecular genetics (ie, MLPA/MSA). Twenty seven were classified as disomy for chromosome 3 (27/70, 38.6%), and 43 were classified as monosomy 3 (43/70, 61.4%). In comparison with published prevalence data,15 the frequency of additional malignancies in our cohort approximately mirrored those in the general UK population (table 4). 2

Table 1 Demographic characteristics of the 206 cases with choroidal or ciliary body melanoma Parameter

Value

No. of patients Age at diagnosis, years Mean (±SD) Median (range, IQR) Gender, no. of patients (percentage) Male Female Tumour size, mm, mean (±SD) Largest basal diameter Tumour height Tumour size, mm, median (range, IQR) Largest basal diameter Tumour height TNM T-categories, no. of patients (%) 1a 1b 2a 2b 3a 3b 3c 3d 4a 4b

206 67.4 (12.3) 69 (26–98, 15) 114 (55.3) 92 (44.7) 12.7 (3.8) 4.9 (3.4) 12.5 (1.9–23.8, 3.5) 4 (0.5–17.8, 3) 74 (35.9) 6 (2.9) 41 (19.9) 8 (3.9) 34 (16.5) 10 (4.9) 1 (0.5) 1 (0.5) 19 (9.2) 9 (4.4)

The majority of cases had a posterior uveal melanoma of size T1–T2 at time of presentation. TNM, tumour, node, metastases.

Mortality Eighty three of the 216 patients (38.4%) had died by the end of the study period. A Kaplan–Meier graph of this data set is given in figure 1. Thirty seven patients died from metastatic UM

Table 2

Demographic characteristics of the 10 iris tumours

Parameter No. of patients Age at diagnosis, years Mean (±SD) Median (range) Gender, no. of patients (%) Male Female Tumour size, mm, mean (±SD) Largest basal diameter Tumour height Tumour size, mm, median (range) Largest basal diameter Tumour height TNM T-categories, no. of patients (%) 1a 1b 2a 4a

Value 10 64.8 (11.9) 67.5 (40–79) 5 (50) 5 (50) 4.6 (1.7) 1.7 (1.2) 4.9 (2.1–7) 1.4 (0.7–4.2) 6 (60) 2 (20) 1 (10) 1 (10)

Most patients presented with iris tumours of sizes T1 or T2. TNM, tumour, node, metastases.



Clinical science Table 3 Complete list of all additional non-ocular primary malignancies, grouped by gender Men

Women

Type of malignancy

Frequency (n) Type of malignancy

Frequency (n)

Prostate carcinoma Skin cancer Bowel and colon carcinoma Lymphoma

45 30 15

45 19 7

Breast carcinoma Skin cancer Renal cell carcinoma

8

Bladder carcinoma Head and neck carcinoma Lung carcinoma Renal cell carcinoma

7 4

Oesophagus carcinoma Thyroid carcinoma Breast carcinoma Chronic lymphatic leukaemia Glioma Mesothelioma Osteosarcoma Seminoma

1 1 1

Bowel and colon carcinoma Lung carcinoma Ovary carcinoma

3 3

6 5 4

2

Bladder carcinoma Chronic lymphatic leukaemia Uterus carcinoma

3 3 3

2 1 1

Thyroid carcinoma Brain tumour Cervix carcinoma

2 1 1

1

Head and neck carcinoma Lymphoma Medulloblastoma Sarcoma Vulva carcinoma

1 1 1 1 1

Other ocular malignancies and benign tumours were not included in the analysis.

(44.6%) and 20 (24.1%) from metastases arising from another non-ocular malignancies; of which, 12 (12/20=60%) were known at the time of presentation to LOOC. Seventeen patients (20.5%) died from another systemic condition (eg, ischaemic heart disease), and 10 (12.0%) died of an unknown cause. Most patients (70/83, 84.3%) died within 5 years of presentation to LOOC, while six survived more than 10 years. Of the 83 patients who died within the study period, 20 (24.1%) had consented to molecular genetic analysis: 18 (90%) UM were classified as monosomy 3 and two as disomy 3. Of the 18 patients with UM and monosomy 3, 11 died of metastatic UM (11/18,

Table 4 Comparison of the prevalence of cancer in the general UK population (adapted from Maddams et al,15) and the corresponding numbers in the LOOC cohort Prevalence* UK population (%) Overall (all types of cancer) Male 2.7 Female 3.8 Subtypes of cancer (as proportion) Prostate (males) 31 Breast (females) 46 Colon/rectum/anus ∼10–15 Lung 3.5

LOOC cohort, % (n/N)

4.4 (119/2563) 3.7 (97/2479) 37.8 (45/119) 46.4 (45/97) ∼9.7 (21/216) 3.7 (8/216)

While the prevalence numbers are only an approximation, and the LOOC cohort is small by comparison, they are very similar overall. *Numbers given for the LOOC cohort do not represent true prevalence values, but rather, the frequency of presence at the time of UM diagnosis. LOOC, Liverpool Ocular Oncology Centre; UM, uveal melanoma.


61.1%), three died of metastatic disease from other cancers (16.7%), three died of other diseases (16.7%) and one patient died of an unknown cause (5.6%). One of the patients with disomy 3 UM died of metastatic lung cancer, while the second one died of metastatic disease from an unknown primary.

DISCUSSION In this study, we found a small, but clinically significant, proportion of patients with UM (4.3%) presented to our unit with a history of an additional non-ocular malignancy. On closer inspection, the distribution and frequency of these other malignancies largely mirrored those of the general population in the UK. To our knowledge, our cohort of 5042 patients with UM is one of the largest reviewed to date, specifically to address the question of additional non-ocular malignancies. We were able to conduct this study because of the data collection system of LOOC, which allows for the recording of all relevant clinical details for all patients with UM on a pro forma since 1993 with immediate entry of data into a computerised database. LOOC also collects outcome data for most consented patients with UM during their subsequent follow-up; this pertains mainly to their UM. A weakness of this study (and of the LOOC data system) is that we were not able to capture data regarding the occurrence of extraocular primary malignancies in patients subsequent to their UM diagnosis in our service. However, we plan to address this information gap by further studies with the appropriate ethical approvals. The lack of exact details regarding the histological classification of some of the primary skin cancers is another weakness of our audit. Often these other skin malignancies were diagnosed and treated elsewhere, thereby restricting access to relevant pathology reports and even treatment information. Concurrent presentation of UM with additional non-ocular malignancies has been described by others.18–20 Previous reports found the lifetime prevalence of additional malignancies to be within the range of 5%–15% of all patients with UM.21–23 Similarly, in Caucasian populations, the percentage of cases with multiple primary cancers is estimated to be around 7%–13%.7–9 Bergman et al22 found a slightly increased incidence of secondary tumours in the Swedish population after diagnosis of UM compared with controls. Al-Jamal et al21 found a lifetime prevalence of 10% for two primary malignancies, and of 1% for three or more, in their group of 530 Finnish patients with UM. Callejo et al retrospectively reviewed 129 UM cases treated in Canada, and found a prevalence of 14% (n=18) for two or more primary malignancies in this relatively small sample.23 Half of these additional malignancies were diagnosed before the UM, the other half afterwards. From our data, it seems that the incidence of other primary non-ocular malignancies in patients with UM is not increased, although the sample size may still be too small to make this assessment with sufficient scientific confidence. At the same time, our data is limited due to the fact that information only pertained to the time of diagnosis of the UM, and was self-reported—in contrast to larger epidemiological studies. Only planned larger multicentre collaborative studies will be able to answer this question more decisively. Although no statement can be made as yet regarding the presence or absence of germline mutations in our patients, this dataset will enable us to approach those patients with the highest likelihood for pathogenic germline mutations for targeted research. Perhaps not surprisingly, the most common second and third malignancies in our cohort of patients with UM coincided with the most common forms of cancer in the UK population. This could indicate that the aetiology of these additional tumours is indeed sporadic in most patients with UM, or at least has the 3


Clinical science

Figure 1 The two graphs depict Kaplan–Meier curves for the survival estimates of our cohort of patients with uveal melanoma with additional primary malignancies. Graph A shows the survival estimate without age correction. Graph B is corrected for a mean age of 65 years. same causes as in patients not affected by UM. In the same way, we could not identify specific patterns of malignancies that differed from the expected background frequencies. Compared with published data, the mortality in this study cohort of patients with UM is relatively high, with a rate of around 50% at 10 years.24 In keeping with these figures, our data revealed that most deaths occurred as a result of metastatic UM. There may be a selection bias in our study as patients who have UM with additional more life-threatening tumours (e.g. lung carcinoma) may have been diagnosed or referred later with their ocular symptoms than patients with UM suffering from the ocular malignancy alone. This is an aspect of this audit that we will pursue further in future studies. Similarly, genetic analyses revealed a relatively high proportion of monosomy 3 UM (46 cases vs 27 cases with disomy 3) in this study cohort. Our data are not sufficient to support or refute the hypothesis that multiple malignancies are associated with a higher percentage of ‘high-risk’ UM. Because BAP1 mutations predispose to renal carcinoma, mesothelioma and various skin cancers, it would be of interest to analyse the paired UM and extraocular malignancies for this mutation. In summary, approximately 4% of patients with UM present with a history of a non-ocular malignancy, with a prevalence of these additional cancers being in line with the overall prevalence of cancer in the UK’s general population. The current study represents one of the largest published series specifically investigating this question, and will enable patient selection for targeted genetic analyses. Acknowledgements We thank the team LOOC, in particular, the data manager, Gary Cheetham, for his help with data retrieval and analysis. Contributors HH, SEC, HK and FMH conceptualised the study, analysed the data, formulated data interpretation and revised the manuscript. FMH collected the required data with the help of Gary Cheetham, performed the statistical analyses and wrote the manuscript. BED helped to interpret the data, and provided valuable additions and corrections to the manuscript.

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Competing interests None declared.

21

Ethics approval Ethics committee of the Royal Liverpool and Broadgreen University Hospital Trust.

22

Provenance and peer review Not commissioned; externally peer reviewed. 23

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Non-ocular primary malignancies in patients with uveal melanoma: the Liverpool experience Florian M Heussen, Sarah E Coupland, Helen Kalirai, Bertil E Damato and Heinrich Heimann Br J Ophthalmol published online July 15, 2015

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